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Wu X, Zhang Z, Li J, Zong J, Yuan L, Shu L, Cheong LY, Huang X, Jiang M, Ping Z, Xu A, Hoo RL. Chchd10: A Novel Metabolic Sensor Modulating Adipose Tissue Homeostasis. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2408763. [PMID: 39985288 PMCID: PMC12005791 DOI: 10.1002/advs.202408763] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 12/30/2024] [Indexed: 02/24/2025]
Abstract
Dysregulation of adipose tissue (AT) homeostasis in obesity contributes to metabolic stress and disorders. Here, we identified that Coiled-coil-helix-coiled-coil-helix domain containing 10 (Chchd10) is a novel regulator of AT remodeling upon excess energy intake. Chchd10 is significantly reduced in the white adipose tissue (WAT) of mice in response to high-fat diet (HFD) feeding. AT-Chchd10 deficiency accelerates adipogenesis predominantly in subcutaneous AT of mice to store excess energy in response to short-term HFD feeding while upregulates glutathione S-transferase A4 (GSTA4) to facilitate 4-HNE clearance mainly in visceral AT to prevent protein carbonylation-induced cell dysfunction after long-term HFD feeding. Hence, Chchd10 deficiency attenuates diet-induced obesity and related metabolic disorders in mice. Mechanistically, Chchd10 deficiency enhances adipogenesis and GSTA4 expression by activating TDP43/Raptor/p62/Keap1/NRF2 axis. Notably, the beneficial effect of Chchd10 deficiency is eliminated in hypertrophic adipocytes, where p62 is strikingly reduced. Collectively, Chchd10 is a metabolic sensor maintaining AT homeostasis, and the loss of p62 in adipose tissue under obese conditions impairs Chchd10-mediated AT remodeling.
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Affiliation(s)
- Xiaoping Wu
- State Key Laboratory of Pharmaceutical BiotechnologyThe University of Hong KongHong Kong SARChina
- Department of Pharmacology and PharmacyThe University of Hong KongHong Kong SARChina
| | - Zixuan Zhang
- State Key Laboratory of Pharmaceutical BiotechnologyThe University of Hong KongHong Kong SARChina
- Department of Pharmacology and PharmacyThe University of Hong KongHong Kong SARChina
| | - Jingjing Li
- Department of Rehabilitation SciencesFaculty of Health and Social SciencesHong Kong Polytechnic UniversityHong Kong SARChina
| | - Jiuyu Zong
- State Key Laboratory of Pharmaceutical BiotechnologyThe University of Hong KongHong Kong SARChina
- Department of Pharmacology and PharmacyThe University of Hong KongHong Kong SARChina
| | - Lufengzi Yuan
- State Key Laboratory of Pharmaceutical BiotechnologyThe University of Hong KongHong Kong SARChina
- Department of Pharmacology and PharmacyThe University of Hong KongHong Kong SARChina
| | - Lingling Shu
- State Key Laboratory of Pharmaceutical BiotechnologyThe University of Hong KongHong Kong SARChina
- State Key Laboratory of Oncology in South ChinaGuangdong Provincial Clinical Research Center for CancerDepartment of Hematological OncologySun Yat‐sen University Cancer CenterChina
- Department of MedicineThe University of Hong KongHong Kong SARChina
| | - Lai Yee Cheong
- State Key Laboratory of Pharmaceutical BiotechnologyThe University of Hong KongHong Kong SARChina
- Department of MedicineThe University of Hong KongHong Kong SARChina
| | - Xiaowen Huang
- State Key Laboratory of Pharmaceutical BiotechnologyThe University of Hong KongHong Kong SARChina
- Department of Pharmacology and PharmacyThe University of Hong KongHong Kong SARChina
| | - Mengxue Jiang
- State Key Laboratory of Pharmaceutical BiotechnologyThe University of Hong KongHong Kong SARChina
- Department of Pharmacology and PharmacyThe University of Hong KongHong Kong SARChina
| | - Zhihui Ping
- State Key Laboratory of Pharmaceutical BiotechnologyThe University of Hong KongHong Kong SARChina
- Department of Pharmacology and PharmacyThe University of Hong KongHong Kong SARChina
| | - Aimin Xu
- State Key Laboratory of Pharmaceutical BiotechnologyThe University of Hong KongHong Kong SARChina
- Department of MedicineThe University of Hong KongHong Kong SARChina
| | - Ruby L.C. Hoo
- State Key Laboratory of Pharmaceutical BiotechnologyThe University of Hong KongHong Kong SARChina
- Department of Pharmacology and PharmacyThe University of Hong KongHong Kong SARChina
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Ma X, Zhao H, Song JK, Zhang Z, Gao CJ, Luo Y, Ding XJ, Xue TT, Zhang Y, Zhang MJ, Zhou M, Wang RP, Kuai L, Li B. Retracing from Outcomes to Causes: NRF2-Driven GSTA4 Transcriptional Regulation Controls Chronic Inflammation and Oxidative Stress in Atopic Dermatitis Recurrence. J Invest Dermatol 2025; 145:334-345.e11. [PMID: 38879155 DOI: 10.1016/j.jid.2024.05.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 04/23/2024] [Accepted: 05/09/2024] [Indexed: 07/14/2024]
Abstract
Atopic dermatitis (AD), a chronic and recurrent inflammatory skin disorder, presents a high incidence and imposes a substantial economic burden. Preventing its recurrence remains a significant challenge in dermatological therapy owing to poorly understood underlying mechanisms. In our study, we adopted a strategy of tracing the mechanisms of recurrence from clinical outcomes. We developed a mouse model of recurrent AD and applied clinically validated treatment regimens. Transcriptomic analyses revealed a pronounced enrichment in the glutathione metabolic pathway in the treated group. Through integrated bioinformatics and in vivo validation, we identified glutathione S-transferase alpha 4 (GSTA4) as a pivotal mediator in AD recurrence. Immunohistochemical analysis demonstrated decreased GSTA4 expression in lesions from patients with AD. Functionally, in vitro overexpression of GSTA4 significantly curtailed AD-like inflammatory responses and ROS production. Moreover, we discovered that NRF2 transcriptional activity regulates GSTA4 expression and function. Our treatment notably augmented NRF2-mediated GSTA4 transcription, yielding pronounced anti-inflammatory and ROS-neutralizing effects. Conclusively, our findings implicate GSTA4 as a critical factor in the recurrence of AD, particularly in the context of oxidative stress and chronic inflammation. Targeting the NRF2-GSTA4 axis emerges as a promising anti-inflammatory and antioxidative strategy for preventing AD recurrence.
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Affiliation(s)
- Xin Ma
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, China; Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China; Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hang Zhao
- Institute of Dermatology, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China; Institute of Dermatology, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
| | - Jian-Kun Song
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, China; Institute of Dermatology, School of Medicine, Tongji University, Shanghai, China
| | - Zhan Zhang
- Institute of Dermatology, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China; Institute of Dermatology, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
| | - Chun-Jie Gao
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, China; Institute of Dermatology, School of Medicine, Tongji University, Shanghai, China
| | - Ying Luo
- Institute of Dermatology, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China; Institute of Dermatology, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
| | - Xiao-Jie Ding
- Institute of Dermatology, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China; Institute of Dermatology, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
| | - Ting-Ting Xue
- Institute of Dermatology, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China; Institute of Dermatology, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
| | - Ying Zhang
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, China; Institute of Dermatology, School of Medicine, Tongji University, Shanghai, China
| | - Meng-Jie Zhang
- Institute of Dermatology, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China; Institute of Dermatology, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
| | - Mi Zhou
- Institute of Dermatology, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China; Institute of Dermatology, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China
| | - Rui-Ping Wang
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, China; Institute of Dermatology, School of Medicine, Tongji University, Shanghai, China
| | - Le Kuai
- Institute of Dermatology, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China; Institute of Dermatology, Shanghai Academy of Traditional Chinese Medicine, Shanghai, China.
| | - Bin Li
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, China; Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China; Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
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Monroe TB, Hertzel AV, Dickey DM, Hagen T, Santibanez SV, Berdaweel IA, Halley C, Puchalska P, Anderson EJ, Camell CD, Robbins PD, Bernlohr DA. Lipid peroxidation products induce carbonyl stress, mitochondrial dysfunction, and cellular senescence in human and murine cells. Aging Cell 2025; 24:e14367. [PMID: 39394673 PMCID: PMC11709094 DOI: 10.1111/acel.14367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2024] [Revised: 09/19/2024] [Accepted: 09/21/2024] [Indexed: 10/14/2024] Open
Abstract
Lipid enals are electrophilic products of lipid peroxidation that induce genotoxic and proteotoxic stress by covalent modification of DNA and proteins, respectively. As lipid enals accumulate to substantial amounts in visceral adipose during obesity and aging, we hypothesized that biogenic lipid enals may represent an endogenously generated, and therefore physiologically relevant, senescence inducers. To that end, we identified that 4-hydroxynonenal (4-HNE), 4-hydroxyhexenal (4-HHE) or 4-oxo-2-nonenal (4-ONE) initiate the cellular senescence program of IMR90 fibroblasts and murine adipose stem cells. In such cells, lipid enals induced accumulation of γH2AX foci, increased p53 signaling, enhanced expression of p21Cip1, and upregulated the expression and secretion of numerous cytokines, chemokines, and regulatory factors independently from NF-κB activation. Concomitantly, lipid enal treatment resulted in covalent modification of mitochondrial proteins, reduced mitochondrial spare respiratory capacity, altered nucleotide pools, and increased the phosphorylation of AMP kinase. Lipid-induced senescent cells upregulated BCL2L1 (Bcl-xL) and BCL2L2 (Bcl-w). and were resistant to apoptosis while pharmacologic inhibition of BAX/BAK macropores attenuated lipid-induced senescence. In situ, the 4-HNE scavenger L-carnosine ameliorated the development of the cellular senescence, while in visceral fat of obese C57BL/6J mice, L-carnosine reduced the abundance of 4-HNE-modified proteins and blunted the expression of senescence biomarkers CDKN1A (p21Cip1), PLAUR, BCL2L1, and BCL2L2. Taken together, the results suggest that lipid enals are endogenous regulators of cellular senescence and that biogenic lipid-induced senescence (BLIS) may represent a mechanistic link between oxidative stress and age-dependent pathologies.
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Affiliation(s)
- T. Blake Monroe
- Department of Biochemistry, Molecular Biology and BiophysicsUniversity of Minnesota‐Twin CitiesMinneapolisMinnesotaUSA
| | - Ann V. Hertzel
- Department of Biochemistry, Molecular Biology and BiophysicsUniversity of Minnesota‐Twin CitiesMinneapolisMinnesotaUSA
| | - Deborah M. Dickey
- Department of Biochemistry, Molecular Biology and BiophysicsUniversity of Minnesota‐Twin CitiesMinneapolisMinnesotaUSA
| | - Thomas Hagen
- Department of Biochemistry, Molecular Biology and BiophysicsUniversity of Minnesota‐Twin CitiesMinneapolisMinnesotaUSA
| | - Simon Vergara Santibanez
- Department of Biochemistry, Molecular Biology and BiophysicsUniversity of Minnesota‐Twin CitiesMinneapolisMinnesotaUSA
| | - Islam A. Berdaweel
- Department of Pharmaceutical Sciences & Experimental Therapeutics, College of Pharmacy, Fraternal Order of Eagles Diabetes Research CenterUniversity of IowaIowa CityIowaUSA
- Present address:
Department of Clinical Pharmacy and Pharmacy Practice, College of PharmacyYarmouk UniversityIrbidJordan
| | - Catherine Halley
- Department of Biochemistry, Molecular Biology and BiophysicsUniversity of Minnesota‐Twin CitiesMinneapolisMinnesotaUSA
| | - Patrycja Puchalska
- Department of MedicineUniversity of Minnesota‐Twin CitiesMinneapolisMinnesotaUSA
| | - Ethan J. Anderson
- Department of Pharmaceutical Sciences & Experimental Therapeutics, College of Pharmacy, Fraternal Order of Eagles Diabetes Research CenterUniversity of IowaIowa CityIowaUSA
| | - Christina D. Camell
- Department of Biochemistry, Molecular Biology and BiophysicsUniversity of Minnesota‐Twin CitiesMinneapolisMinnesotaUSA
- Institute for the Biology of Aging and MetabolismUniversity of Minnesota‐Twin CitiesMinneapolisMinnesotaUSA
| | - Paul D. Robbins
- Department of Biochemistry, Molecular Biology and BiophysicsUniversity of Minnesota‐Twin CitiesMinneapolisMinnesotaUSA
- Institute for the Biology of Aging and MetabolismUniversity of Minnesota‐Twin CitiesMinneapolisMinnesotaUSA
| | - David A. Bernlohr
- Department of Biochemistry, Molecular Biology and BiophysicsUniversity of Minnesota‐Twin CitiesMinneapolisMinnesotaUSA
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Svobodová G, Šadibolová M, Velecká E, Mráziková L, Vaculová P, Matoušková P, Kuneš J, Maletínská L, Boušová I. Metabolic Dysfunction-Associated Steatotic Liver Disease Is Accompanied by Increased Activities of Superoxide Dismutase, Catalase, and Carbonyl Reductase 1 and Levels of miR-200b-3p in Mouse Models. Antioxidants (Basel) 2024; 13:1371. [PMID: 39594513 PMCID: PMC11591148 DOI: 10.3390/antiox13111371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 10/30/2024] [Accepted: 11/07/2024] [Indexed: 11/28/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD), one of the leading causes of chronic liver disorders, is characterized by hepatic lipid accumulation. MASLD causes alterations in the antioxidant defense system, lipid, and drug metabolism, resulting in impaired antioxidant status, hepatic metabolic processes, and clearance of therapeutic drugs, respectively. In the MASLD pathogenesis, dysregulated epigenetic mechanisms (e.g., histone modifications, DNA methylation, microRNAs) play a substantial role. In this study, the development of MASLD was investigated in mice fed a high-fat, high-fructose, and high-cholesterol (FFC) diet from 2 months of age, mice treated neonatally with monosodium glutamate (MSG) on a standard diet (STD), and mice treated with MSG on an FFC diet at 7 months of age and compared to control mice (C) on STD. Changes in liver histology, detoxification enzymes, epigenetic regulation, and genes involved in lipid metabolism were characterized and compared. The strong liver steatosis was observed in MSG STD, C FFC, and MSG FFC, with significant fibrosis in the latter one. Moreover, substantial alterations in hepatic lipid metabolism, epigenetic regulatory factors, and expressions and activities of various detoxification enzymes (namely superoxide dismutase, catalase, and carbonyl reductase 1) were observed in MASLD mice compared to control mice. miR-200b-3p, highly significantly upregulated in both FFC groups, could be considered as a potential diagnostic marker of MASLD. The MSG mice fed FFC seem to be a suitable model of MASLD characterized by both liver steatosis and fibrosis and substantial metabolic dysregulation.
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Affiliation(s)
- Gabriela Svobodová
- Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University, 50003 Hradec Králové, Czech Republic; (G.S.); (M.Š.); (E.V.); (P.M.)
| | - Michaela Šadibolová
- Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University, 50003 Hradec Králové, Czech Republic; (G.S.); (M.Š.); (E.V.); (P.M.)
| | - Eva Velecká
- Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University, 50003 Hradec Králové, Czech Republic; (G.S.); (M.Š.); (E.V.); (P.M.)
| | - Lucia Mráziková
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, 16000 Prague, Czech Republic; (L.M.); (P.V.); (J.K.); (L.M.)
| | - Petra Vaculová
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, 16000 Prague, Czech Republic; (L.M.); (P.V.); (J.K.); (L.M.)
| | - Petra Matoušková
- Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University, 50003 Hradec Králové, Czech Republic; (G.S.); (M.Š.); (E.V.); (P.M.)
| | - Jaroslav Kuneš
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, 16000 Prague, Czech Republic; (L.M.); (P.V.); (J.K.); (L.M.)
- Institute of Physiology, Czech Academy of Sciences, 14200 Prague, Czech Republic
| | - Lenka Maletínská
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, 16000 Prague, Czech Republic; (L.M.); (P.V.); (J.K.); (L.M.)
| | - Iva Boušová
- Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University, 50003 Hradec Králové, Czech Republic; (G.S.); (M.Š.); (E.V.); (P.M.)
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Hellberg A, Salamon D, Ujvari D, Rydén M, Hirschberg AL. Weight Changes Are Linked to Adipose Tissue Genes in Overweight Women with Polycystic Ovary Syndrome. Int J Mol Sci 2024; 25:11566. [PMID: 39519120 PMCID: PMC11547111 DOI: 10.3390/ijms252111566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 10/22/2024] [Accepted: 10/24/2024] [Indexed: 11/16/2024] Open
Abstract
Women with polycystic ovary syndrome (PCOS) have varying difficulties in achieving weight loss by lifestyle intervention, which may depend on adipose tissue metabolism. The objective was to study baseline subcutaneous adipose tissue gene expression as a prediction of weight loss by lifestyle intervention in obese/overweight women with PCOS. This is a secondary analysis of a randomized controlled trial where women with PCOS, aged 18-40 and body mass index (BMI) ≥ 27 were initially randomized to either a 4-month behavioral modification program or minimal intervention according to standard care. Baseline subcutaneous adipose tissue gene expression was related to weight change after the lifestyle intervention. A total of 55 obese/overweight women provided subcutaneous adipose samples at study entry. Weight loss was significant after behavioral modification (-2.2%, p = 0.0014), while there was no significant weight loss in the control group (-1.1%, p = 0.12). In microarray analysis of adipose samples, expression of 40 genes differed significantly between subgroups of those with the greatest weight loss or weight gain. 10 genes were involved in metabolic pathways including glutathione metabolism, gluconeogenesis, and pyruvate metabolism. Results were confirmed by real-time polymerase chain reaction (RT-PCR) in all 55 subjects. Expressions of GSTM5, ANLN, and H3C2 correlated with weight change (R = -0.41, p = 0.002; R = -0.31, p = 0.023 and R = -0.32, p = 0.016, respectively). GSTM5, involved in glutathione metabolism, was the strongest predictor of weight loss, and together with baseline waist-hip ratio (WHR) explained 31% of the variation in body weight change. This study shows that baseline subcutaneous adipose tissue genes play a role for body weight outcome in response to lifestyle intervention in overweight/obese women with PCOS.
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Affiliation(s)
- Anton Hellberg
- Department of Women’s and Children’s Health, Karolinska Institutet, 17177 Stockholm, Sweden; (D.S.); (D.U.); (A.L.H.)
| | - Daniel Salamon
- Department of Women’s and Children’s Health, Karolinska Institutet, 17177 Stockholm, Sweden; (D.S.); (D.U.); (A.L.H.)
| | - Dorina Ujvari
- Department of Women’s and Children’s Health, Karolinska Institutet, 17177 Stockholm, Sweden; (D.S.); (D.U.); (A.L.H.)
- Department of Microbiology, Tumor and Cell Biology, National Pandemic Centre, Centre for Translational Microbiome Research, Karolinska Institutet, 17165 Solna, Sweden
| | - Mikael Rydén
- Department of Medicine Huddinge (H7), Karolinska Institutet, C2-94 Karolinska University Hospital Huddinge, 14186 Stockholm, Sweden;
| | - Angelica Lindén Hirschberg
- Department of Women’s and Children’s Health, Karolinska Institutet, 17177 Stockholm, Sweden; (D.S.); (D.U.); (A.L.H.)
- Department of Gynecology and Reproductive Medicine, Karolinska University Hospital Solna, 17176 Stockholm, Sweden
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Barbosa S, Pedrosa MB, Ferreira R, Moreira-Gonçalves D, Santos LL. The impact of chemotherapy on adipose tissue remodeling: The molecular players involved in this tissue wasting. Biochimie 2024; 223:1-12. [PMID: 38537739 DOI: 10.1016/j.biochi.2024.03.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 03/21/2024] [Accepted: 03/23/2024] [Indexed: 04/05/2024]
Abstract
The depletion of visceral and subcutaneous adipose tissue (AT) during chemotherapy significantly correlates with diminished overall survival and progression-free survival. Despite its clinical significance, the intricate molecular mechanisms governing this AT loss and its chemotherapy-triggered initiation remain poorly understood. Notably, the evaluation of AT remodeling in most clinical trials has predominantly relied on computerized tomography scans or bioimpedance, with molecular studies often conducted using animal or in vitro models. To address this knowledge gap, a comprehensive narrative review was conducted. The findings underscore that chemotherapy serves as a key factor in inducing AT loss, exacerbating cachexia, a paraneoplastic syndrome that significantly compromises patient quality of life and survival. The mechanism driving AT loss appears intricately linked to alterations in AT metabolic remodeling, marked by heightened lipolysis and fatty acid oxidation, coupled with diminished lipogenesis. However, adipocyte stem cells' lost ability to divide due to chemotherapy also appears to be at the root of the loss of AT. Notably, chemotherapy seems to deactivate the mitochondrial antioxidant system by reducing key regulatory enzymes responsible for neutralizing reactive oxygen species (ROS), thereby impeding lipogenesis. Despite FDG-PET evidence of AT browning, no molecular evidence of thermogenesis was reported. Prospective investigations unraveling the molecular mechanisms modulated in AT by chemotherapy, along with therapeutic strategies aimed at preventing AT loss, promise to refine treatment paradigms and enhance patient outcomes.
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Affiliation(s)
- Samuel Barbosa
- Research Centre in Physical Activity, Health and Leisure (CIAFEL), Faculty of Sport, University of Porto, 4200-450, Porto, Portugal; Experimental Pathology and Therapeutics Group, Research Center (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto)/Porto Comprehensive Cancer Center (P.CCC), 4200-072, Porto, Portugal.
| | - Mafalda Barbosa Pedrosa
- Research Centre in Physical Activity, Health and Leisure (CIAFEL), Faculty of Sport, University of Porto, 4200-450, Porto, Portugal; Experimental Pathology and Therapeutics Group, Research Center (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto)/Porto Comprehensive Cancer Center (P.CCC), 4200-072, Porto, Portugal; Associated Laboratory for Green Chemistry of the Network of Chemistry and Technology (LAQV-REQUIMTE), Department of Chemistry, University of Aveiro, 3810-193, Aveiro, Portugal
| | - Rita Ferreira
- Associated Laboratory for Green Chemistry of the Network of Chemistry and Technology (LAQV-REQUIMTE), Department of Chemistry, University of Aveiro, 3810-193, Aveiro, Portugal
| | - Daniel Moreira-Gonçalves
- Research Centre in Physical Activity, Health and Leisure (CIAFEL), Faculty of Sport, University of Porto, 4200-450, Porto, Portugal; Laboratory for Integrative and Translational Research in Population Health (ITR), 4050-600, Porto, Portugal
| | - Lúcio Lara Santos
- Experimental Pathology and Therapeutics Group, Research Center (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto)/Porto Comprehensive Cancer Center (P.CCC), 4200-072, Porto, Portugal
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Das S, Mukhuty A, Mullen GP, Rudolph MC. Adipocyte Mitochondria: Deciphering Energetic Functions across Fat Depots in Obesity and Type 2 Diabetes. Int J Mol Sci 2024; 25:6681. [PMID: 38928386 PMCID: PMC11203708 DOI: 10.3390/ijms25126681] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Revised: 06/13/2024] [Accepted: 06/15/2024] [Indexed: 06/28/2024] Open
Abstract
Adipose tissue, a central player in energy balance, exhibits significant metabolic flexibility that is often compromised in obesity and type 2 diabetes (T2D). Mitochondrial dysfunction within adipocytes leads to inefficient lipid handling and increased oxidative stress, which together promote systemic metabolic disruptions central to obesity and its complications. This review explores the pivotal role that mitochondria play in altering the metabolic functions of the primary adipocyte types, white, brown, and beige, within the context of obesity and T2D. Specifically, in white adipocytes, these dysfunctions contribute to impaired lipid processing and an increased burden of oxidative stress, worsening metabolic disturbances. Conversely, compromised mitochondrial function undermines their thermogenic capabilities, reducing the capacity for optimal energy expenditure in brown adipocytes. Beige adipocytes uniquely combine the functional properties of white and brown adipocytes, maintaining morphological similarities to white adipocytes while possessing the capability to transform into mitochondria-rich, energy-burning cells under appropriate stimuli. Each type of adipocyte displays unique metabolic characteristics, governed by the mitochondrial dynamics specific to each cell type. These distinct mitochondrial metabolic phenotypes are regulated by specialized networks comprising transcription factors, co-activators, and enzymes, which together ensure the precise control of cellular energy processes. Strong evidence has shown impaired adipocyte mitochondrial metabolism and faulty upstream regulators in a causal relationship with obesity-induced T2D. Targeted interventions aimed at improving mitochondrial function in adipocytes offer a promising therapeutic avenue for enhancing systemic macronutrient oxidation, thereby potentially mitigating obesity. Advances in understanding mitochondrial function within adipocytes underscore a pivotal shift in approach to combating obesity and associated comorbidities. Reigniting the burning of calories in adipose tissues, and other important metabolic organs such as the muscle and liver, is crucial given the extensive role of adipose tissue in energy storage and release.
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Affiliation(s)
- Snehasis Das
- Harold Hamm Diabetes Center, Department of Biochemistry and Physiology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Alpana Mukhuty
- Department of Zoology, Rampurhat College, Rampurhat 731224, India
| | - Gregory P. Mullen
- Harold Hamm Diabetes Center, Department of Biochemistry and Physiology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Michael C. Rudolph
- Harold Hamm Diabetes Center, Department of Biochemistry and Physiology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
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Xu M, Wang W, Cheng J, Qu H, Xu M, Wang L. Effects of mitochondrial dysfunction on cellular function: Role in atherosclerosis. Biomed Pharmacother 2024; 174:116587. [PMID: 38636397 DOI: 10.1016/j.biopha.2024.116587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 04/02/2024] [Accepted: 04/10/2024] [Indexed: 04/20/2024] Open
Abstract
Atherosclerosis, an immunoinflammatory disease of medium and large arteries, is associated with life-threatening clinical events, such as acute coronary syndromes and stroke. Chronic inflammation and impaired lipoprotein metabolism are considered to be among the leading causes of atherosclerosis, while numerous risk factors, including arterial hypertension, diabetes mellitus, obesity, and aging, can contribute to the development of the disease. In recent years, emerging evidence has underlined the key role of mitochondrial dysfunction in the pathogenesis of atherosclerosis. Mitochondrial dysfunction is believed to result in an increase in reactive oxygen species, leading to oxidative stress, chronic inflammation, and intracellular lipid deposition, all of which can contribute to the pathogenesis of atherosclerosis. Critical cells, including endothelial cells, vascular smooth muscle cells, and macrophages, play an important role in atherosclerosis. Mitochondrial function is also involved in maintaining the normal function of these cells. To better understand the relationship between mitochondrial dysfunction and atherosclerosis, this review summarizes the findings of recent studies and discusses the role of mitochondrial dysfunction in the risk factors and critical cells of atherosclerosis. FACTS: OPEN QUESTIONS.
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Affiliation(s)
- Minwen Xu
- Clinical Skills Center, First Affiliated Hospital of Gannan Medical University, Ganzhou 341000, China
| | - Wenjun Wang
- Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Jingpei Cheng
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou 341000, China; Basic Medical College, Gannan Medical University, Ganzhou 341000, China
| | - Hongen Qu
- Gannan Normal University, Ganzhou 341000, China.
| | - Minjuan Xu
- Department of Obstetrics and Gynecology, Ganzhou People's Hospital, Ganzhou 341000, China.
| | - Liefeng Wang
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou 341000, China; Basic Medical College, Gannan Medical University, Ganzhou 341000, China.
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Bir A, Ghosh A, Müller WE, Ganguly A. Mitochondrial dysfunction and metabolic syndrome. METABOLIC SYNDROME 2024:157-172. [DOI: 10.1016/b978-0-323-85732-1.00043-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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10
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Li Q, Jiang X, Zhou Y, Gu Y, Ding Y, Luo J, Pang N, Sun Y, Pei L, Pan J, Gao M, Ma S, Xiao Y, Hu D, Wu F, Yang L. Improving Mitochondrial Function in Skeletal Muscle Contributes to the Amelioration of Insulin Resistance by Nicotinamide Riboside. Int J Mol Sci 2023; 24:10015. [PMID: 37373163 DOI: 10.3390/ijms241210015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 06/01/2023] [Accepted: 06/07/2023] [Indexed: 06/29/2023] Open
Abstract
High-fat diet (HFD)-induced insulin resistance (IR) in skeletal muscle is often accompanied by mitochondrial dysfunction and oxidative stress. Boosting nicotinamide adenine dinucleotide (NAD) using nicotinamide riboside (NR) can effectively decrease oxidative stress and increase mitochondrial function. However, whether NR can ameliorate IR in skeletal muscle is still inconclusive. We fed male C57BL/6J mice with an HFD (60% fat) ± 400 mg/kg·bw NR for 24 weeks. C2C12 myotube cells were treated with 0.25 mM palmitic acid (PA) ± 0.5 mM NR for 24 h. Indicators for IR and mitochondrial dysfunction were analyzed. NR treatment alleviated IR in HFD-fed mice with regard to improved glucose tolerance and a remarkable decrease in the levels of fasting blood glucose, fasting insulin and HOMA-IR index. NR-treated HFD-fed mice also showed improved metabolic status regarding a significant reduction in body weight and lipid contents in serum and the liver. NR activated AMPK in the skeletal muscle of HFD-fed mice and PA-treated C2C12 myotube cells and upregulated the expression of mitochondria-related transcriptional factors and coactivators, thereby improving mitochondrial function and alleviating oxidative stress. Upon inhibiting AMPK using Compound C, NR lost its ability in enhancing mitochondrial function and protection against IR induced by PA. In summary, improving mitochondrial function through the activation of AMPK pathway in skeletal muscle may play an important role in the amelioration of IR using NR.
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Affiliation(s)
- Qiuyan Li
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Xuye Jiang
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
- Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, 1172 Copenhagen, Denmark
| | - Yujia Zhou
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Yingying Gu
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Yijie Ding
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Jing Luo
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Nengzhi Pang
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Yan Sun
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Lei Pei
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Jie Pan
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Mengqi Gao
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Sixi Ma
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Ying Xiao
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - De Hu
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Feilong Wu
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Lili Yang
- Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
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11
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Wu X, Xu M, Geng M, Chen S, Little PJ, Xu S, Weng J. Targeting protein modifications in metabolic diseases: molecular mechanisms and targeted therapies. Signal Transduct Target Ther 2023; 8:220. [PMID: 37244925 PMCID: PMC10224996 DOI: 10.1038/s41392-023-01439-y] [Citation(s) in RCA: 91] [Impact Index Per Article: 45.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 03/01/2023] [Accepted: 04/06/2023] [Indexed: 05/29/2023] Open
Abstract
The ever-increasing prevalence of noncommunicable diseases (NCDs) represents a major public health burden worldwide. The most common form of NCD is metabolic diseases, which affect people of all ages and usually manifest their pathobiology through life-threatening cardiovascular complications. A comprehensive understanding of the pathobiology of metabolic diseases will generate novel targets for improved therapies across the common metabolic spectrum. Protein posttranslational modification (PTM) is an important term that refers to biochemical modification of specific amino acid residues in target proteins, which immensely increases the functional diversity of the proteome. The range of PTMs includes phosphorylation, acetylation, methylation, ubiquitination, SUMOylation, neddylation, glycosylation, palmitoylation, myristoylation, prenylation, cholesterylation, glutathionylation, S-nitrosylation, sulfhydration, citrullination, ADP ribosylation, and several novel PTMs. Here, we offer a comprehensive review of PTMs and their roles in common metabolic diseases and pathological consequences, including diabetes, obesity, fatty liver diseases, hyperlipidemia, and atherosclerosis. Building upon this framework, we afford a through description of proteins and pathways involved in metabolic diseases by focusing on PTM-based protein modifications, showcase the pharmaceutical intervention of PTMs in preclinical studies and clinical trials, and offer future perspectives. Fundamental research defining the mechanisms whereby PTMs of proteins regulate metabolic diseases will open new avenues for therapeutic intervention.
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Affiliation(s)
- Xiumei Wu
- Department of Endocrinology, Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Clinical Research Hospital of Chinese Academy of Sciences (Hefei), University of Science and Technology of China, Hefei, Anhui, 230001, China
- Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, The Third Affiliated Hospital of Sun Yat-sen University, 510000, Guangzhou, China
| | - Mengyun Xu
- Department of Endocrinology, Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Clinical Research Hospital of Chinese Academy of Sciences (Hefei), University of Science and Technology of China, Hefei, Anhui, 230001, China
| | - Mengya Geng
- Department of Endocrinology, Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Clinical Research Hospital of Chinese Academy of Sciences (Hefei), University of Science and Technology of China, Hefei, Anhui, 230001, China
| | - Shuo Chen
- Department of Endocrinology, Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Clinical Research Hospital of Chinese Academy of Sciences (Hefei), University of Science and Technology of China, Hefei, Anhui, 230001, China
| | - Peter J Little
- School of Pharmacy, University of Queensland, Pharmacy Australia Centre of Excellence, Woolloongabba, QLD, 4102, Australia
- Sunshine Coast Health Institute and School of Health and Behavioural Sciences, University of the Sunshine Coast, Birtinya, QLD, 4575, Australia
| | - Suowen Xu
- Department of Endocrinology, Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Clinical Research Hospital of Chinese Academy of Sciences (Hefei), University of Science and Technology of China, Hefei, Anhui, 230001, China
| | - Jianping Weng
- Department of Endocrinology, Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Clinical Research Hospital of Chinese Academy of Sciences (Hefei), University of Science and Technology of China, Hefei, Anhui, 230001, China.
- Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, The Third Affiliated Hospital of Sun Yat-sen University, 510000, Guangzhou, China.
- Bengbu Medical College, Bengbu, 233000, China.
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12
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Santamarina AB, Calder PC, Estadella D, Pisani LP. Anthocyanins ameliorate obesity-associated metainflammation: Preclinical and clinical evidence. Nutr Res 2023; 114:50-70. [PMID: 37201432 DOI: 10.1016/j.nutres.2023.04.004] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 03/13/2023] [Accepted: 04/10/2023] [Indexed: 05/20/2023]
Abstract
The growing rates of obesity worldwide call for intervention strategies to help control the pathophysiological consequences of weight gain. The use of natural foods and bioactive compounds has been suggested as such a strategy because of their recognized antioxidant and anti-inflammatory properties. For example, polyphenols, especially anthocyanins, are candidates for managing obesity and its related metabolic disorders. Obesity is well known for the presence of metainflammation, which has been labeled as an inflammatory activation that leads to a variety of metabolic disorders, usually related to increased oxidative stress. Considering this, anthocyanins may be promising natural compounds able to modulate several intracellular mechanisms, mitigating oxidative stress and metainflammation. A wide variety of foods and extracts rich in anthocyanins have become the focus of research in the field of obesity. Here, we bring together the current knowledge regarding the use of anthocyanins as an intervention tested in vitro, in vivo, and in clinical trials to modulate metainflammation. Most recent research applies a wide variety of extracts and natural sources of anthocyanins, in diverse experimental models, which represents a limitation of the research field. However, the literature is sufficiently consistent to establish that the in-depth molecular analysis of gut microbiota, insulin signaling, TLR4-triggered inflammation, and oxidative stress pathways reveals their modulation by anthocyanins. These targets are interconnected at the cellular level and interact with one another, leading to obesity-associated metainflammation. Thus, the positive findings with anthocyanins observed in preclinical models might directly relate to the positive outcomes in clinical studies. In summary and based on the entirety of the relevant literature, anthocyanins can mitigate obesity-related perturbations in gut microbiota, insulin resistance, oxidative stress and inflammation and therefore may contribute as a therapeutic tool in people living with obesity.
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Affiliation(s)
- Aline B Santamarina
- Biosciences Department, Institute of Health and Society, Federal University of São Paulo, Campus Baixada Santista - UNIFESP, Santos, São Paulo, Brazil
| | - Philip C Calder
- School of Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK; NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust and University of Southampton, Southampton, UK
| | - Debora Estadella
- Biosciences Department, Institute of Health and Society, Federal University of São Paulo, Campus Baixada Santista - UNIFESP, Santos, São Paulo, Brazil
| | - Luciana P Pisani
- Biosciences Department, Institute of Health and Society, Federal University of São Paulo, Campus Baixada Santista - UNIFESP, Santos, São Paulo, Brazil.
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13
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Transcriptome profile of skeletal muscle using different sources of dietary fatty acids in male pigs. Funct Integr Genomics 2023; 23:73. [PMID: 36867299 DOI: 10.1007/s10142-023-00997-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 02/20/2023] [Accepted: 02/21/2023] [Indexed: 03/04/2023]
Abstract
Pork is of great importance in world trade and represents the largest source of fatty acids in the human diet. Lipid sources such as soybean oil (SOY), canola (CO), and fish oil (FO) are used in pig diets and influence blood parameters and the ratio of deposited fatty acids. In this study, the main objective was to evaluate changes in gene expression in porcine skeletal muscle tissue resulting from the dietary oil sources and to identify metabolic pathways and biological process networks through RNA-Seq. The addition of FO in the diet of pigs led to intramuscular lipid with a higher FA profile composition of C20:5 n-3, C22:6 n-3, and SFA (C16:0 and C18:0). Blood parameters for the FO group showed lower cholesterol and HDL content compared with CO and SOY groups. Skeletal muscle transcriptome analyses revealed 65 differentially expressed genes (DEG, FDR 10%) between CO vs SOY, and 32 DEG for CO vs FO, and 531 DEG for SOY vs FO comparison. Several genes, including AZGP1, PDE3B, APOE, PLIN1, and LIPS, were found to be down-regulated in the diet of the SOY group compared to the FO group. The enrichment analysis revealed DEG involved in lipid metabolism, metabolic diseases, and inflammation between the oil groups, with specific gene functions in each group and altered blood parameters. The results provide mechanisms to help us understand the behavior of genes according to fatty acids.
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14
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Dehondt H, Marino A, Butruille L, Mogilenko DA, Nzoussi Loubota AC, Chávez-Talavera O, Dorchies E, Vallez E, Haas J, Derudas B, Bongiovanni A, Tardivel M, Kuipers F, Lefebvre P, Lestavel S, Tailleux A, Dombrowicz D, Caron S, Staels B. Adipocyte-specific FXR-deficiency protects adipose tissue from oxidative stress and insulin resistance and improves glucose homeostasis. Mol Metab 2023; 69:101686. [PMID: 36746333 PMCID: PMC9958065 DOI: 10.1016/j.molmet.2023.101686] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Accepted: 01/29/2023] [Indexed: 02/05/2023] Open
Abstract
OBJECTIVE Obesity is associated with metabolic dysfunction of white adipose tissue (WAT). Activated adipocytes secrete pro-inflammatory cytokines resulting in the recruitment of pro-inflammatory macrophages, which contribute to WAT insulin resistance. The bile acid (BA)-activated nuclear Farnesoid X Receptor (FXR) controls systemic glucose and lipid metabolism. Here, we studied the role of FXR in adipose tissue function. METHODS We first investigated the immune phenotype of epididymal WAT (eWAT) from high fat diet (HFD)-fed whole-body FXR-deficient (FXR-/-) mice by flow cytometry and gene expression analysis. We then generated adipocyte-specific FXR-deficient (Ad-FXR-/-) mice and analyzed systemic and eWAT metabolism and immune phenotype upon HFD feeding. Transcriptomic analysis was done on mature eWAT adipocytes from HFD-fed Ad-FXR-/- mice. RESULTS eWAT from HFD-fed whole-body FXR-/- and Ad-FXR-/- mice displayed decreased pro-inflammatory macrophage infiltration and inflammation. Ad-FXR-/- mice showed lower blood glucose concentrations, improved systemic glucose tolerance and WAT insulin sensitivity and oxidative stress. Transcriptomic analysis identified Gsta4, a modulator of oxidative stress in WAT, as the most upregulated gene in Ad-FXR-/- mouse adipocytes. Finally, chromatin immunoprecipitation analysis showed that FXR binds the Gsta4 gene promoter. CONCLUSIONS These results indicate a role for the adipocyte FXR-GSTA4 axis in controlling HFD-induced inflammation and systemic glucose homeostasis.
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Affiliation(s)
- Hélène Dehondt
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France
| | - Arianna Marino
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France
| | - Laura Butruille
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France
| | - Denis A Mogilenko
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France
| | | | - Oscar Chávez-Talavera
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France
| | - Emilie Dorchies
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France
| | - Emmanuelle Vallez
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France
| | - Joel Haas
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France
| | - Bruno Derudas
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France
| | - Antonino Bongiovanni
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, US 41 - UAR 2014 - PLBS, F-59000 Lille, France
| | - Meryem Tardivel
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, US 41 - UAR 2014 - PLBS, F-59000 Lille, France
| | - Folkert Kuipers
- Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Philippe Lefebvre
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France
| | - Sophie Lestavel
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France
| | - Anne Tailleux
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France
| | - David Dombrowicz
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France
| | - Sandrine Caron
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France.
| | - Bart Staels
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France
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15
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Moroni-González D, Sarmiento-Ortega VE, Diaz A, Brambila E, Treviño S. Pancreas-Liver-Adipose Axis: Target of Environmental Cadmium Exposure Linked to Metabolic Diseases. TOXICS 2023; 11:223. [PMID: 36976988 PMCID: PMC10059892 DOI: 10.3390/toxics11030223] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 02/17/2023] [Accepted: 02/19/2023] [Indexed: 06/18/2023]
Abstract
Cadmium has been well recognized as a critical toxic agent in acute and chronic poisoning cases in occupational and nonoccupational settings and environmental exposure situations. Cadmium is released into the environment after natural and anthropogenic activities, particularly in contaminated and industrial areas, causing food pollution. In the body, cadmium has no biological activity, but it accumulates primarily in the liver and kidney, which are considered the main targets of its toxicity, through oxidative stress and inflammation. However, in the last few years, this metal has been linked to metabolic diseases. The pancreas-liver-adipose axis is largely affected by cadmium accumulation. Therefore, this review aims to collect bibliographic information that establishes the basis for understanding the molecular and cellular mechanisms linked to cadmium with carbohydrate, lipids, and endocrine impairments that contribute to developing insulin resistance, metabolic syndrome, prediabetes, and diabetes.
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Affiliation(s)
- Diana Moroni-González
- Laboratory of Chemical-Clinical Investigations, Department of Clinical Chemistry, Faculty of Chemistry Science, Meritorious Autonomous University of Puebla, Ciudad Universitaria, Puebla 72560, Mexico
| | - Victor Enrique Sarmiento-Ortega
- Laboratory of Chemical-Clinical Investigations, Department of Clinical Chemistry, Faculty of Chemistry Science, Meritorious Autonomous University of Puebla, Ciudad Universitaria, Puebla 72560, Mexico
| | - Alfonso Diaz
- Department of Pharmacy, Faculty of Chemistry Science, Meritorious Autonomous University of Puebla, 22 South. FCQ9, Ciudad Universitaria, Puebla 72560, Mexico
| | - Eduardo Brambila
- Laboratory of Chemical-Clinical Investigations, Department of Clinical Chemistry, Faculty of Chemistry Science, Meritorious Autonomous University of Puebla, Ciudad Universitaria, Puebla 72560, Mexico
| | - Samuel Treviño
- Laboratory of Chemical-Clinical Investigations, Department of Clinical Chemistry, Faculty of Chemistry Science, Meritorious Autonomous University of Puebla, Ciudad Universitaria, Puebla 72560, Mexico
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Narasimhan A, Flores RR, Camell CD, Bernlohr DA, Robbins PD, Niedernhofer LJ. Cellular Senescence in Obesity and Associated Complications: a New Therapeutic Target. Curr Diab Rep 2022; 22:537-548. [PMID: 36239841 PMCID: PMC10123542 DOI: 10.1007/s11892-022-01493-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/11/2022] [Indexed: 01/13/2023]
Abstract
PURPOSE OF REVIEW Obesity has increased worldwide recently and represents a major global health challenge. This review focuses on the obesity-associated cellular senescence in various organs and the role of these senescent cells (SnCs) in driving complications associated with obesity. Also, the ability to target SnCs pharmacologically with drugs termed senotherapeutics as a therapy for these complications is discussed. RECENT FINDINGS Several studies have shown a positive correlation between obesity and SnC burden in organs such as adipose tissue, liver, and pancreatic-β-cells. These SnCs produce several secretory factors which affect other cells and tissues in a paracrine manner resulting in organ dysfunction. The accumulation of SnCs in adipocytes affects their lipid storage and impairs adipogenesis. The inflammatory senescence-associated secretory phenotype (SASP) of SnCs downregulates the antioxidant capacity and mitochondrial function in tissues. Senescent hepatocytes cannot oxidize fatty acids, which leads to lipid deposition and senescence in β-cells decrease function. These and other adverse effects of SnCs contribute to insulin resistance and type-2 diabetes. The reduction in the SnC burden genetically or pharmacologically improves the complications associated with obesity. The accumulation of SnCs with age and disease accelerates aging. Obesity is a key driver of SnC accumulation, and the complications associated with obesity can be controlled by reducing the SnC burden. Thus, senotherapeutic drugs have the potential to be an effective therapeutic option.
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Affiliation(s)
- Akilavalli Narasimhan
- Institute On the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, 6-155 Jackson Hall, 321 Church Street, SE, Minneapolis, MN, 55455, USA
| | - Rafael R Flores
- Institute On the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, 6-155 Jackson Hall, 321 Church Street, SE, Minneapolis, MN, 55455, USA
| | - Christina D Camell
- Institute On the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, 6-155 Jackson Hall, 321 Church Street, SE, Minneapolis, MN, 55455, USA
| | - David A Bernlohr
- Institute On the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, 6-155 Jackson Hall, 321 Church Street, SE, Minneapolis, MN, 55455, USA
| | - Paul D Robbins
- Institute On the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, 6-155 Jackson Hall, 321 Church Street, SE, Minneapolis, MN, 55455, USA.
| | - Laura J Niedernhofer
- Institute On the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, 6-155 Jackson Hall, 321 Church Street, SE, Minneapolis, MN, 55455, USA.
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17
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Effects of Avocado Oil Supplementation on Insulin Sensitivity, Cognition, and Inflammatory and Oxidative Stress Markers in Different Tissues of Diet-Induced Obese Mice. Nutrients 2022; 14:nu14142906. [PMID: 35889863 PMCID: PMC9319255 DOI: 10.3390/nu14142906] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 07/04/2022] [Accepted: 07/08/2022] [Indexed: 11/16/2022] Open
Abstract
Obesity induces insulin resistance, chronic inflammation, oxidative stress, and neurocognitive impairment. Avocado oil (AO) has antioxidants and anti-inflammatory effects. This study evaluated the effect of AO supplementation on obese mice in the adipose tissue, muscle, liver, and hippocampus. Male C57BL/6J mice received a standard and high-fat diet (20 weeks) and then were supplemented with AO (4 mL/kg of body weight, 90 days) and divided into the following groups: control (control), control + avocado oil (control + AO), diet-induced obesity (DIO), and diet-induced obesity + avocado oil (DIO + AO) (n = 10/group). AO supplementation was found to improve insulin sensitivity and decrease hepatic fat accumulation and serum triglyceride levels in DIO mice. AO improved cognitive performance and did not affect mood parameters. Oxidative marker levels were decreased in DIO + AO mice in all the tissues and were concomitant with increased catalase and superoxide dismutase activities in the epididymal adipose tissue and quadriceps, as well as increased catalase activity in the liver. AO in obese animals further induced reductions in TNF-α and IL-1β expressions in the epididymal adipose tissue and quadriceps. These results suggest that AO supplementation has the potential to be an effective strategy for combating the effects of obesity in rats, and human studies are needed to confirm these findings.
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18
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Maurya M, Jaiswal A, Gupta S, Ali W, Gaikwad AN, Dikshit M, Barthwal MK. Galectin-3 S-glutathionylation regulates its effect on adipocyte insulin signaling. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2022; 1869:119234. [PMID: 35143900 DOI: 10.1016/j.bbamcr.2022.119234] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 01/27/2022] [Accepted: 02/03/2022] [Indexed: 06/14/2023]
Abstract
Protein-S-glutathionylation promotes redox signaling in physiological and oxidative distress conditions. Galectin-3 (Gal-3) promotes insulin resistance by down-regulating adipocyte insulin signaling, however, its S-glutathionylation and significance is not known. In this context, we report reversible S-glutathionylation of Gal-3. Site-directed mutagenesis established Gal-3 Cys187 as the putative S-glutathionylation site. Glutathionylated Gal-3 prevents Gal-3(WT)-Insulin Receptor interaction and facilitates insulin-induced murine adipocyte p-IRS1(tyr895) and p-AKT(ser473) signaling and glucose uptake in a Gal-3 Cys187 glutathionylation dependent manner in murine adipocytes, as assessed by Western blotting and 2-NBDG uptake assay respectively. Pre-glutathionylated Gal-3 at Cys187 resisted irreversible oxidation by H2O2. M2 macrophages showed enhanced Gal-3 S-glutathionylation when compared to M1 phenotype. Serum and stromal vascular fraction (SVF) isolated from control mice showed increased Gal-3 S-glutathionylation as compared to db/db mice. A significant increase in Gal-3 S-glutathionylation was observed in metformin-treated db/db mice when compared to db/db mice alone. Similar to murine, enhanced Gal-3 S-glutathionylation is observed in primary human monocyte derived M2 macrophages when compared to the M1 macrophage phenotype and Gal-3 regulates primary human adipocyte insulin signaling in a glutathionylation dependent manner. Collectively, we identified Gal-3 S-glutathionylation as a protective phenomenon, which relieves its inhibitory effect on adipocyte insulin signaling.
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Affiliation(s)
- Mohita Maurya
- Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Anant Jaiswal
- Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Sanchita Gupta
- Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Wahid Ali
- King George's Medical University, Lucknow 226003, India
| | | | - Madhu Dikshit
- Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Manoj Kumar Barthwal
- Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad - 201002, India.
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19
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Huang Y, Yong P, Dickey D, Vora SM, Wu H, Bernlohr DA. Inflammasome Activation and Pyroptosis via a Lipid-regulated SIRT1-p53-ASC Axis in Macrophages From Male Mice and Humans. Endocrinology 2022; 163:6523230. [PMID: 35136993 PMCID: PMC8896164 DOI: 10.1210/endocr/bqac014] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Indexed: 02/07/2023]
Abstract
Obesity-linked diabetes is associated with accumulation of proinflammatory macrophages into adipose tissue leading to inflammasome activation and pyroptotic secretion of interleukin (IL)-1β and IL-18. Targeting fatty acid binding protein 4 (FABP4) uncouples obesity from inflammation, attenuates characteristics of type 2 diabetes and is mechanistically linked to the cellular accumulation of monounsaturated fatty acids in macrophages. Herein we show that pharmacologic inhibition or genetic deletion of FABP4 activates silent mating type information regulation 2 homolog 1 (SIRT1) and deacetylates its downstream targets p53 and signal transducer and activator of transcription 3 (STAT3). Pharmacologic inhibition of fatty acid synthase or stearoyl-coenzyme A desaturase inhibits, whereas exogenous addition of C16:1 or C18:1 but not their saturated acyl chain counterparts, activates SIRT1 and p53/STAT3 signaling and IL-1β/IL-18 release. Expression of the p53 target gene ASC [apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (CARD)] required for assembly of the NLR family pyrin domain containing 3 (NLRP3) inflammasome is downregulated in FABP4 null mice and macrophage cell lines leading to loss of procaspase 1 activation and pyroptosis. Concomitant with loss of ASC expression in FABP4-/- macrophages, inflammasome activation, gasdermin D processing, and functional activation of pyroptosis are all diminished in FABP4 null macrophages but can be rescued by silencing SIRT1 or exogenous expression of ASC. Taken together, these results reveal a novel lipid-regulated pathway linking to SIRT1-p53-ASC signaling and activation of inflammasome action and pyroptosis.
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Affiliation(s)
- Yimao Huang
- Departments of Biochemistry, Molecular Biology and Biophysics
| | - Peter Yong
- Departments of Biochemistry, Molecular Biology and Biophysics
| | - Deborah Dickey
- Departments of Biochemistry, Molecular Biology and Biophysics
| | - Setu M Vora
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, and Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Boston, MA, USA
| | - Hao Wu
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, and Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Boston, MA, USA
| | - David A Bernlohr
- Departments of Biochemistry, Molecular Biology and Biophysics
- Institute for Diabetes, Obesity and Metabolism University of Minnesota-Twin Cities, Minneapolis, MN, USA
- Correspondence: David A. Bernlohr, Department of Biochemistry, Molecular Biology and Biophysics, The University of Minnesota-Twin Cities, Minneapolis, MN 55455, USA.
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20
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Liu Z, Wang M, Zhang C, Zhou S, Ji G. Molecular Functions of Ceruloplasmin in Metabolic Disease Pathology. Diabetes Metab Syndr Obes 2022; 15:695-711. [PMID: 35264864 PMCID: PMC8901420 DOI: 10.2147/dmso.s346648] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 02/04/2022] [Indexed: 12/12/2022] Open
Abstract
Ceruloplasmin (CP) is a multicopper oxidase and antioxidant that is mainly produced in the liver. CP not only plays a crucial role in the metabolic balance of copper and iron through its oxidase function but also exhibits antioxidant activity. In addition, CP is an acute-phase protein. In addition to being associated with aceruloplasminemia and neurodegenerative diseases such as Wilson's disease, Alzheimer's disease, and Parkinson's disease, CP also plays an important role in metabolic diseases, which are caused by metabolic disorders and vigorous metabolism, mainly including diabetes, obesity, hyperlipidemia, etc. Based on the physiological functions of CP, we provide an overview of the association of type 2 diabetes, obesity, hyperlipidemia, coronary heart disease, CP oxidative stress, inflammation, and metabolism of copper and iron. Studies have shown that metabolic diseases are closely related to systemic inflammation, oxidative stress, and disorders of copper and iron metabolism. Therefore, we conclude that CP, which can reduce the formation of free radicals in tissues, can be induced during inflammation and infection, and can correct the metabolic disorder of copper and iron, has protective and diagnostic effects on metabolic diseases.
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Affiliation(s)
- Zhidong Liu
- Department of Internal Medicine of Traditional Chinese Medicine, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, People’s Republic of China
| | - Miao Wang
- Department of Internal Medicine of Traditional Chinese Medicine, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, People’s Republic of China
| | - Chunbo Zhang
- School of Pharmacy, Nanchang University, Nanchang, Jiangxi, 330031, People’s Republic of China
| | - Shigao Zhou
- Department of Internal Medicine of Traditional Chinese Medicine, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, People’s Republic of China
| | - Guang Ji
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, People’s Republic of China
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21
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Santamarina AB, de Souza Mesquita LM, Casagrande BP, Sertorio MN, Vitor de Souza D, Mennitti LV, Ribeiro DA, Estadella D, Ventura SP, de Rosso VV, Pisani LP. Supplementation of carotenoids from peach palm waste (Bactris gasipaes) obtained with an ionic liquid mediated process displays kidney anti-inflammatory and antioxidant outcomes. Food Chem X 2022; 13:100245. [PMID: 35499011 PMCID: PMC9040030 DOI: 10.1016/j.fochx.2022.100245] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 01/31/2022] [Accepted: 02/02/2022] [Indexed: 01/02/2023] Open
Abstract
Carotenoid’s supplementation can control weight gain even in the HFD model. Carotenoids extracted with ionic liquids displayed antioxidant activity on the kidney. Carotenoids extracted with ionic liquids display an anti-inflammatory effect. Carotenoids extracted with acetone increase pro-inflammatory cytokines on the kidney. Carotenoids extracted with acetone display oxidative stress on the kidney. Sustainable extraction processes based on alternative solvents to recover bioactive compounds of different raw materials have been highlighted as excellent alternatives to supply the needs of society towards a bioeconomy strategy. Little is known about the safety and biological effect of compounds extracted by these processes. In this work, carotenoids from Bactris gasipaes wastes obtained by an IL-based process were investigated in terms of safety, anti-inflammatory and, antioxidant activity in a high-fat-diet animal model on the kidney. Wistar rats were supplemented or not by carotenoids extracted with IL or VOS. The animals supplemented with carotenoids had lower weight than control and high-fat diets. In the animals supplemented with carotenoids, the group IL improved anti-inflammatory and antioxidant activity compared with carotenoids obtained by VOS. Also, the group HFD-VOS showed moderate-severe injuries on the kidney. Then, ILs could represent a novel tool for natural pigments safely applied to food industry.
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Affiliation(s)
- Aline B. Santamarina
- Department of Biosciences, Federal University of São Paulo (UNIFESP), Silva Jardim Street, 136, Vila Mathias, Santos, SP, Brazil
| | - Leonardo M. de Souza Mesquita
- Department of Biosciences, Federal University of São Paulo (UNIFESP), Silva Jardim Street, 136, Vila Mathias, Santos, SP, Brazil
| | - Breno P. Casagrande
- Department of Biosciences, Federal University of São Paulo (UNIFESP), Silva Jardim Street, 136, Vila Mathias, Santos, SP, Brazil
| | - Marcela N. Sertorio
- Department of Biosciences, Federal University of São Paulo (UNIFESP), Silva Jardim Street, 136, Vila Mathias, Santos, SP, Brazil
| | - Daniel Vitor de Souza
- Department of Biosciences, Federal University of São Paulo (UNIFESP), Silva Jardim Street, 136, Vila Mathias, Santos, SP, Brazil
| | - Laís V. Mennitti
- Department of Biosciences, Federal University of São Paulo (UNIFESP), Silva Jardim Street, 136, Vila Mathias, Santos, SP, Brazil
| | - Daniel A. Ribeiro
- Department of Biosciences, Federal University of São Paulo (UNIFESP), Silva Jardim Street, 136, Vila Mathias, Santos, SP, Brazil
| | - Débora Estadella
- Department of Biosciences, Federal University of São Paulo (UNIFESP), Silva Jardim Street, 136, Vila Mathias, Santos, SP, Brazil
| | - Sónia P.M. Ventura
- CICECO – Aveiro Institute of Materials, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Veridiana V. de Rosso
- Department of Biosciences, Federal University of São Paulo (UNIFESP), Silva Jardim Street, 136, Vila Mathias, Santos, SP, Brazil
| | - Luciana P. Pisani
- Department of Biosciences, Federal University of São Paulo (UNIFESP), Silva Jardim Street, 136, Vila Mathias, Santos, SP, Brazil
- Corresponding author.
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22
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Vitale E. A Chronic Inflammatory Inductive Condition in the Nursing Profession: A Scoping Review. Endocr Metab Immune Disord Drug Targets 2022; 22:1235-1244. [PMID: 35578870 DOI: 10.2174/1871530322666220516163936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 01/14/2022] [Accepted: 01/17/2022] [Indexed: 11/22/2022]
Abstract
BACKGROUND Literature focuses on the well-being of patients and little on the wellbeing of nurses who, in turn, should be educated about well-being. On the other hand, the latter often work under serious pressure with inadequate resources and shift organizations, exposing them to health risk factors. OBJECTIVE To highlight which relationships exist between diet, physical activity, body mass index (BMI) and mental health in nursing. METHODS The author searched the Medline (PubMed) database for medical subheadings terms and free full text referred to "Diet," "Mental Health," "Physical Activity," and "Nurses" before 31st December 2020. RESULTS A total of 11 studies were included in this perspective review, which better defined the relationships between diet, physical activity, mental health and the nursing profession. CONCLUSION From the studies present in the literature, it emerges that the nursing profession has an inherent imbalance in the regular circadian activity of human nature, as nursing assistance is provided 24 hours a day and during the night. Numerous studies have highlighted significant differences between mental and eating disorder levels among nurses who work at night versus those who only work during the day. Therefore, it is possible to speak of the nursing profession as an "inductive inflammatory-chronic" activity based on the extensive scientific evidence provided by the literature.
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Affiliation(s)
- Elsa Vitale
- Centre of Mental Health Modugno, Local Health Authority Bari, Bari, Italy
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23
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Ma N, Liang Y, Coleman DN, Li Y, Ding H, Liu F, Cardoso FF, Parys C, Cardoso FC, Shen X, Loor JJ. Methionine supplementation during a hydrogen peroxide challenge alters components of insulin signaling and antioxidant proteins in subcutaneous adipose explants from dairy cows. J Dairy Sci 2021; 105:856-865. [PMID: 34635354 DOI: 10.3168/jds.2021-20541] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 08/25/2021] [Indexed: 12/22/2022]
Abstract
Enhanced postruminal supply of methionine (Met) during the peripartal period alters protein abundance of insulin, AA, and antioxidant signaling pathways in subcutaneous adipose tissue (SAT). Whether SAT is directly responsive to supply of Met and can induce molecular alterations is unknown. Our objective was to examine whether enhanced Met supply during an oxidative stress challenge in vitro alters insulin, AA, inflammation, and antioxidant signaling-related protein networks. Four late-lactation Holstein cows (average 27.0 kg of milk per day) were used for SAT collection. Tissue was incubated in duplicate for 4 h in a humidified incubator with 5% CO2 at 37°C according to the following experimental design: control medium with an "ideal" profile of essential AA (CTR; Lys:Met 2.9:1), CTR plus 100 μM H2O2 (HP), or CTR with greater Met supply plus 100 μM H2O2 (HPMET; Lys:Met 2.5:1). Molecular targets associated with insulin signaling, lipolysis, antioxidant nuclear factor, erythroid 2 like 2 (NFE2L2), inflammation, and AA metabolism were determined through reverse-transcription quantitative PCR and western blotting. Data were analyzed using the MIXED procedure of SAS 9.4 (SAS Institute Inc.). Among proteins associated with insulin signaling, compared with CTR, HP led to lower abundance of phosphorylated AKT serine/threonine kinase (p-AKT) and solute carrier family 2 member 4 (SLC2A4; insulin-induced glucose transporter). Although incubation with HPMET restored abundance of SLC2A4 to levels in the CTR and upregulated abundance of fatty acid synthase (FASN) and phosphorylated 5'-prime-AMP-activated protein kinase (p-AMPK), it did not alter p-AKT, which remained similar to HP. Among proteins associated with AA signaling, compared with CTR, challenge with HP led to lower abundance of phosphorylated mechanistic target of rapamycin (p-MTOR), and HPMET did not restore abundance to CTR levels. Among inflammation-related targets studied, incubation with HPMET led to greater protein abundance of nuclear factor kappa B subunit p65 (NFKB-RELA). The response in NFKB observed with HPMET was associated with a marked upregulation of the antioxidant transcription regulator NFE2L2 and the antioxidant enzyme glutathione peroxidase 1 (GPX1). No effects of treatment were detected for mRNA abundance of proinflammatory cytokines or antioxidant enzymes, underscoring the importance of post-transcriptional regulation. Overall, data indicated that short-term challenge with H2O2 was particularly effective in reducing insulin and AA signaling. Although a greater supply of Met had little effect on those pathways, it seemed to restore the protein abundance of the insulin-induced glucose transporter. Overall, the concomitant upregulation of key inflammation and antioxidant signaling proteins when a greater level of Met was supplemented to oxidant-challenged SAT highlighted the potential role of this AA in regulating the inflammatory response and oxidant status. Further studies should be conducted to assess the role of postruminal supply of Met and other AA in the regulation of immune, antioxidant, and metabolic systems in peripartal cow adipose tissue.
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Affiliation(s)
- N Ma
- Department of Animal Sciences, Division of Nutritional Sciences, University of Illinois, Urbana 61801; College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu, China
| | - Y Liang
- Department of Animal Sciences, Division of Nutritional Sciences, University of Illinois, Urbana 61801
| | - D N Coleman
- Department of Animal Sciences, Division of Nutritional Sciences, University of Illinois, Urbana 61801
| | - Y Li
- Department of Animal Sciences, Division of Nutritional Sciences, University of Illinois, Urbana 61801; Department of Veterinary Medicine, College of Animal Science and Technology, Anhui Agricultural University, Hefei, 230036, Anhui, China
| | - H Ding
- Department of Animal Sciences, Division of Nutritional Sciences, University of Illinois, Urbana 61801; Department of Veterinary Medicine, College of Animal Science and Technology, Anhui Agricultural University, Hefei, 230036, Anhui, China
| | - F Liu
- Department of Animal Sciences, Division of Nutritional Sciences, University of Illinois, Urbana 61801; Department of Animal Science and Veterinary Medicine, Henan Agricultural University, Zhengzhou, 450086, Henan, China
| | - F F Cardoso
- Department of Animal Sciences, Division of Nutritional Sciences, University of Illinois, Urbana 61801
| | - C Parys
- Evonik Operations GmbH
- Nutrition & Care, Hanau 63457, Germany
| | - F C Cardoso
- Department of Animal Sciences, Division of Nutritional Sciences, University of Illinois, Urbana 61801
| | - X Shen
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu, China
| | - J J Loor
- Department of Animal Sciences, Division of Nutritional Sciences, University of Illinois, Urbana 61801.
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24
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Gangwar A, Paul S, Arya A, Ahmad Y, Bhargava K. Altitude acclimatization via hypoxia-mediated oxidative eustress involves interplay of protein nitrosylation and carbonylation: A redoxomics perspective. Life Sci 2021; 296:120021. [PMID: 34626604 DOI: 10.1016/j.lfs.2021.120021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 09/22/2021] [Accepted: 09/30/2021] [Indexed: 12/17/2022]
Abstract
AIM Hypoxia is an important feature of multiple diseases like cancer and obesity and also an environmental stressor to high altitude travelers. Emerging research suggests the importance of redox signaling in physiological responses transforming the notion of oxidative stress into eustress and distress. However, the behavior of redox protein post-translational modifications (PTMs), and their correlation with stress acclimatization in humans remains sketchy. Scant information exists about modifications in redoxome during physiological exposure to environmental hypoxia. In this study, we investigated redox PTMs, nitrosylation and carbonylation, in context of extended environmental hypoxia exposure. METHODS The volunteers were confirmed to be free of any medical conditions and matched for age and weight. The human global redoxome and the affected networks were investigated using TMT-labeled quantitative proteo-bioinformatics and biochemical assays. The percolator PSM algorithm was used for peptide-spectrum match (PSM) validation in database searches. The FDR for peptide matches was set to 0.01. 1-way ANOVA and Tukey's Multiple Comparison test were used for biochemical assays. p-value<0.05 was considered statistically significant. Three independent experiments (biological replicates) were performed. Results were presented as Mean ± standard error of mean (SEM). KEY FINDINGS This investigation revealed direct and indirect interplay between nitrosylation and carbonylation especially within coagulation and inflammation networks; interlinked redox signaling (via nitrosylation‑carbonylation); and novel nitrosylation and carbonylation sites in individual proteins. SIGNIFICANCE This study elucidates the role of redox PTMs in hypoxia signaling favoring tolerance and survival. Also, we demonstrated direct and indirect interplay between nitrosylation and carbonylation is crucial to extended hypoxia tolerance.
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Affiliation(s)
- Anamika Gangwar
- Defence Institute of Physiology & Allied Sciences (DIPAS), Defence R&D Organization (DRDO), Timarpur, New Delhi 110054, India
| | - Subhojit Paul
- Defence Institute of Physiology & Allied Sciences (DIPAS), Defence R&D Organization (DRDO), Timarpur, New Delhi 110054, India
| | - Aditya Arya
- Defence Institute of Physiology & Allied Sciences (DIPAS), Defence R&D Organization (DRDO), Timarpur, New Delhi 110054, India
| | - Yasmin Ahmad
- Defence Institute of Physiology & Allied Sciences (DIPAS), Defence R&D Organization (DRDO), Timarpur, New Delhi 110054, India.
| | - Kalpana Bhargava
- Defence Institute of Physiology & Allied Sciences (DIPAS), Defence R&D Organization (DRDO), Timarpur, New Delhi 110054, India.
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25
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Roberts FL, Markby GR. New Insights into Molecular Mechanisms Mediating Adaptation to Exercise; A Review Focusing on Mitochondrial Biogenesis, Mitochondrial Function, Mitophagy and Autophagy. Cells 2021; 10:cells10102639. [PMID: 34685618 PMCID: PMC8533934 DOI: 10.3390/cells10102639] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 09/27/2021] [Accepted: 09/29/2021] [Indexed: 12/25/2022] Open
Abstract
Exercise itself is fundamental for good health, and when practiced regularly confers a myriad of metabolic benefits in a range of tissues. These benefits are mediated by a range of adaptive responses in a coordinated, multi-organ manner. The continued understanding of the molecular mechanisms of action which confer beneficial effects of exercise on the body will identify more specific pathways which can be manipulated by therapeutic intervention in order to prevent or treat various metabolism-associated diseases. This is particularly important as exercise is not an available option to all and so novel methods must be identified to confer the beneficial effects of exercise in a therapeutic manner. This review will focus on key emerging molecular mechanisms of mitochondrial biogenesis, autophagy and mitophagy in selected, highly metabolic tissues, describing their regulation and contribution to beneficial adaptations to exercise.
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26
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Crewe C, Funcke JB, Li S, Joffin N, Gliniak CM, Ghaben AL, An YA, Sadek HA, Gordillo R, Akgul Y, Chen S, Samovski D, Fischer-Posovszky P, Kusminski CM, Klein S, Scherer PE. Extracellular vesicle-based interorgan transport of mitochondria from energetically stressed adipocytes. Cell Metab 2021; 33:1853-1868.e11. [PMID: 34418352 PMCID: PMC8429176 DOI: 10.1016/j.cmet.2021.08.002] [Citation(s) in RCA: 242] [Impact Index Per Article: 60.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 05/25/2021] [Accepted: 08/04/2021] [Indexed: 12/14/2022]
Abstract
Adipocytes undergo intense energetic stress in obesity resulting in loss of mitochondrial mass and function. We have found that adipocytes respond to mitochondrial stress by rapidly and robustly releasing small extracellular vesicles (sEVs). These sEVs contain respiration-competent, but oxidatively damaged mitochondrial particles, which enter circulation and are taken up by cardiomyocytes, where they trigger a burst of ROS. The result is compensatory antioxidant signaling in the heart that protects cardiomyocytes from acute oxidative stress, consistent with a preconditioning paradigm. As such, a single injection of sEVs from energetically stressed adipocytes limits cardiac ischemia/reperfusion injury in mice. This study provides the first description of functional mitochondrial transfer between tissues and the first vertebrate example of "inter-organ mitohormesis." Thus, these seemingly toxic adipocyte sEVs may provide a physiological avenue of potent cardio-protection against the inevitable lipotoxic or ischemic stresses elicited by obesity.
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Affiliation(s)
- Clair Crewe
- Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Jan-Bernd Funcke
- Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Shujuan Li
- Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Pediatric Cardiology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Nolwenn Joffin
- Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Christy M Gliniak
- Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Alexandra L Ghaben
- Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Yu A An
- Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Hesham A Sadek
- Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Internal Medicine, Division of Cardiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Ruth Gordillo
- Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Yucel Akgul
- Department of Plastic Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Shiuhwei Chen
- Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Dmitri Samovski
- Center for Human Nutrition and the Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Pamela Fischer-Posovszky
- Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, 89075 Ulm, Germany
| | - Christine M Kusminski
- Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Samuel Klein
- Center for Human Nutrition and the Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Philipp E Scherer
- Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
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27
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Zou X, Ahmad MI, Zhao D, Zhang M, Li C. Glutaredoxin1 knockout promotes high-fat diet-induced obesity in male mice but not in female ones. Food Funct 2021; 12:7415-7427. [PMID: 34190288 DOI: 10.1039/d1fo01241j] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
This study aims to explore how a high-fat diet and glutaredoxin1 (Glrx1) deficiency affect the development of obesity in male and female mice. A high-fat diet induced great differences in calorie intake and body weight gain between male and female mice; furthermore, the Glrx1 deficiency made male mice more sensitive to a high-fat diet than females. Male mice had higher glucose intolerance, and Glrx1 deficiency aggravated gender differences in glucose intolerance. Glrx1 deficiency aggravated high-fat diet-induced hyperlipidemia. The mRNA levels of HMGCR, Srebf-1c, Srebf-2, CD36, FASN and SCD1 were consistently lower in females than in males. Glrx1 deficiency exacerbated high-fat diet induced liver injury and oxidative stress. Diet but not gender or genotype altered the composition of gut microbiota. These findings provide a new insight into the different susceptibilities to obesity caused by a high-fat diet between males and females.
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Affiliation(s)
- Xiaoyu Zou
- Jiangsu Collaborative Innovation Center of Meat Production and Processing, Quality and Safety Control; Key Laboratory of Meat Processing and Quality Control, MOE; Key Laboratory of Meat Products Processing, MOA; Nanjing Agricultural University, Nanjing 210095, P.R. China.
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28
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DesOrmeaux GJ, Petrick HL, Brunetta HS, Holloway GP. Independent of mitochondrial respiratory function, dietary nitrate attenuates HFD-induced lipid accumulation and mitochondrial ROS emission within the liver. Am J Physiol Endocrinol Metab 2021; 321:E217-E228. [PMID: 34229472 DOI: 10.1152/ajpendo.00610.2020] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 06/14/2021] [Indexed: 11/22/2022]
Abstract
The liver is particularly susceptible to the detrimental effects of a high-fat diet (HFD), rapidly developing lipid accumulation and impaired cellular homeostasis. Recently, dietary nitrate has been shown to attenuate HFD-induced whole body glucose intolerance and liver steatosis, however, the underlying mechanism(s) remain poorly defined. In the current study, we investigated the ability of dietary nitrate to minimize possible impairments in liver mitochondrial bioenergetics following 8 wk of HFD (60% fat) in male C57BL/6J mice. Consumption of a HFD caused whole body glucose intolerance (P < 0.0001), and within the liver, increased lipid accumulation (P < 0.0001), mitochondrial-specific reactive oxygen species emission (P = 0.007), and markers of oxidative stress. Remarkably, dietary nitrate attenuated almost all of these pathological responses. Despite the reduction in lipid accumulation and redox stress (reduced TBARS and nitrotyrosine), nitrate did not improve insulin signaling within the liver or whole body pyruvate tolerance (P = 0.313 HFD vs. HFD + nitrate). Moreover, the beneficial effects of nitrate were independent of changes in weight gain, 5' AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) signaling, mitochondrial content, mitochondrial respiratory capacity and ADP sensitivity or antioxidant protein content. Combined, these data suggest nitrate supplementation represents a potential therapeutic strategy to attenuate hepatic lipid accumulation and decrease mitochondrial ROS emission following HFD, processes linked to improvements in whole body glucose tolerance. However, the beneficial effects of nitrate within the liver do not appear to be a result of increased oxidative capacity or mitochondrial substrate sensitivity.NEW & NOTEWORTHY The mechanism(s) for how dietary nitrate prevents high-fat diet (HFD)-induced glucose intolerance remain poorly defined. We show that dietary nitrate attenuates HFD-induced increases in lipid accumulation, mitochondrial-specific reactive oxygen species (ROS) emission, and markers of oxidative stress within the liver. The beneficial effects of nitrate were independent of changes 5' AMP-activated protein kinase signaling, mitochondrial content/respiratory capacity, or lipid-supported respiratory sensitivity. Combined, these data provide potential mechanisms underlying the therapeutic potential of dietary nitrate.
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Affiliation(s)
| | - Heather L Petrick
- Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada
| | - Henver S Brunetta
- Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada
- Department of Physiological Sciences, Federal University of Santa Catarina, Florianopolis, Brazil
| | - Graham P Holloway
- Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada
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Rodríguez-Fierros FL, Guarner-Lans V, Soto ME, Manzano-Pech L, Díaz-Díaz E, Soria-Castro E, Rubio-Ruiz ME, Jiménez-Trejo F, Pérez-Torres I. Modulation of Renal Function in a Metabolic Syndrome Rat Model by Antioxidants in Hibiscus sabdariffa L. Molecules 2021; 26:molecules26072074. [PMID: 33916540 PMCID: PMC8038460 DOI: 10.3390/molecules26072074] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 03/30/2021] [Accepted: 03/31/2021] [Indexed: 12/16/2022] Open
Abstract
Metabolic syndrome (MS) is the association of three or more pathologies among which obesity, hypertension, insulin resistance, dyslipidemia, and diabetes are included. It causes oxidative stress (OS) and renal dysfunction. Hibiscus sabdariffa L. (HSL) is a source of natural antioxidants that may control the renal damage caused by the MS. The objective of this work was to evaluate the effect of a 2% HSL infusion on renal function in a MS rat model induced by the administration of 30% sucrose in drinking water. 24 male Wistar rats were divided into 3 groups: Control rats, MS rats and MS + HSL rats. MS rats had increased body weight, systolic blood pressure, triglycerides, insulin, HOMA index, and leptin (p ≤ 0.04). Renal function was impaired by an increase in perfusion pressure in the isolated and perfused kidney, albuminuria (p ≤ 0.03), and by a decrease in clearance of creatinine (p ≤ 0.04). The activity of some antioxidant enzymes including the superoxide dismutase isoforms, peroxidases, glutathione peroxidase, glutathione-S-transferase was decreased (p ≤ 0.05). Lipoperoxidation and carbonylation were increased (p ≤ 0.001). The nitrates/nitrites ratio, total antioxidant capacity, glutathione levels and vitamin C were decreased (p ≤ 0.03). The treatment with 2% HSL reversed these alterations. The results suggest that the treatment with 2% HSL infusion protects renal function through its natural antioxidants which favor an improved renal vascular response. The infusion contributes to the increase in the glomerular filtration rate, by promoting an increase in the enzymatic and non-enzymatic antioxidant systems leading to a decrease in OS and reestablishing the normal renal function.
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Affiliation(s)
- Félix Leao Rodríguez-Fierros
- Department of Cardiovascular Biomedicine, Instituto Nacional de Cardiología “Ignacio Chávez”, Juan Badiano 1, Sección XVI, Tlalpan, Mexico City 14080, Mexico; (F.L.R.-F.); (L.M.-P.); (E.S.-C.)
| | - Verónica Guarner-Lans
- Department of Physiology, Instituto Nacional de Cardiología “Ignacio Chávez”, Juan Badiano 1, Sección XVI, Tlalpan, Mexico City 14080, Mexico; (V.G.-L.); (M.E.R.-R.)
| | - María Elena Soto
- Department of Immunology, Instituto Nacional de Cardiología “Ignacio Chávez”, Juan Badiano 1, Sección XVI, Tlalpan, Mexico City 14080, Mexico;
| | - Linaloe Manzano-Pech
- Department of Cardiovascular Biomedicine, Instituto Nacional de Cardiología “Ignacio Chávez”, Juan Badiano 1, Sección XVI, Tlalpan, Mexico City 14080, Mexico; (F.L.R.-F.); (L.M.-P.); (E.S.-C.)
| | - Eulises Díaz-Díaz
- Department of Reproductive Biology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga 15, Sección XVI, Tlalpan, Mexico City 14000, Mexico;
| | - Elizabeth Soria-Castro
- Department of Cardiovascular Biomedicine, Instituto Nacional de Cardiología “Ignacio Chávez”, Juan Badiano 1, Sección XVI, Tlalpan, Mexico City 14080, Mexico; (F.L.R.-F.); (L.M.-P.); (E.S.-C.)
| | - María Esther Rubio-Ruiz
- Department of Physiology, Instituto Nacional de Cardiología “Ignacio Chávez”, Juan Badiano 1, Sección XVI, Tlalpan, Mexico City 14080, Mexico; (V.G.-L.); (M.E.R.-R.)
| | - Francisco Jiménez-Trejo
- Department of Reproductive Biology, Instituto Nacional de Pediatría, Insurgentes Sur No. 3700-C, Coyoacán, Mexico City 04530, Mexico;
| | - Israel Pérez-Torres
- Department of Cardiovascular Biomedicine, Instituto Nacional de Cardiología “Ignacio Chávez”, Juan Badiano 1, Sección XVI, Tlalpan, Mexico City 14080, Mexico; (F.L.R.-F.); (L.M.-P.); (E.S.-C.)
- Correspondence: or ; Tel.: +52-5573-2911 (ext. 25203); Fax: +52-5573-0926
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Zhou Y, Li H, Xia N. The Interplay Between Adipose Tissue and Vasculature: Role of Oxidative Stress in Obesity. Front Cardiovasc Med 2021; 8:650214. [PMID: 33748199 PMCID: PMC7969519 DOI: 10.3389/fcvm.2021.650214] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Accepted: 02/10/2021] [Indexed: 12/15/2022] Open
Abstract
Cardiovascular diseases (CVDs) rank the leading cause of morbidity and mortality globally. Obesity and its related metabolic syndrome are well-established risk factors for CVDs. Therefore, understanding the pathophysiological role of adipose tissues is of great importance in maintaining cardiovascular health. Oxidative stress, characterized by excessive formation of reactive oxygen species, is a common cellular stress shared by obesity and CVDs. While plenty of literatures have illustrated the vascular oxidative stress, very few have discussed the impact of oxidative stress in adipose tissues. Adipose tissues can communicate with vascular systems, in an endocrine and paracrine manner, through secreting several adipocytokines, which is largely dysregulated in obesity. The aim of this review is to summarize current understanding of the relationship between oxidative stress in obesity and vascular endothelial dysfunction. In this review, we briefly describe the possible causes of oxidative stress in obesity, and the impact of obesity-induced oxidative stress on adipose tissue function. We also summarize the crosstalk between adipose tissue and vasculature mediated by adipocytokines in vascular oxidative stress. In addition, we highlight the potential target mediating adipose tissue oxidative stress.
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Affiliation(s)
- Yawen Zhou
- Department of Pharmacology, Johannes Gutenberg University Medical Center, Mainz, Germany
| | - Huige Li
- Department of Pharmacology, Johannes Gutenberg University Medical Center, Mainz, Germany
| | - Ning Xia
- Department of Pharmacology, Johannes Gutenberg University Medical Center, Mainz, Germany
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Antioxidant Activity of Sprouts Extracts Is Correlated with Their Anti-Obesity and Anti-Inflammatory Effects in High-Fat Diet-Fed Mice. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:8367802. [PMID: 33643424 PMCID: PMC7902152 DOI: 10.1155/2021/8367802] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 01/22/2021] [Accepted: 01/30/2021] [Indexed: 01/24/2023]
Abstract
Obesity is closely associated with oxidative stress and chronic inflammation leading to related metabolic diseases. Some natural extracts or polyphenols reportedly possess anti-obesity and anti-inflammatory effects as well as antioxidant activity. In this study, we assessed the correlations between the antioxidant, anti-obesity, and anti-inflammatory activities of plant extracts with potent antioxidant activity in diet-induced obese mice. Sprouts of Cedrela sinensis (CS) and Oenothera biennis L. (OB) were selected as the most potent antioxidant plant based on analysis of in vitro antioxidant activity of the extracts of ten different edible plants. C57BL/6 mice were fed with a high-fat diet (HFD) and orally treated with 50% ethanol extract of CS or OB at 50 or 100 mg/kg body weight 5 days a week for 14 weeks. Body weight gain, weight of adipose tissue, adipocyte size, and levels of lipid metabolism, inflammation, and oxidative stress markers were investigated. The CS or OB extract reduced body weight gain, visceral adipose tissue weight, adipocyte size, and plasma leptin levels, and expressions of adipogenic genes (PPARγ and fatty acid synthase) in the adipose tissue and liver of HFD-fed mice. Both extracts also reduced mRNA levels of pro-inflammatory cytokines (IL-6 and TNF-α) and oxidative stress-related genes (heme oxygenase- (HO-) 1 and p40phox). Body weight gain of mice was significantly correlated with visceral adipose tissue weight and adipocyte size. Body weight gain and adipocyte size were significantly correlated with plasma total cholesterol and 8-epi PGF2α levels, mRNA levels of leptin, HO-1, p40phox, and CD-11 in the adipose tissue, and mRNA levels of TNF-α in the adipose tissue and liver. These results suggest that the CS and OB extracts with potent antioxidant activity may inhibit fat deposition in adipose tissue and subsequent inflammation.
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Choi MJ, Jung SB, Chang JY, Shong M. Cellular and Intercellular Homeostasis in Adipose Tissue with Mitochondria-Specific Stress. Endocrinol Metab (Seoul) 2021; 36:1-11. [PMID: 33677920 PMCID: PMC7937835 DOI: 10.3803/enm.2021.956] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 01/31/2021] [Indexed: 12/24/2022] Open
Abstract
Paracrine interactions are imperative for the maintenance of adipose tissue intercellular homeostasis, and intracellular organelle dysfunction results in local and systemic alterations in metabolic homeostasis. It is currently accepted that mitochondrial proteotoxic stress activates the mitochondrial unfolded protein response (UPRmt) in vitro and in vivo. The induction of mitochondrial chaperones and proteases during the UPRmt is a key cell-autonomous mechanism of mitochondrial quality control. The UPRmt also affects systemic metabolism through the secretion of cell non-autonomous peptides and cytokines (hereafter, metabokines). Mitochondrial function in adipose tissue plays a pivotal role in whole-body metabolism and human diseases. Despite continuing interest in the role of the UPRmt and quality control pathways of mitochondria in energy metabolism, studies on the roles of the UPRmt and metabokines in white adipose tissue are relatively sparse. Here, we describe the role of the UPRmt in adipose tissue, including adipocytes and resident macrophages, and the interactive roles of cell non-autonomous metabokines, particularly growth differentiation factor 15, in local adipose cellular homeostasis and systemic energy metabolism.
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Affiliation(s)
- Min Jeong Choi
- Department of Medical Science, Chungnam National University College of Medicine, Daejeon, Korea
| | - Saet-Byel Jung
- Center for Biomolecular & Cellular Structure, Institute for Basic Science, Daejeon, Korea
| | - Joon Young Chang
- Department of Medical Science, Chungnam National University College of Medicine, Daejeon, Korea
| | - Minho Shong
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon, Korea
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Bucktrout RE, Ma N, Aboragah A, Alharthi AS, Liang Y, Lopreiato V, Lopes MG, Trevisi E, Alhidary IA, Fernandez C, Loor JJ. One-carbon, carnitine, and glutathione metabolism-related biomarkers in peripartal Holstein cows are altered by prepartal body condition. J Dairy Sci 2021; 104:3403-3417. [PMID: 33455750 DOI: 10.3168/jds.2020-19402] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Accepted: 10/15/2020] [Indexed: 12/13/2022]
Abstract
We investigated how prepartal body condition score (BCS) alters key hepatic enzymes associated with 1-carbon, carnitine, and glutathione metabolism and the related biomarkers in liver tissue and plasma of periparturient dairy cows. Twenty-six multiparous Holstein dairy cows were retrospectively selected according to BCS at 4 wk prepartum and divided into high (HighBCS, BCS ≥ 3.50) and normal (NormBCS, BCS ≤ 3.25) BCS groups (n = 13 each). Blood plasma samples were obtained at -30, -10, 7, 15, and 30 d relative to calving. Liver tissue biopsies were performed at -15, 7, and 30 d relative to calving, and samples were used to assess protein abundance via Western blot assay. Cows in the HighBCS group lost ∼1 unit of BCS between -4 and 4 wk around calving, while NormBCS cows lost ∼0.5 unit in the same period. Prepartal dry matter intake (DMI, kg/d) did not differ between groups. Compared with NormBCS cows, HighBCS cows had higher postpartal DMI and milk yield (+5.34 kg/d). In addition, greater overall plasma concentrations of fatty acids and activity of the neutrophil-enriched enzyme myeloperoxidase were observed in HighBCS compared with NormBCS cows. Despite similar reactive oxygen metabolite concentrations in both groups at 30 d, HighBCS cows had lower overall concentrations of β-carotene and tocopherol, explaining the lower (BCS × Time) antioxidant capacity (ferric reducing ability of plasma). The HighBCS cows also had greater liver malondialdehyde concentrations and superoxide dismutase activity at 30 d. Overall, compared with NormBCS cows, HighBCS cows had lower hepatic protein abundance of the 1-carbon metabolism enzymes cystathionine-β-synthase, betaine-homocysteine methyltransferase, and methionine adenosyltransferase 1 A (MAT1A), as well as the glutathione metabolism-related enzymes glutathione S-transferase α 4 and glutathione peroxidase 3 (GPX3). A lower protein abundance of glutathione S-transferase mu 1 (GSTM1) at -15 and 7 d was also observed. Regardless of BCS, cows had increased abundance of GSTM1 and GPX3 between -15 and 7 d around calving. A marked decrease of gamma-butyrobetaine dioxygenase 1 from -10 to 7 d in HighBCS compared with NormBCS cows suggested a decrease in de novo carnitine synthesis that was partly explained by the lower abundance of MAT1A. Overall, data suggest biologic links between BCS before calving, milk yield, immune response, and hepatic reactions encompassing 1-carbon metabolism, carnitine, and antioxidant synthesis.
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Affiliation(s)
- R E Bucktrout
- Department of Animal Sciences and Division of Nutritional Sciences, University of Illinois, Urbana 61801
| | - N Ma
- Department of Animal Sciences and Division of Nutritional Sciences, University of Illinois, Urbana 61801; College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, P. R. China
| | - A Aboragah
- Department of Animal Sciences and Division of Nutritional Sciences, University of Illinois, Urbana 61801
| | - A S Alharthi
- Department of Animal Production, College of Food and Agriculture Sciences, King Saud University, Riyadh 11451, Saudi Arabia
| | - Y Liang
- Department of Animal Sciences and Division of Nutritional Sciences, University of Illinois, Urbana 61801
| | - V Lopreiato
- Department of Animal Sciences, Food and Nutrition, Faculty of Agriculture, Food and Environmental Science, Università Cattolica del Sacro Cuore, 29122 Piacenza, Italy
| | - M G Lopes
- Department of Animal Sciences and Division of Nutritional Sciences, University of Illinois, Urbana 61801; NUPEEC (Núcleo de Pesquisa, Ensino e Extensão em Pecuária), Departamento de Clínicas Veterinária, Programa de Pós-Graduação em Biotecnologia, Universidade Federal de Pelotas, 96010-610, Pelotas, RS, Brazil
| | - E Trevisi
- Department of Animal Sciences, Food and Nutrition, Faculty of Agriculture, Food and Environmental Science, Università Cattolica del Sacro Cuore, 29122 Piacenza, Italy
| | - I A Alhidary
- Department of Animal Production, College of Food and Agriculture Sciences, King Saud University, Riyadh 11451, Saudi Arabia
| | - C Fernandez
- Animal Science Department, Universitàt Politècnica de Valencia, 46022 Valencia, Spain
| | - J J Loor
- Department of Animal Sciences and Division of Nutritional Sciences, University of Illinois, Urbana 61801.
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Hauck AK, Zhou T, Upadhyay A, Sun Y, O’Connor MB, Chen Y, Bernlohr DA. Histone Carbonylation Is a Redox-Regulated Epigenomic Mark That Accumulates with Obesity and Aging. Antioxidants (Basel) 2020; 9:antiox9121210. [PMID: 33271806 PMCID: PMC7761391 DOI: 10.3390/antiox9121210] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Revised: 11/23/2020] [Accepted: 11/27/2020] [Indexed: 02/07/2023] Open
Abstract
Oxidative stress is a hallmark of metabolic disease, though the mechanisms that define this link are not fully understood. Irreversible modification of proteins by reactive lipid aldehydes (protein carbonylation) is a major consequence of oxidative stress in adipose tissue and the substrates and specificity of this modification are largely unexplored. Here we show that histones are avidly modified by 4-hydroxynonenal (4-HNE) in vitro and in vivo. Carbonylation of histones by 4-HNE increased with age in male flies and visceral fat depots of mice and was potentiated in genetic (ob/ob) and high-fat feeding models of obesity. Proteomic evaluation of in vitro 4-HNE- modified histones led to the identification of both Michael and Schiff base adducts. In contrast, mapping of sites in vivo from obese mice exclusively revealed Michael adducts. In total, we identified 11 sites of 4-hydroxy hexenal (4-HHE) and 10 sites of 4-HNE histone modification in visceral adipose tissue. In summary, these results characterize adipose histone carbonylation as a redox-linked epigenomic mark associated with metabolic disease and aging.
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Affiliation(s)
- Amy K. Hauck
- Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA; (A.K.H.); (T.Z.); (Y.C.)
| | - Tong Zhou
- Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA; (A.K.H.); (T.Z.); (Y.C.)
| | - Ambuj Upadhyay
- Department of Molecular Biology, Cell Biology, Developmental Biology and Genetics, University of Minnesota, Minneapolis, MN 55455, USA; (A.U.); (M.B.O.)
| | - Yuxiang Sun
- Department of Nutrition, Texas A&M University, College Station, TX 77843, USA;
| | - Michael B. O’Connor
- Department of Molecular Biology, Cell Biology, Developmental Biology and Genetics, University of Minnesota, Minneapolis, MN 55455, USA; (A.U.); (M.B.O.)
| | - Yue Chen
- Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA; (A.K.H.); (T.Z.); (Y.C.)
| | - David A. Bernlohr
- Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA; (A.K.H.); (T.Z.); (Y.C.)
- Correspondence:
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Bhargava M, Viken KJ, Barkes B, Griffin TJ, Gillespie M, Jagtap PD, Sajulga R, Peterson EJ, Dincer HE, Li L, Restrepo CI, O'Connor BP, Fingerlin TE, Perlman DM, Maier LA. Novel protein pathways in development and progression of pulmonary sarcoidosis. Sci Rep 2020; 10:13282. [PMID: 32764642 PMCID: PMC7413390 DOI: 10.1038/s41598-020-69281-8] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Accepted: 06/17/2020] [Indexed: 12/15/2022] Open
Abstract
Pulmonary involvement occurs in up to 95% of sarcoidosis cases. In this pilot study, we examine lung compartment-specific protein expression to identify pathways linked to development and progression of pulmonary sarcoidosis. We characterized bronchoalveolar lavage (BAL) cells and fluid (BALF) proteins in recently diagnosed sarcoidosis cases. We identified 4,306 proteins in BAL cells, of which 272 proteins were differentially expressed in sarcoidosis compared to controls. These proteins map to novel pathways such as integrin-linked kinase and IL-8 signaling and previously implicated pathways in sarcoidosis, including phagosome maturation, clathrin-mediated endocytic signaling and redox balance. In the BALF, the differentially expressed proteins map to several pathways identified in the BAL cells. The differentially expressed BALF proteins also map to aryl hydrocarbon signaling, communication between innate and adaptive immune response, integrin, PTEN and phospholipase C signaling, serotonin and tryptophan metabolism, autophagy, and B cell receptor signaling. Additional pathways that were different between progressive and non-progressive sarcoidosis in the BALF included CD28 signaling and PFKFB4 signaling. Our studies demonstrate the power of contemporary proteomics to reveal novel mechanisms operational in sarcoidosis. Application of our workflows in well-phenotyped large cohorts maybe beneficial to identify biomarkers for diagnosis and prognosis and therapeutically tenable molecular mechanisms.
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Affiliation(s)
- Maneesh Bhargava
- Division of Pulmonary, Critical Care and Sleep Medicine, University of Minnesota, MMC 276, 420 Delaware St SE, Minneapolis, MN, USA.
| | - K J Viken
- Division of Pulmonary, Critical Care and Sleep Medicine, University of Minnesota, MMC 276, 420 Delaware St SE, Minneapolis, MN, USA
| | - B Barkes
- Division of Environmental and Occupational Health Sciences, National Jewish Health, Denver, CO, USA
| | - T J Griffin
- Biochemistry, Molecular Biology and Biophysics, College of Biological Sciences, University of Minnesota, Minneapolis, MN, USA
| | - M Gillespie
- Division of Environmental and Occupational Health Sciences, National Jewish Health, Denver, CO, USA
| | - P D Jagtap
- Biochemistry, Molecular Biology and Biophysics, College of Biological Sciences, University of Minnesota, Minneapolis, MN, USA
| | - R Sajulga
- Biochemistry, Molecular Biology and Biophysics, College of Biological Sciences, University of Minnesota, Minneapolis, MN, USA
| | - E J Peterson
- Center for Immunology, University of Minnesota, Minneapolis, MN, USA
| | - H E Dincer
- Division of Pulmonary, Critical Care and Sleep Medicine, University of Minnesota, MMC 276, 420 Delaware St SE, Minneapolis, MN, USA
| | - L Li
- Division of Environmental and Occupational Health Sciences, National Jewish Health, Denver, CO, USA
| | - C I Restrepo
- Division of Environmental and Occupational Health Sciences, National Jewish Health, Denver, CO, USA
| | - B P O'Connor
- Center for Genes, Environment and Health, National Jewish Health, Denver, CO, USA
| | - T E Fingerlin
- Center for Genes, Environment and Health, National Jewish Health, Denver, CO, USA
| | - D M Perlman
- Division of Pulmonary, Critical Care and Sleep Medicine, University of Minnesota, MMC 276, 420 Delaware St SE, Minneapolis, MN, USA
| | - L A Maier
- Division of Environmental and Occupational Health Sciences, National Jewish Health, Denver, CO, USA
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Bojková B, Winklewski PJ, Wszedybyl-Winklewska M. Dietary Fat and Cancer-Which Is Good, Which Is Bad, and the Body of Evidence. Int J Mol Sci 2020; 21:ijms21114114. [PMID: 32526973 PMCID: PMC7312362 DOI: 10.3390/ijms21114114] [Citation(s) in RCA: 79] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 05/27/2020] [Accepted: 06/02/2020] [Indexed: 12/13/2022] Open
Abstract
A high-fat diet (HFD) induces changes in gut microbiota leading to activation of pro-inflammatory pathways, and obesity, as a consequence of overnutrition, exacerbates inflammation, a known risk factor not only for cancer. However, experimental data showed that the composition of dietary fat has a greater impact on the pathogenesis of cancer than the total fat content in isocaloric diets. Similarly, human studies did not prove that a decrease in total fat intake is an effective strategy to combat cancer. Saturated fat has long been considered as harmful, but the current consensus is that moderate intake of saturated fatty acids (SFAs), including palmitic acid (PA), does not pose a health risk within a balanced diet. In regard to monounsaturated fat, plant sources are recommended. The consumption of plant monounsaturated fatty acids (MUFAs), particularly from olive oil, has been associated with lower cancer risk. Similarly, the replacement of animal MUFAs with plant MUFAs decreased cancer mortality. The impact of polyunsaturated fatty acids (PUFAs) on cancer risk depends on the ratio between ω-6 and ω-3 PUFAs. In vivo data showed stimulatory effects of ω-6 PUFAs on tumour growth while ω-3 PUFAs were protective, but the results of human studies were not as promising as indicated in preclinical reports. As for trans FAs (TFAs), experimental data mostly showed opposite effects of industrially produced and natural TFAs, with the latter being protective against cancer progression, but human data are mixed, and no clear conclusion can be made. Further studies are warranted to establish the role of FAs in the control of cell growth in order to find an effective strategy for cancer prevention/treatment.
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Affiliation(s)
- Bianka Bojková
- Department of Animal Physiology, Institute of Biology and Ecology, Faculty of Science, P.J. Šafárik University in Košice, 041 54 Košice, Slovakia;
| | - Pawel J. Winklewski
- Department of Human Physiology, Medical University of Gdansk, 80-210 Gdansk, Poland;
- Department of Anatomy and Physiology, Pomeranian University of Slupsk, 76-200 Slupsk, Poland
- Correspondence: ; Tel./Fax: +48-58-3491515
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Docrat TF, Nagiah S, Naicker N, Baijnath S, Singh S, Chuturgoon AA. The protective effect of metformin on mitochondrial dysfunction and endoplasmic reticulum stress in diabetic mice brain. Eur J Pharmacol 2020; 875:173059. [PMID: 32131023 DOI: 10.1016/j.ejphar.2020.173059] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Revised: 02/23/2020] [Accepted: 02/28/2020] [Indexed: 12/26/2022]
Abstract
Diabetes is a metabolic disorder associated with mitochondrial (mt) dysfunction and oxidative stress. The molecular mechanisms involved in diabetes-associated neurological complications remain elusive. This study aims to investigate the protective effect of metformin (MF) on regulatory networks and integrated stress responses in brain tissue of Streptozotocin (STZ)-induced diabetic mice. STZ-induced diabetic mice were treated with MF (20 mg/kg BW), and whole brain tissue was harvested for further analysis. Protein carbonylation was measured as a marker of neuronal oxidative stress. Protein expression of mt chaperones, maintenance proteins, and regulators of the unfolded protein response (UPR) were measured by Western blot. Transcript levels of antioxidant enzyme GSTA4; mt biogenesis markers, ER stress regulators, and miR-132 and miR-148a were analysed using qPCR. The results showed that MF efficiently reduced protein carbonylation and oxidation. Mt function was improved by MF-treatment through upregulation of chaperone proteins (HSP60, HSP70 and LonP1). MF elicits the UPR to attenuate ER stress through a miR-132 repression mechanism. Additionally, MF was found to elevate deacetylases- Sirt1, Sirt3; and mt biogenesis marker PGC-1α through miR-148a repression. This is the first study to demonstrate the epigenetic regulation of mt maintenance by MF in diabetic C57BL/6 mouse whole brain tissue. We thus conclude that MF, beyond its anti-hyperglycaemic role, mediates neuroprotection through epigenomic and integrated stress responses in diabetic mice.
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Affiliation(s)
- Taskeen Fathima Docrat
- Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Sciences, College of Health Science, University of KwaZulu-Natal, South Africa
| | - Savania Nagiah
- Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Sciences, College of Health Science, University of KwaZulu-Natal, South Africa
| | - Nikita Naicker
- Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Sciences, College of Health Science, University of KwaZulu-Natal, South Africa
| | - Sooraj Baijnath
- Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Sciences, College of Health Science, University of KwaZulu-Natal, South Africa
| | - Sanil Singh
- Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Sciences, College of Health Science, University of KwaZulu-Natal, South Africa
| | - Anil A Chuturgoon
- Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Sciences, College of Health Science, University of KwaZulu-Natal, South Africa.
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Can Medicinal Plants and Bioactive Compounds Combat Lipid Peroxidation Product 4-HNE-Induced Deleterious Effects? Biomolecules 2020; 10:biom10010146. [PMID: 31963301 PMCID: PMC7022924 DOI: 10.3390/biom10010146] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2019] [Revised: 01/13/2020] [Accepted: 01/14/2020] [Indexed: 12/27/2022] Open
Abstract
The toxic reactive aldehyde 4-hydroxynonenal (4-HNE) belongs to the advanced lipid peroxidation end products. Accumulation of 4-HNE and formation of 4-HNE adducts induced by redox imbalance participate in several cytotoxic processes, which contribute to the pathogenesis and progression of oxidative stress-related human disorders. Medicinal plants and bioactive natural compounds are suggested to be attractive sources of potential agents to mitigate oxidative stress, but little is known about the therapeutic potentials especially on combating 4-HNE-induced deleterious effects. Of note, some investigations clarify the attenuation of medicinal plants and bioactive compounds on 4-HNE-induced disturbances, but strong evidence is needed that these plants and compounds serve as potent agents in the prevention and treatment of disorders driven by 4-HNE. Therefore, this review highlights the pharmacological basis of these medicinal plants and bioactive compounds to combat 4-HNE-induced deleterious effects in oxidative stress-related disorders, such as neurotoxicity and neurological disorder, eye damage, cardiovascular injury, liver injury, and energy metabolism disorder. In addition, this review briefly discusses with special attention to the strategies for developing potential therapies by future applications of these medicinal plants and bioactive compounds, which will help biological and pharmacological scientists to explore the new vistas of medicinal plants in combating 4-HNE-induced deleterious effects.
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Cells deficient for Krüppel-like factor 4 exhibit mitochondrial dysfunction and impaired mitophagy. Eur J Cell Biol 2020; 99:151061. [DOI: 10.1016/j.ejcb.2019.151061] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 11/09/2019] [Accepted: 11/28/2019] [Indexed: 01/19/2023] Open
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Funcke JB, Scherer PE. Beyond adiponectin and leptin: adipose tissue-derived mediators of inter-organ communication. J Lipid Res 2019; 60:1648-1684. [PMID: 31209153 PMCID: PMC6795086 DOI: 10.1194/jlr.r094060] [Citation(s) in RCA: 211] [Impact Index Per Article: 35.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Revised: 06/17/2019] [Indexed: 01/10/2023] Open
Abstract
The breakthrough discoveries of leptin and adiponectin more than two decades ago led to a widespread recognition of adipose tissue as an endocrine organ. Many more adipose tissue-secreted signaling mediators (adipokines) have been identified since then, and much has been learned about how adipose tissue communicates with other organs of the body to maintain systemic homeostasis. Beyond proteins, additional factors, such as lipids, metabolites, noncoding RNAs, and extracellular vesicles (EVs), released by adipose tissue participate in this process. Here, we review the diverse signaling mediators and mechanisms adipose tissue utilizes to relay information to other organs. We discuss recently identified adipokines (proteins, lipids, and metabolites) and briefly outline the contributions of noncoding RNAs and EVs to the ever-increasing complexities of adipose tissue inter-organ communication. We conclude by reflecting on central aspects of adipokine biology, namely, the contribution of distinct adipose tissue depots and cell types to adipokine secretion, the phenomenon of adipokine resistance, and the capacity of adipose tissue to act both as a source and sink of signaling mediators.
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Affiliation(s)
- Jan-Bernd Funcke
- Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, TX
| | - Philipp E Scherer
- Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, TX
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Tissue-Specific Oxidative Stress Modulation by Exercise: A Comparison between MICT and HIIT in an Obese Rat Model. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:1965364. [PMID: 31396298 PMCID: PMC6664693 DOI: 10.1155/2019/1965364] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Revised: 05/16/2019] [Accepted: 06/11/2019] [Indexed: 12/11/2022]
Abstract
Background and Aim Exercise is an effective strategy to reduce obesity-induced oxidative stress. The purpose of this study was to compare the effects of two training modalities (moderate-intensity continuous training (MICT) and high-intensity interval training (HIIT)) on the pro/antioxidant status of different tissues in obese Zucker rats. Methods Eight-week-old male Zucker rats (fa/fa, n = 36) were subdivided in three groups: MICT, HIIT, and control (no exercise) groups. Trained animals ran on a treadmill (0° slope), 5 days/week for 10 weeks (MICT: 51 min at 12 m·min-1; HIIT: 6 sets of 3 min at 10 m·min-1 followed by 4 min at 18 m·min-1). Epididymal (visceral) and subcutaneous adipose tissue, gastrocnemius muscle, and plasma samples were collected to measure oxidative stress markers (advanced oxidation protein products (AOPP), oxidized low-density lipoprotein (oxLDL)), antioxidant system markers (ferric-reducing ability of plasma (FRAP), superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPx) activities), and prooxidant enzymes (NADPH oxidase and xanthine oxidase (XO) activities, myeloperoxidase content). Results Compared with the control, MICT increased GPx and catalase activities and the FRAP level in epididymal adipose tissue. HIIT increased the AOPP level in subcutaneous adipose tissue. In the muscle, HIIT increased both SOD and GPx activities and reduced the AOPP level, whereas MICT increased only SOD activity. Finally, plasma myeloperoxidase content was similarly decreased by both training modalities, whereas oxLDL was reduced only in the MICT group. Conclusion Both HIIT and MICT improved the pro/antioxidant status. However, HIIT was more efficient than MICT in the skeletal muscle, whereas MICT was more efficient in epididymal adipose tissue. This suggests that oxidative stress responses to HIIT and MICT are tissue-specific. This could result in ROS generation via different pathways in these tissues. From a practical point of view, the two training modalities should be combined to obtain a global response in people with obesity.
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Galal AAA, Ramadan RA, Metwally MMM, El-Sheikh SMA. Protective effect of N-acetylcysteine on fenitrothion-induced toxicity: The antioxidant status and metabolizing enzymes expression in rats. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2019; 171:502-510. [PMID: 30639957 DOI: 10.1016/j.ecoenv.2019.01.004] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Revised: 12/30/2018] [Accepted: 01/02/2019] [Indexed: 06/09/2023]
Abstract
The existence of fenitrothion (FNT) in the soil, water, and food products has harmful effects on non-target organisms. Therefore, this study was conducted to evaluate the hepatotoxic, nephrotoxic and neurotoxic effects of FNT and the possible ameliorative effect of N-acetylcysteine (NAC), a precursor of intracellular GSH, on FNT-induced toxicity. For this purpose, thirty-two adult male albino rats were allocated into control group and groups treated with NAC (200 mg/kg), FNT (10 mg/kg) and FNT + NAC via gastric tube daily for 28 days. FNT intoxication significantly reduced food intake, water intake, body weight, and body weight gain and altered the expression of phase I and phase II xenobiotic-metabolizing enzymes-cytochrome P450 (CYP1A1) and glutathione S-transferase (GSTA4-4). In hepatic, renal and brain tissues, FNT induced oxidative stress, hepatopathy, nephropathy, and encephalopathy, and significantly increased pro-inflammatory cytokines. Furthermore, FNT exposure significantly elevated the level of hepatic and renal injury biomarkers and significantly inhibited the brain acetylcholinesterase activity. Co-administration of NAC with FNT modulated most of these altered biochemical, oxidative and inflammatory markers and restored the xenobiotic-metabolizing enzymes expression and histological structures. Our study indicated the involvement of oxidative damage, inflammation, and alteration of xenobiotic-metabolizing enzymes expression in FNT-induced toxicity and revealed that they were significantly improved by NAC co-treatment. These findings suggest that NAC administration might protect against FNT-induced toxicity in non-target organisms, including humans.
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Affiliation(s)
- Azza A A Galal
- Department of Pharmacology, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44511, Egypt.
| | - Raghda A Ramadan
- Department of Pharmacology, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44511, Egypt
| | - Mohamed M M Metwally
- Department of Pathology, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44511, Egypt
| | - Sawsan M A El-Sheikh
- Department of Pharmacology, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44511, Egypt
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Liang Y, Batistel F, Parys C, Loor JJ. Glutathione metabolism and nuclear factor erythroid 2-like 2 (NFE2L2)-related proteins in adipose tissue are altered by supply of ethyl-cellulose rumen-protected methionine in peripartal Holstein cows. J Dairy Sci 2019; 102:5530-5541. [PMID: 30954259 DOI: 10.3168/jds.2018-15687] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Accepted: 02/21/2019] [Indexed: 11/19/2022]
Abstract
Enhancing the supply of rumen-protected Met (RPM) during the peripartum period alleviates inflammation and oxidative stress status in dairy cows. We tested the hypothesis that RPM could increase abundance of genes and proteins related to glutathione (GSH) metabolism and the antioxidant transcription factor nuclear factor erythroid 2-like 2 (NFE2L2) in subcutaneous adipose tissue. Multiparous Holstein cows were fed a basal diet [control prepartum diet = 1.47 Mcal/kg of dry matter (DM) and 15.3% crude protein; control postpartum diet = 1.67 Mcal/kg of DM and 17.7% crude protein] or the control plus ethyl-cellulose RPM at a rate of 0.09 and 0.10% of DM intake before expected calving and after calving, respectively. Sixty cows were assigned to treatments based on parity, previous 305-d milk yield, and body condition score at 28 d from parturition. Diets were fed from -28 to 30 d. Biopsies of subcutaneous adipose tissue collected on d -10, 10, and 30 relative to parturition from 7 cows in each group were used for measuring concentrations of GSH, reactive oxygen species, superoxide dismutase, malondialdehyde, and mRNA and protein abundance (Western blotting). A repeated-measures ANOVA was used for statistics. The statistical model included the random effect of block and fixed effects of treatment, time, and its interaction. There was a diet × time effect for reactive oxygen species due to lower concentrations in Met versus control cows specifically at d -10. Cows fed Met also had lower concentrations of malondialdehyde in subcutaneous adipose tissue. Compared with controls, overall mRNA abundance of the GSH metabolism-related genes cystathionine-β-synthase (CBS), glutamate-cysteine ligase modifier subunit (GCLM), glutathione reductase (GSR), and glutathione peroxidase 1 (GPX1) was greater in cows fed Met. Furthermore, supply of Met resulted in an overall upregulation of protein abundance of glutathione peroxidase (GPX) 1, GPX3, glutathione S-transferase mu 1 (GSTM1), and glutathione S-transferase α 4 (GSTA4), all related to GSH metabolism. There was a diet × time effect for protein abundance of NFE2L2 and its repressor Kelch-like ECH associated protein 1 (KEAP1) due to lower values at 30 d in cows fed Met versus controls. The abundance of phosphorylated NFE2L2 was lower at 30 d in response to Met. Overall, the data suggest that exogenous Met may play a role in activating GSH metabolism and the antioxidant NFE2L2 pathways in subcutaneous adipose tissue.
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Affiliation(s)
- Y Liang
- Department of Animal Sciences and Division of Nutritional Sciences, University of Illinois, Urbana 61801
| | - F Batistel
- Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan 84322
| | - C Parys
- Evonik Nutrition and Care GmbH, Hanau-Wolfgang, 63457, Germany
| | - J J Loor
- Department of Animal Sciences and Division of Nutritional Sciences, University of Illinois, Urbana 61801.
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Myocardial Protection from Ischemia-Reperfusion Damage by the Antioxidant Effect of Hibiscus sabdariffa Linnaeus on Metabolic Syndrome Rats. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:1724194. [PMID: 31049126 PMCID: PMC6458956 DOI: 10.1155/2019/1724194] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Revised: 11/07/2018] [Accepted: 02/24/2019] [Indexed: 12/13/2022]
Abstract
Cardiovascular diseases (CVD) constitute one of the most prevalent health problems worldwide, being strongly associated with metabolic syndrome (MS). Oxidative stress (OS) is present in both CVD and MS. Infusions of Hibiscus sabdariffa Linnaeus (HSL) have antioxidant properties and could therefore decrease the presence of OS in these diseases. The aim of this study was to evaluate myocardial protection during ischemia/reperfusion due to the antioxidant effect of HSL infusion (3%) on a MS rat model induced by the administration of 30% sucrose in drinking water. We determined in control, MS, and MS + HSL rat hearts (n = 6 per group) cardiac mechanical performance (CMP), coronary vascular resistance (CVR), and activities of manganese and copper/zinc superoxide dismutases (Mn and Cu/Zn-SOD), peroxidases, glutathione peroxidase (GPx), catalase (CAT), glutathione s-transferase (GST), glutathione reductase (GR), and glutathione (GSH). We also determined lipoperoxidation (LPO), total antioxidant capacity (TAC), and the nitrate/nitrite ratio (NO3−/NO2−). The treatment with the HSL infusion restored the CMP (p = 0.01) and CVR (p = 0.04) and increased the Mn- (p = 0.02), Cu/Zn-SOD (p = 0.05), peroxidases (p = 0.04), GST (p = 0.02) activity, GHS (p = 0.02), TAC (p = 0.04), and NO3−/NO2− (p = 0.01) and decreased the LPO (p = 0.02) in the heart of MS rats undergoing ischemia/reperfusion. The results suggest that the treatment with an infusion from HSL calices protects the cardiac function from damage by ischemia and reperfusion through the antioxidant activities of the substances it possesses. It favors antioxidant enzymatic activities and nonenzymatic antioxidant capacity.
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Hauck AK, Huang Y, Hertzel AV, Bernlohr DA. Adipose oxidative stress and protein carbonylation. J Biol Chem 2018; 294:1083-1088. [PMID: 30563836 DOI: 10.1074/jbc.r118.003214] [Citation(s) in RCA: 105] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Increased oxidative stress and abundance of reactive oxygen species (ROS) are positively correlated with a variety of pathophysiologies, including cardiovascular disease, type 2 diabetes, Alzheimer's disease, and neuroinflammation. In adipose biology, diabetic obesity is correlated with increased ROS in an age- and depot-specific manner and is mechanistically linked to mitochondrial dysfunction, endoplasmic reticulum (ER) stress, potentiated lipolysis, and insulin resistance. The cellular quality control systems that homeostatically regulate oxidative stress in the lean state are down-regulated in obesity as a consequence of inflammatory cytokine pressure leading to the accumulation of oxidized biomolecules. New findings have linked protein, DNA, and lipid oxidation at the biochemical level, and the structures and potential functions of protein adducts such as carbonylation that accumulate in stressed cells have been characterized. The sum total of such regulation and biochemical changes results in alteration of cellular metabolism and function in the obese state relative to the lean state and underlies metabolic disease progression. In this review, we discuss the molecular mechanisms and events underlying these processes and their implications for human health and disease.
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Affiliation(s)
- Amy K Hauck
- Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104
| | - Yimao Huang
- Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota-Twin Cities, Minneapolis, Minnesota 55455
| | - Ann V Hertzel
- Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota-Twin Cities, Minneapolis, Minnesota 55455
| | - David A Bernlohr
- Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota-Twin Cities, Minneapolis, Minnesota 55455.
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Ghosh Dastidar S, Jagatheesan G, Haberzettl P, Shah J, Hill BG, Bhatnagar A, Conklin DJ. Glutathione S-transferase P deficiency induces glucose intolerance via JNK-dependent enhancement of hepatic gluconeogenesis. Am J Physiol Endocrinol Metab 2018; 315:E1005-E1018. [PMID: 30153066 PMCID: PMC6293160 DOI: 10.1152/ajpendo.00345.2017] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Hepatic glutathione S-transferases (GSTs) are dysregulated in human obesity, nonalcoholic fatty liver disease, and diabetes. The multifunctional GST pi-isoform (GSTP) catalyzes the conjugation of glutathione with acrolein and inhibits c-Jun NH2-terminal kinase (JNK) activation. Herein, we tested whether GSTP deficiency disturbs glucose homeostasis in mice. Hepatic GST proteins were downregulated by short-term high-fat diet in wild-type (WT) mice concomitant with increased glucose intolerance, JNK activation, and cytokine mRNAs in the liver. Genetic deletion of GSTP did not affect body composition, fasting blood glucose levels, or insulin levels in mice maintained on a normal chow diet; however, compared with WT mice, the GSTP-null mice were glucose intolerant. In GSTP-null mice, pyruvate intolerance, reflecting increased hepatic gluconeogenesis, was accompanied by elevated levels of activated JNK, cytokine mRNAs, and glucose-6-phosphatase proteins in the liver. Treatment of GSTP-null mice with the JNK inhibitor 1,9-pyrazoloanthrone (SP600125) significantly attenuated pyruvate-induced hepatic gluconeogenesis and significantly altered correlations between hepatic cytokine mRNAs and metabolic outcomes in GSTP-null mice. Collectively, these findings suggest that hepatic GSTP plays a pivotal role in glucose handling by regulating JNK-dependent control of hepatic gluconeogenesis. Thus, hepatic GSTP-JNK dysregulation may be a target of new therapeutic interventions during early stages of glucose intolerance to prevent the worsening metabolic derangements associated with human obesity and its relentless progression to diabetes.
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Affiliation(s)
- Shubha Ghosh Dastidar
- Diabetes and Obesity Center, School of Medicine, University of Louisville , Louisville, Kentucky
| | - Ganapathy Jagatheesan
- Diabetes and Obesity Center, School of Medicine, University of Louisville , Louisville, Kentucky
| | - Petra Haberzettl
- Diabetes and Obesity Center, School of Medicine, University of Louisville , Louisville, Kentucky
| | - Jasmit Shah
- Diabetes and Obesity Center, School of Medicine, University of Louisville , Louisville, Kentucky
- Department of Internal Medicine, Aga Khan University , Nairobi , Kenya
| | - Bradford G Hill
- Diabetes and Obesity Center, School of Medicine, University of Louisville , Louisville, Kentucky
| | - Aruni Bhatnagar
- Diabetes and Obesity Center, School of Medicine, University of Louisville , Louisville, Kentucky
| | - Daniel J Conklin
- Diabetes and Obesity Center, School of Medicine, University of Louisville , Louisville, Kentucky
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Abstract
The concept of cell signaling in the context of nonenzyme-assisted protein modifications by reactive electrophilic and oxidative species, broadly known as redox signaling, is a uniquely complex topic that has been approached from numerous different and multidisciplinary angles. Our Review reflects on five aspects critical for understanding how nature harnesses these noncanonical post-translational modifications to coordinate distinct cellular activities: (1) specific players and their generation, (2) physicochemical properties, (3) mechanisms of action, (4) methods of interrogation, and (5) functional roles in health and disease. Emphasis is primarily placed on the latest progress in the field, but several aspects of classical work likely forgotten/lost are also recollected. For researchers with interests in getting into the field, our Review is anticipated to function as a primer. For the expert, we aim to stimulate thought and discussion about fundamentals of redox signaling mechanisms and nuances of specificity/selectivity and timing in this sophisticated yet fascinating arena at the crossroads of chemistry and biology.
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Affiliation(s)
- Saba Parvez
- Department of Pharmacology and Toxicology, College of
Pharmacy, University of Utah, Salt Lake City, Utah, 84112, USA
- Department of Chemistry and Chemical Biology, Cornell
University, Ithaca, New York, 14853, USA
| | - Marcus J. C. Long
- Department of Chemistry and Chemical Biology, Cornell
University, Ithaca, New York, 14853, USA
| | - Jesse R. Poganik
- Ecole Polytechnique Fédérale de Lausanne,
Institute of Chemical Sciences and Engineering, 1015, Lausanne, Switzerland
- Department of Chemistry and Chemical Biology, Cornell
University, Ithaca, New York, 14853, USA
| | - Yimon Aye
- Ecole Polytechnique Fédérale de Lausanne,
Institute of Chemical Sciences and Engineering, 1015, Lausanne, Switzerland
- Department of Chemistry and Chemical Biology, Cornell
University, Ithaca, New York, 14853, USA
- Department of Biochemistry, Weill Cornell Medicine, New
York, New York, 10065, USA
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Hauck AK, Zhou T, Hahn W, Petegrosso R, Kuang R, Chen Y, Bernlohr DA. Obesity-induced protein carbonylation in murine adipose tissue regulates the DNA-binding domain of nuclear zinc finger proteins. J Biol Chem 2018; 293:13464-13476. [PMID: 30012885 DOI: 10.1074/jbc.ra118.003469] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2018] [Revised: 06/20/2018] [Indexed: 11/06/2022] Open
Abstract
In obesity-linked insulin resistance, oxidative stress in adipocytes leads to lipid peroxidation and subsequent carbonylation of proteins by diffusible lipid electrophiles. Reduction in oxidative stress attenuates protein carbonylation and insulin resistance, suggesting that lipid modification of proteins may play a role in metabolic disease, but the mechanisms remain incompletely understood. Herein, we show that in vivo, diet-induced obesity in mice surprisingly results in preferential carbonylation of nuclear proteins by 4-hydroxy-trans-2,3-nonenal (4-HNE) or 4-hydroxy-trans-2,3-hexenal (4-HHE). Proteomic and structural analyses revealed that residues in or around the sites of zinc coordination of zinc finger proteins, such as those containing the C2H2 or MATRIN, RING, C3H1, or N4-type DNA-binding domains, are particularly susceptible to carbonylation by lipid aldehydes. These observations strongly suggest that carbonylation functionally disrupts protein secondary structure supported by metal coordination. Analysis of one such target, the nuclear protein estrogen-related receptor γ (ERR-γ), showed that ERR-γ is modified by 4-HHE in the obese state. In vitro carbonylation decreased the DNA-binding capacity of ERR-γ and correlated with the obesity-linked down-regulation of many key genes promoting mitochondrial bioenergetics. Taken together, these findings reveal a novel mechanistic connection between oxidative stress and metabolic dysfunction arising from carbonylation of nuclear zinc finger proteins, such as the transcriptional regulator ERR-γ.
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Affiliation(s)
- Amy K Hauck
- From the Departments of Biochemistry, Molecular Biology, and Biophysics and
| | - Tong Zhou
- From the Departments of Biochemistry, Molecular Biology, and Biophysics and
| | - Wendy Hahn
- From the Departments of Biochemistry, Molecular Biology, and Biophysics and
| | - Raphael Petegrosso
- Computer Science and Engineering, University of Minnesota-Twin Cities, Minneapolis, Minnesota 55455
| | - Rui Kuang
- Computer Science and Engineering, University of Minnesota-Twin Cities, Minneapolis, Minnesota 55455
| | - Yue Chen
- From the Departments of Biochemistry, Molecular Biology, and Biophysics and
| | - David A Bernlohr
- From the Departments of Biochemistry, Molecular Biology, and Biophysics and
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Carreras NL, Martorell P, Chenoll E, Genovés S, Ramón D, Aleixandre A. Anti-obesity properties of the strain Bifidobacterium animalis subsp. lactis CECT 8145 in Zücker fatty rats. Benef Microbes 2018; 9:629-641. [DOI: 10.3920/bm2017.0141] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
We evaluated the effect of oral administration of Bifidobacterium animalis subsp. lactis CECT 8145 strain in Zücker fatty rats. The Zücker fatty rats were randomly divided into two groups (n=10 each) and administered either B. animalis subsp. lactis CECT 8145 (1010 cfu/day) suspended in skim milk, or skim milk alone (control group). Each treatment was administered in drinking bottles from week 5 until week 17 of age. A lean Zücker rat group (standard group) was included to provide normal values for the Zücker strain. This group was administered skim milk in the drinking bottle for the same experimental period as Zücker fatty rats. Body weight gain was greater in the fatty control group than in the fatty rats treated daily with B. animalis subsp. lactis CECT 8145. Furthermore, dry and liquid food intake significantly decreased in the treated Zücker fatty group and these rats also showed decreased plasma ghrelin levels as compared with the Zücker fatty control group. B. animalis subsp. lactis CECT 8145 intake also decreased plasma tumour necrosis factor-α (a proinflammatory cytokine) and plasma malondialdehyde (a biomarker of oxidative stress). Moreover, the ratio plasma total cholesterol/plasma cholesterol transported by high-density lipoproteins, considered as an index for cardiovascular disease, also significantly decreased in the Zücker fatty rats treated with B. animalis subsp. lactis CECT 8145. By contrast, this bacterial strain significantly increased plasma adiponectin (an insulin-sensitising adipokine), but did not produce significant effects on triglyceride levels or glucose metabolism biomarkers. Although further research is required to confirm B. animalis subsp. lactis CECT 8145 is an efficient anti-obesity treatment in humans, the results obtained in this study are promising and point to the health and anti-obesity properties of this bacterial strain.
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Affiliation(s)
- N. López Carreras
- Departamento de Farmacología, Facultad de Medicina, Universidad Complutense de Madrid, Avenida Complutense s/n, 28040 Madrid, Spain
| | - P. Martorell
- Department of Food Biotechnology; Biópolis S.L. Parc Científic Universitat De València, Edif. 2, C/Catedrático Agustín Escardino Benlloch, 9, 46980 Paterna, Spain
| | - E. Chenoll
- Department of Food Biotechnology; Biópolis S.L. Parc Científic Universitat De València, Edif. 2, C/Catedrático Agustín Escardino Benlloch, 9, 46980 Paterna, Spain
| | - S. Genovés
- Department of Food Biotechnology; Biópolis S.L. Parc Científic Universitat De València, Edif. 2, C/Catedrático Agustín Escardino Benlloch, 9, 46980 Paterna, Spain
| | - D. Ramón
- Department of Food Biotechnology; Biópolis S.L. Parc Científic Universitat De València, Edif. 2, C/Catedrático Agustín Escardino Benlloch, 9, 46980 Paterna, Spain
| | - A. Aleixandre
- Departamento de Farmacología, Facultad de Medicina, Universidad Complutense de Madrid, Avenida Complutense s/n, 28040 Madrid, Spain
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Liu KL, Kuo WC, Lin CY, Lii CK, Liu YL, Cheng YH, Tsai CW. Prevention of 4-hydroxynonenal-induced lipolytic activation by carnosic acid is related to the induction of glutathione S-transferase in 3T3-L1 adipocytes. Free Radic Biol Med 2018; 121:1-8. [PMID: 29698741 DOI: 10.1016/j.freeradbiomed.2018.04.567] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2017] [Revised: 04/12/2018] [Accepted: 04/21/2018] [Indexed: 02/07/2023]
Abstract
UNLABELLED Induction of 4-hydroxynonenal (4-HNE), a major lipid peroxidation aldehyde, is observed in patients with obesity and type 2 diabetes mellitus. The lipolytic response by 4-HNE has been linked to insulin resistance. In this study, we investigated the effects of carnosic acid (CA) on 4-HNE-induced lipolysis and the inhibition of β-oxidation in 3T3-L1 adipocytes. The results indicated that cells pretreated with CA reduced 4-HNE-mediated free fatty acid (FFA) release. Furthermore, CA reversed the inhibition of phosphorylation of Tyr632 of insulin receptor substrate-1 (IRS-1) and Akt and the phosphorylation of Ser307 of IRS-1. CA inhibited 4-HNE-induced phosphorylation of protein kinase A (PKA) and hormone-sensitive lipase (HSL), and reversed the suppression by 4-HNE of phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (p < 0.05). Pretreatment of cells with forskolin (a cAMP agonist) and compound C (an AMPK inhibitor) reversed these effects, respectively (p < 0.05). In human subcutaneous adipocytes, CA also attenuated 4-HNE-induced FFA release and the phosphorylation of PKA and HSL (p < 0.05). Moreover, CA increased the protein expression of glutathione S-transferase (GST) A and M. Pretreatment with ethacrynic acid, a GST inhibitor, prevented the 4-HNE-conjugated proteins suppression, the PKA and HSL phosphorylation reduction, and the FFA release inhibition by CA (p < 0.05). CONCLUSION The attenuation by CA of the lipolytic response by 4-HNE is likely related to the induction of GST, which in turn reduced 4-HNE-conjugated proteins and decreased the activation of the PKA/HSL pathway. The observed effects may explain how CA improves 4-HNE-induced insulin resistance.
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Affiliation(s)
- Kai-Li Liu
- Department of Nutrition, Chung Shan Medical University, Taichung, Taiwan; Department of Dietitian, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Wen-Chen Kuo
- Department of Nutrition, China Medical University, Taichung, Taiwan
| | - Chia-Yuan Lin
- Department of Nutrition, China Medical University, Taichung, Taiwan
| | - Chong-Kuei Lii
- Department of Nutrition, China Medical University, Taichung, Taiwan
| | - Yen-Lin Liu
- Department of Nutrition, China Medical University, Taichung, Taiwan
| | - Yun-Hsin Cheng
- Department of Nutrition, China Medical University, Taichung, Taiwan
| | - Chia-Wen Tsai
- Department of Nutrition, China Medical University, Taichung, Taiwan.
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