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Preciado-Ortiz ME, Martínez-López E, Pedraza-Chaverri J, Medina-Campos ON, Rodríguez-Echevarría R, Reyes-Pérez SD, Rivera-Valdés JJ. 10-Gingerol Increases Antioxidant Enzymes and Attenuates Lipopolysaccharide-Induced Inflammation by Modulating Adipokines in 3T3-L1 Adipocytes. Antioxidants (Basel) 2024; 13:1093. [PMID: 39334752 PMCID: PMC11429246 DOI: 10.3390/antiox13091093] [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: 07/12/2024] [Revised: 08/29/2024] [Accepted: 09/04/2024] [Indexed: 09/30/2024] Open
Abstract
BACKGROUND Obesity increases reactive oxygen species production and alters adipokines levels, resulting in a low-grade chronic inflammation state, which contributes to tissue metabolic dysfunction. 10-gingerol, a phenol present in ginger, has shown potential anti-obesogenic effects in vitro. However, the antioxidant and anti-inflammatory properties of 10-gingerol have not been approached. The aim of this study was to investigate the effects of 10-gingerol on antioxidant enzymes' expression and adipokine production in 3T3-L1 adipocytes in response to lipopolysaccharide (LPS)-induced inflammation. METHODS 10-gingerol antioxidant capacity was assessed through Oxygen Radical Absorbance Capacity (ORAC) , Ferric Reducing Antioxidant Power (FRAP), and radical scavenging activity of 2,2-diphenyl-2-picrylhydrazyl (DPPH) assays. 3T3-L1 cells were differentiated and stimulated with 100 ng/mL LPSs. Then, 15 µg/mL 10-gingerol was added for 48 h. The mRNA expression and protein abundance of antioxidant enzymes were evaluated by qPCR and Western blot, respectively. Adipokine levels were determined by ELISA. RESULTS 10-gingerol showed low FRAP and DPPH values but a moderate ORAC value. Moreover, 10-gingerol increased Gpx1 and Sod1 but downregulated Cat expression. Additionally, 10-gingerol significantly increased CAT and GPx1 levels but not SOD-1. Finally, adiponectin and leptin concentrations were increased while resistin and tumor necrosis factor alpha (TNFα) were decreased by 10-gingerol. CONCLUSIONS 10-gingerol presented antioxidant potential by increasing antioxidant enzymes and attenuated LPS-induced inflammation by modulating adipokines in 3T3-L1 adipocytes.
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Affiliation(s)
- María Elizabeth Preciado-Ortiz
- Doctorado en Ciencias de la Nutrición Traslacional, Departamento de Clínicas de la Reproducción Humana, Crecimiento y Desarrollo Infantil, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico;
- Instituto de Nutrigenética y Nutrigenómica Traslacional, Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico; (R.R.-E.); (S.D.R.-P.)
| | - Erika Martínez-López
- Instituto de Nutrigenética y Nutrigenómica Traslacional, Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico; (R.R.-E.); (S.D.R.-P.)
| | - José Pedraza-Chaverri
- Departamento de Biología, Facultad de Química, Universidad Nacional Autónoma de México, Ciudad de México 04510, Mexico; (J.P.-C.); (O.N.M.-C.)
| | - Omar Noel Medina-Campos
- Departamento de Biología, Facultad de Química, Universidad Nacional Autónoma de México, Ciudad de México 04510, Mexico; (J.P.-C.); (O.N.M.-C.)
| | - Roberto Rodríguez-Echevarría
- Instituto de Nutrigenética y Nutrigenómica Traslacional, Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico; (R.R.-E.); (S.D.R.-P.)
| | - Samantha Desireé Reyes-Pérez
- Instituto de Nutrigenética y Nutrigenómica Traslacional, Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico; (R.R.-E.); (S.D.R.-P.)
- Doctorado en Ciencias en Biología Molecular en Medicina, Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico
| | - Juan José Rivera-Valdés
- Instituto de Nutrigenética y Nutrigenómica Traslacional, Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico; (R.R.-E.); (S.D.R.-P.)
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V P V, Rajamanikandan S, Perumal MK. Morin inhibits the activity of pancreatic lipase and adipogenesis. Eur J Pharmacol 2024; 977:176705. [PMID: 38830457 DOI: 10.1016/j.ejphar.2024.176705] [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: 02/19/2024] [Revised: 05/10/2024] [Accepted: 05/31/2024] [Indexed: 06/05/2024]
Abstract
Obesity is a major health issue that contributes significantly to increased mortality and morbidity worldwide. Obesity is caused by uncontrolled adipogenesis and lipogenesis, leading to several metabolism-associated problems. Pancreatic lipase, an enzyme that breaks down dietary lipids, is a prominent target for obesity. Orlistat, a known inhibitor of pancreatic lipase, is commonly employed for the management of obesity. However, its side effects, such as diarrhoea, nausea and bladder pain, urge to look out for safer alternatives. Morin is a pentahydroxyflavone, exerts a broad spectrum of pharmacological effects including antioxidant, anti-inflammatory, lipid lowering, anti-diabetic, anti-fibrotic, anti-cancer, etc. This study investigated the effect of morin on pancreatic lipase activity, in vitro and in vivo adipogenesis. Molecular docking and simulation studies showed morin to have a higher binding affinity towards pancreatic lipase compared with orlistat, which also inhibited its activity in vitro. Morin also reduced lipid droplet accretion and downregulated the expression of adipogenic and lipogenic genes. The acute oral toxicity of morin was determined in C57BL/6 mice, where morin did not show toxicity up to 2000 mg/kg body weight dose. Oral administration of morin to high fat diet fed mice reduced body weight, glucose and insulin levels. Also, the histopathological examination revealed reduction in adipocyte size and decreased mRNA expression of adipogenesis markers in white adipose tissue of morin administered group compared to high fat diet group. Overall, the results suggested morin inhibited pancreatic lipase activity, adipogenesis and further studies are warranted to explore its therapeutic potential for obesity.
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Affiliation(s)
- Venkateish V P
- Department of Biochemistry, CSIR-Central Food Technological Research Institute, Mysore, 570020, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Sundarraj Rajamanikandan
- Centre for Drug Discovery, Department of Biochemistry, Karpagam Academy of Higher Education, Coimbatore, 641021, Tamil Nadu, India
| | - Madan Kumar Perumal
- Department of Biochemistry, CSIR-Central Food Technological Research Institute, Mysore, 570020, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
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Yang MH, Jung YY, Um J, Sethi G, Ahn KS. Brassinin alleviates cancer cachexia by suppressing diverse inflammatory mechanisms in mice. MedComm (Beijing) 2024; 5:e558. [PMID: 38807976 PMCID: PMC11130637 DOI: 10.1002/mco2.558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 04/02/2024] [Accepted: 04/06/2024] [Indexed: 05/30/2024] Open
Abstract
Cancer cachexia is a multifactorial condition that contributes to the death of about 20% of cancer patients. It has the potential to cause weight loss, reduction in muscle mass, and loss of fat tissue, significantly lowering the quality of life. Currently, there are no approved drugs for cancer cachexia. Here, we have explored the possible impact of brassinin (BSN) on cancer cachexia under in vitro and in vivo settings. After differentiation, C2C12 and 3T3-L1 cells were incubated with colorectal carcinoma cells conditioned media or BSN. For preclinical studies, mice were injected with HT-29 cells followed by intraperitoneal administration of BSN, and muscle and adipose tissues were evaluated by Western blotting and hematoxylin and eosin staining. BSN effectively suppressed muscle atrophy by down-regulating the levels of Muscle RING-finger protein-1 and Atrogin-1, while also increasing the expression of myosin heavy chain in cachexia-induced-C2C12 myotubes. The induction of adipogenesis by BSN prevented adipocyte atrophy in cachexia-induced 3T3-L1 adipocytes. We also noted that BSN disrupted the interaction between COX-2 and signaling transducer and activator of transcription 3 (STAT3) promoter, leading to down-regulation of STAT3 activation. Moreover, it was found that BSN inhibited weight loss in mice and demonstrated anti-cachexic effects. Overall, our observations indicate that BSN can attenuate cancer cachexia through diverse mechanisms.
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Affiliation(s)
- Min Hee Yang
- Department of Science in Korean MedicineKyung Hee UniversitySeoulSouth Korea
| | - Young Yun Jung
- Department of Science in Korean MedicineKyung Hee UniversitySeoulSouth Korea
| | - Jae‐Young Um
- Department of Science in Korean MedicineKyung Hee UniversitySeoulSouth Korea
| | - Gautam Sethi
- Department of Pharmacology and NUS Centre for Cancer Research (N2CR)Yong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore
| | - Kwang Seok Ahn
- Department of Science in Korean MedicineKyung Hee UniversitySeoulSouth Korea
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Rial SA, You Z, Vivoli A, Sean D, Al-Khoury A, Lavoie G, Civelek M, Martinez-Sanchez A, Roux PP, Durcan TM, Lim GE. 14-3-3ζ regulates adipogenesis by modulating chromatin accessibility during the early stages of adipocyte differentiation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.03.18.585495. [PMID: 38562727 PMCID: PMC10983991 DOI: 10.1101/2024.03.18.585495] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/04/2024]
Abstract
We previously established the scaffold protein 14-3-3ζ as a critical regulator of adipogenesis and adiposity, but the temporal specificity of its action during adipocyte differentiation remains unclear. To decipher if 14-3-3ζ exerts its regulatory functions on mature adipocytes or on adipose precursor cells (APCs), we generated Adipoq14-3-3ζKO and Pdgfra14-3-3ζKO mouse models. Our findings revealed a pivotal role for 14-3-3ζ in APC differentiation in a sex-dependent manner, whereby male and female Pdgfra14-3-3ζKO mice display impaired or potentiated weight gain, respectively, as well as fat mass. To better understand how 14-3-3ζ regulates the adipogenic transcriptional program in APCs, CRISPR-Cas9 was used to generate TAP-tagged 14-3-3ζ-expressing 3T3-L1 preadipocytes. Using these cells, we examined if the 14-3-3ζ nuclear interactome is enriched with adipogenic regulators during differentiation. Regulators of chromatin remodeling, such as DNMT1 and HDAC1, were enriched in the nuclear interactome of 14-3-3ζ, and their activities were impacted upon 14-3-3ζ depletion. The interactions between 14-3-3ζ and chromatin-modifying enzymes suggested that 14-3-3ζ may control chromatin remodeling during adipogenesis, and this was confirmed by ATAC-seq, which revealed that 14-3-3ζ depletion impacted the accessibility of up to 1,244 chromatin regions corresponding in part to adipogenic genes, promoters, and enhancers during the initial stages of adipogenesis. Moreover, 14-3-3ζ-dependent chromatin accessibility was found to directly correlate with the expression of key adipogenic genes. Altogether, our study establishes 14-3-3ζ as a crucial epigenetic regulator of adipogenesis and highlights the usefulness of deciphering the nuclear 14-3-3ζ interactome to identify novel pro-adipogenic factors and pathways.
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Affiliation(s)
- SA Rial
- Department of Medicine, Université de Montréal, Montreal, QC, Canada
- Cardiometabolic Axis, Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montreal, QC, Canada
| | - Z You
- The Neuro’s Early Drug Discovery Unit (EDDU), McGill University, 3801 University Street, Montreal, QC, H3A 2B4, Canada
| | - A Vivoli
- Department of Medicine, Université de Montréal, Montreal, QC, Canada
- Cardiometabolic Axis, Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montreal, QC, Canada
| | - D Sean
- Department of Medicine, Université de Montréal, Montreal, QC, Canada
- Cardiometabolic Axis, Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montreal, QC, Canada
| | - Amal Al-Khoury
- Department of Medicine, Université de Montréal, Montreal, QC, Canada
- Cardiometabolic Axis, Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montreal, QC, Canada
| | - G Lavoie
- Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montréal, Québec, Canada
- Department of Pathology and Cell Biology, Faculty of Medicine, Université de Montréal, Montréal, Québec, Canada
| | - M Civelek
- Department of Biomedical Engineering, University of Virginia, Charlottesville, United States
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908
| | - A Martinez-Sanchez
- Section of Cell Biology and Functional Genomics, Department of Metabolism, Digestion and Reproduction, Imperial College London, Hammersmith Hospital, London, UK
| | - Roux PP
- Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montréal, Québec, Canada
- Department of Pathology and Cell Biology, Faculty of Medicine, Université de Montréal, Montréal, Québec, Canada
| | - TM Durcan
- The Neuro’s Early Drug Discovery Unit (EDDU), McGill University, 3801 University Street, Montreal, QC, H3A 2B4, Canada
| | - GE Lim
- Department of Medicine, Université de Montréal, Montreal, QC, Canada
- Cardiometabolic Axis, Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Montreal, QC, Canada
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Yin Y, Gong S, Han M, Wang J, Shi H, Jiang X, Guo L, Duan Y, Guo Q, Chen Q, Li F. Leucine regulates lipid metabolism in adipose tissue through adipokine-mTOR-SIRT1 signaling pathway and bile acid-microbe axis in a finishing pig model. ANIMAL NUTRITION (ZHONGGUO XU MU SHOU YI XUE HUI) 2024; 16:158-173. [PMID: 38357569 PMCID: PMC10864217 DOI: 10.1016/j.aninu.2023.10.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 10/07/2023] [Accepted: 10/12/2023] [Indexed: 02/16/2024]
Abstract
This study was conducted to explore the regulatory mechanism of leucine (Leu) on lipid metabolism of finishing pigs. Twenty-four Duroc × Landrace × Large cross pigs with an average body weight of 68.33 ± 0.97 kg were randomly allocated into 3 treatment groups with 8 replicates per group (1 pig per replicate). The dietary treatments were as follows: control group (CON), 0.25% Leu group and 0.50% Leu group. The experimental period was 42 d. The results showed as follows. (1) Compared with the CON, 0.25% and 0.50% Leu increased (P < 0.01) the average daily gain (ADG), while the average backfat thickness (ABT) and the ratio of feed intake to body weight gain (F:G ratio) were decreased (P < 0.05). (2) In the 0.25% Leu group, the relative mRNA expression levels of sterol regulatory element binding protein-1c (SREBP1c), recombinant fatty acid transport protein 1 (FATP1), chemerin and peroxisome proliferator-activated receptor γ (PPARγ) were decreased but the level of fatty acid binding protein 4 (FABP4) and fatty acid translocase (FAT/CD36) were increased in backfat tissue. In the 0.25% Leu group, the protein levels of p-Rictor, p-Raptor, p-eIF4E-binding protein 1 (p-4EBP1), p-silent mating type information regulator 2 homolog 1 (p-SIRT1) and acetylation ribosome s6 protein kinase 1 (Ac-S6K1) were increased (P < 0.05). (3) Compared to the CON, the diversity of gut microbiota in the 0.25% Leu group was increased. Principal component analysis showed that the relative abundance of Bacteroidetes, Lactobacillus and Desulfovibrio was higher in the 0.25% Leu group than the CON, but the relative abundance of Firmicutes, Treponema and Shigella was lower than in the CON (P < 0.05). (4) Four different metabolites were screened out from the serum of finishing pigs including allolithocholic acid (alloLCA), isolithocholic acid (isoLCA), ursodeoxycholic acid (UDCA) and hyodeoxycholic acid (HDCA), which correlate to various degrees with the above microorganisms. In conclusion, Leu could promote adipose tissue lipolysis of finishing pigs through the mTOR-SIRT1 signaling pathway, and S6K1 is acetylated at the same time, and the interaction between gut microbiota and bile acid metabolism is also involved.
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Affiliation(s)
- Yunju Yin
- Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, Hunan Provincial Engineering Research Center for Healthy Livestock and Poultry Production, Changsha 410125, China
- College of Animal Science and Technology, Hunan Agricultural University, Changsha 410128, China
| | - Saiming Gong
- Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, Hunan Provincial Engineering Research Center for Healthy Livestock and Poultry Production, Changsha 410125, China
- College of Animal Science and Technology, Hunan Agricultural University, Changsha 410128, China
| | - Mengmeng Han
- Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, Hunan Provincial Engineering Research Center for Healthy Livestock and Poultry Production, Changsha 410125, China
- College of Modern Agricultural Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Jingzun Wang
- College of Life Science and Engineering, Northwest Minzu University, Lanzhou 730124, China
| | - Hanjing Shi
- Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, Hunan Provincial Engineering Research Center for Healthy Livestock and Poultry Production, Changsha 410125, China
- College of Life Sciences, Hunan Normal University, Changsha 410128, China
| | - Xianji Jiang
- Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, Hunan Provincial Engineering Research Center for Healthy Livestock and Poultry Production, Changsha 410125, China
- College of Animal Science and Technology, Hunan Agricultural University, Changsha 410128, China
| | - Liu Guo
- Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, Hunan Provincial Engineering Research Center for Healthy Livestock and Poultry Production, Changsha 410125, China
- College of Modern Agricultural Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yehui Duan
- Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, Hunan Provincial Engineering Research Center for Healthy Livestock and Poultry Production, Changsha 410125, China
| | - Qiuping Guo
- Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, Hunan Provincial Engineering Research Center for Healthy Livestock and Poultry Production, Changsha 410125, China
| | - Qinghua Chen
- College of Animal Science and Technology, Hunan Agricultural University, Changsha 410128, China
| | - Fengna Li
- Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, Hunan Provincial Engineering Research Center for Healthy Livestock and Poultry Production, Changsha 410125, China
- College of Modern Agricultural Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
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Tran TT, Huang WJ, Lin H, Chen HH. New Synthesized Activating Transcription Factor 3 Inducer SW20.1 Suppresses Resistin-Induced Metabolic Syndrome. Biomedicines 2023; 11:1509. [PMID: 37371606 DOI: 10.3390/biomedicines11061509] [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: 03/31/2023] [Revised: 05/15/2023] [Accepted: 05/18/2023] [Indexed: 06/29/2023] Open
Abstract
Obesity is an emerging concern globally with increasing prevalence. Obesity is associated with many diseases, such as cardiovascular disease, dyslipidemia, and cancer. Thus, effective new antiobesity drugs should be urgently developed. We synthesized SW20.1, a compound that induces activating transcription factor 3 (ATF3) expression. The results of Oil Red O staining and quantitative real-time polymerase chain reaction revealed that SW20.1 was more effective in reducing lipid accumulation in 3T3-L1 preadipocytes than the previously synthesized ST32db, and that it inhibited the expression of the genes involved in adipogenesis and lipogenesis. A chromatin immunoprecipitation assay indicated that SW20.1 inhibited adipogenesis and lipogenesis by binding to the upstream promoter region of resistin at two sites (-2861/-2854 and -241/-234). In mice, the intraperitoneal administration of SW20.1 reduced body weight, white adipocyte weight in different regions, serum cholesterol levels, adipogenesis-related gene expression, hepatic steatosis, and serum resistin levels. Overall, SW20.1 exerts antiobesity effects by inhibiting resistin through the ATF3 pathway. Our study results indicate that SW20.1 is a promising therapeutic drug for diet-induced obesity.
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Affiliation(s)
- Tu T Tran
- International Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
- Department of Internal Medicine, Thai Nguyen University of Medicine and Pharmacy, Thai Nguyen 241-17, Vietnam
| | - Wei-Jan Huang
- School of Pharmacy, Taipei Medical University, Taipei 110, Taiwan
| | - Heng Lin
- Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
| | - Hsi-Hsien Chen
- TMU Research Center of Urology and Kidney, Taipei Medical University, Taipei 110, Taiwan
- Division of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
- Division of Nephrology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei 110, Taiwan
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Inhibitory Effect of Bacterial Lysates Extracted from Pediococcus acidilactici on the Differentiation of 3T3-L1 Pre-Adipocytes. Int J Mol Sci 2022; 23:ijms231911614. [PMID: 36232912 PMCID: PMC9570163 DOI: 10.3390/ijms231911614] [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: 08/18/2022] [Revised: 09/22/2022] [Accepted: 09/28/2022] [Indexed: 11/17/2022] Open
Abstract
Postbiotics, including bacterial lysates, are considered alternatives to probiotics. The aim of the current study was to investigate the effect of bacterial lysates (BLs) extracted from Pediococcus acidilactici K10 (K10 BL) and P. acidilactici HW01 (HW01 BL) on the differentiation of 3T3-L1 pre-adipocytes. Both K10 and HW01 BLs significantly reduced the accumulation of lipid droplets and the amounts of cellular glycerides in 3T3-L1 cells (p < 0.05). However, another postbiotic molecule, peptidoglycan of P. acidilactici K10 and P. acidilactici HW01, moderately inhibited the accumulation of lipid droplets, whereas heat-killed P. acidilactici did not effectively inhibit the lipid accumulation. The mRNA and protein levels of the transcription factors, peroxisome proliferator-activated receptor γ and CCAAT/enhancer-binding protein α, responsible for the differentiation of 3T3-L1 cells, were significantly inhibited by K10 BL and HW01 BL (p < 0.05). Both K10 and HW01 BLs decreased adipocyte-related molecules, adipocyte fatty acid-binding protein and lipoprotein lipase, at the mRNA and protein levels. Furthermore, both K10 and HW01 BLs also downregulated the mRNA expression of leptin, but not resistin. Taken together, these results suggest that P. acidilactici BLs mediate anti-adipogenic effects by inhibiting adipogenic-related transcription factors and their target molecules.
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Chen X, Min S, Chen C, Lin X, Wang D, Jiang G. Influence of RETN, IL‐1, and IL‐6 gene polymorphisms on the risk of acne vulgaris in the Chinese population. J Cosmet Dermatol 2022; 21:4965-4973. [PMID: 35279931 DOI: 10.1111/jocd.14911] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Revised: 02/16/2022] [Accepted: 02/22/2022] [Indexed: 11/30/2022]
Affiliation(s)
- Xi Chen
- Department of Dermatology Affiliated Hospital of Xuzhou Medical University Xuzhou 221002 China
- Department of Dermatology Huzhou First People's Hospital
| | - Shuhui Min
- Department of Dermatology Affiliated Hospital of Xuzhou Medical University Xuzhou 221002 China
| | - Can Chen
- Department of Tumor Biological Treatment The Third Affiliated Hospital of Soochow University
| | - Xiao Lin
- Department of Dermatology Affiliated Hospital of Xuzhou Medical University Xuzhou 221002 China
| | - Danfeng Wang
- Department of Dermatology Affiliated Hospital of Xuzhou Medical University Xuzhou 221002 China
| | - Guan Jiang
- Department of Dermatology Affiliated Hospital of Xuzhou Medical University Xuzhou 221002 China
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Iontophoresis of Biological Macromolecular Drugs. Pharmaceutics 2022; 14:pharmaceutics14030525. [PMID: 35335900 PMCID: PMC8953920 DOI: 10.3390/pharmaceutics14030525] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 02/22/2022] [Accepted: 02/24/2022] [Indexed: 12/11/2022] Open
Abstract
Over the last few decades, biological macromolecular drugs (e.g., peptides, proteins, and nucleic acids) have become a significant therapeutic modality for the treatment of various diseases. These drugs are considered superior to small-molecule drugs because of their high specificity and favorable safety profiles. However, such drugs are limited by their low oral bioavailability and short half-lives. Biological macromolecular drugs are typically administrated via invasive methods, e.g., intravenous or subcutaneous injections, which can be painful and induce needle phobia. Noninvasive transdermal delivery is an alternative administration route for the local and systemic delivery of biological macromolecular drugs. However, a challenge with the noninvasive transdermal delivery of biological macromolecular drugs is the outermost layer of the skin, known as the stratum corneum, which is a physical barrier that restricts the entry of extraneous macromolecules. Iontophoresis (IP) relies on the application of a low level of electricity for transdermal drug delivery, in order to facilitate the skin permeation of hydrophilic and charged molecules. The IP of several biological macromolecular drugs has recently been investigated. Herein, we review the IP-mediated noninvasive transdermal delivery of biological macromolecular drugs, their routes of skin permeation, their underlying mechanisms, and their advance applications.
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Hasan M, Fukuta T, Inoue S, Mori H, Kagawa M, Kogure K. Iontophoresis-mediated direct delivery of nucleic acid therapeutics, without use of carriers, to internal organs via non-blood circulatory pathways. J Control Release 2022; 343:392-399. [DOI: 10.1016/j.jconrel.2022.01.052] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Revised: 12/11/2021] [Accepted: 01/31/2022] [Indexed: 12/12/2022]
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Wu C, Fang S, Zhang H, Li X, Du Y, Zhang Y, Lin X, Wang L, Ma X, Xue Y, Guan M. Long noncoding RNA XIST regulates brown preadipocytes differentiation and combats high-fat diet induced obesity by targeting C/EBPα. Mol Med 2022; 28:6. [PMID: 35062859 PMCID: PMC8781062 DOI: 10.1186/s10020-022-00434-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Accepted: 01/05/2022] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND Activation of brown adipose tissue (BAT) increases energy expenditure, which makes it an attractive therapeutic strategy for obesity. LncRNAs play an important role in adipocyte differentiation and regulation. Here we assessed the effect of lncRNA XIST on brown preadipocytes differentiation and metabolic regulation. METHODS XIST expression levels were detected in human perirenal (peri-N) and subcutaneous adipose tissues (sub-Q), brown preadipocytes and 3T3-L1 preadipocytes. XIST overexpression and knockdown experiments were performed in brown preadipocytes. XIST overexpression mouse model was established by plasmid injection through tail vein. RESULTS In human adipose tissues, XIST expression was significantly higher in female than in male individuals. In vitro, XIST expression was significantly up-regulated during brown adipocyte differentiation. XIST knockdown inhibited differentiation of brown preadipocytes, while overexpression of XIST promotes brown preadipocytes to fully differentiation. RNA Binding Protein Immunoprecipitation (RIP) experiment revealed that XIST could directly bind to C/EBPα. In vivo, XIST overexpression prevents high-fat diet induced obesity and improves metabolic dysorder in male mice. CONCLUSION Our results suggest that XIST combats obesity through BAT activation at least partly by combination with transcription factor C/EBPα.
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Affiliation(s)
- Chunyan Wu
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.,Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Southern Medical University, Guangzhou, 510515, China
| | - Shu Fang
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Huijian Zhang
- Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Xiaoqiang Li
- Department of Plastic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Yuejun Du
- Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Yudan Zhang
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Xiaochun Lin
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Ling Wang
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Xiaoqin Ma
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Yaoming Xue
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Meiping Guan
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
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12
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Mandujano-Lázaro G, Galaviz-Hernández C, Reyes-López CA, Almanza-Pérez JC, Giacoman-Martínez A, López-Camarillo C, Huang F, Marchat LA. A Short S-Equol Exposure Has a Long-Term Inhibitory Effect on Adipogenesis in Mouse 3T3-L1 Cells. APPLIED SCIENCES 2021; 11:9657. [DOI: 10.3390/app11209657] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/10/2025]
Abstract
In the search for new drugs against obesity, the chronic disease that threatens human health worldwide, several works have focused on the study of estrogen homologs because of the role of estrogen receptors (ERs) in adipocyte growth. The isoflavone equol, an ERβ agonist, has shown beneficial metabolic effects in in vivo and in vitro assays; however, additional studies are required to better characterize its potential for body weight control. Here, we showed that the treatment of 3T3-L1 cells with 10 μM of S-equol for the first three days of the adipocyte differentiation protocol was able to prevent cells becoming semi-rounded and having a lipid droplet formation until the seventh day of culture; moreover, lipid accumulation was reduced by about 50%. Congruently, S-equol induced a reduction in mRNA expression of the adipogenic markers C/EBPα and PPARγ, and adipokines secretion, mainly Adiponectin, Leptin, Resistin, and MCP-1, while the release of PAI-1 was augmented. Moreover, it also reduced the expression of ERα and attenuated the subexpression of ERβ associated with adipogenesis. Altogether, our data suggested that S-equol binding to ERβ affects the transcriptional program that regulates adipogenesis and alters adipocyte functions. Future efforts will focus on studying the impact of S-equol on ER signaling pathways.
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Affiliation(s)
- Gilberto Mandujano-Lázaro
- Laboratorio 2 de Biomedicina Molecular, ENMH, Instituto Politécnico Nacional, Ciudad de México 07320, Mexico
| | | | - César A. Reyes-López
- Laboratorio de Bioquímica Estructural, ENMH, Instituto Politécnico Nacional, Ciudad de México 07320, Mexico
| | - Julio C. Almanza-Pérez
- Laboratorio de Farmacología, Departamento de Ciencias de la Salud, División de Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana-Iztapalapa, Ciudad de México 09340, Mexico
| | - Abraham Giacoman-Martínez
- Laboratorio de Farmacología, Departamento de Ciencias de la Salud, División de Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana-Iztapalapa, Ciudad de México 09340, Mexico
- Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados del IPN, Sede Sur, Ciudad de México 14330, Mexico
| | - César López-Camarillo
- Posgrado en Ciencias Genómicas, Universidad Autónoma de la Ciudad de México, Ciudad de México 03100, Mexico
| | - Fengyang Huang
- Laboratorio de Farmacología y Toxicología, Hospital Infantil de México Federico Gómez, Ciudad de México 06720, Mexico
| | - Laurence A. Marchat
- Laboratorio 2 de Biomedicina Molecular, ENMH, Instituto Politécnico Nacional, Ciudad de México 07320, Mexico
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Hyun IK, Lee JS, Yoon JW, Kang SS. Skimmed milk fermented by lactic acid bacteria inhibits adipogenesis in 3T3-L1 pre-adipocytes by downregulating PPARγ via TNF-α induction in vitro. Food Funct 2021; 12:8605-8614. [PMID: 34342323 DOI: 10.1039/d1fo00076d] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
The murine 3T3-L1 pre-adipocyte cell line is widely used as an in vitro model for adipogenesis because of its similarities to primary fat cells. The aim of this study was to investigate the intracellular mechanisms by which skimmed milk fermented by two lactic acid bacteria (LAB), Enterococcus faecalis and Lactobacillus plantarum, inhibited the differentiation of 3T3-L1 pre-adipocytes. Skimmed milk fermented by both LAB, but not non-fermented skimmed milk, significantly reduced the accumulation of lipid droplets and cellular triglycerides in a concentration-dependent manner. The mRNA and protein levels of peroxisome proliferator-activated receptor γ (PPARγ) were markedly inhibited in the presence of skimmed milk fermented by both LAB. Furthermore, the skimmed milk fermented by both LAB decreased the mRNA and protein expressions of PPARγ-targeting genes, lipoprotein lipase and adipocyte fatty acid-binding protein. Under the same circumstances, resistin mRNA expression was downregulated, but not leptin mRNA expression. In contrast, skimmed milk fermented by both LAB significantly upregulated tumor necrosis factor-α (TNF-α). These results suggest that LAB-fermented skimmed milk inhibits adipogenesis by inhibiting a master transcription factor PPARγ via the upregulation of the proinflammatory cytokine TNF-α in 3T3-L1 cells.
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Affiliation(s)
- In Kyung Hyun
- Department of Food Science and Biotechnology, College of Life Science and Biotechnology, Dongguk University-Seoul, Goyang 10326, Republic of Korea.
| | - Ji Soo Lee
- Department of Food Science and Biotechnology, College of Life Science and Biotechnology, Dongguk University-Seoul, Goyang 10326, Republic of Korea.
| | - Ji-Won Yoon
- Department of Food Science and Biotechnology, College of Life Science and Biotechnology, Dongguk University-Seoul, Goyang 10326, Republic of Korea.
| | - Seok-Seong Kang
- Department of Food Science and Biotechnology, College of Life Science and Biotechnology, Dongguk University-Seoul, Goyang 10326, Republic of Korea.
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A Novel Role of Bergamottin in Attenuating Cancer Associated Cachexia by Diverse Molecular Mechanisms. Cancers (Basel) 2021; 13:cancers13061347. [PMID: 33802674 PMCID: PMC8002497 DOI: 10.3390/cancers13061347] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Accepted: 03/13/2021] [Indexed: 11/16/2022] Open
Abstract
Simple Summary Cachexia has been generally associated with cancer causing skeletal muscle atrophy, adipose tissue atrophy, weight loss, anorexia, asthenia, and anemia, which can significantly reduce the quality of life. Our aim was to evaluate the potential effects of bergamottin on cancer-cachexia-induced muscle and fat loss. We observed a decrease in the levels of the muscle atrophy factors MuRF-1 and Atrogin-1 and increases in C/EBPα and PPARγ expression levels by bergamottin under in vitro settings. The in vivo effect of bergamottin on the inhibition of weight loss in mice and its potential inhibitory effects on cancer-induced cachexia were confirmed through analysis using tissue samples from a pancreatic cancer mouse model. Abstract Purpose: The potential effects of bergamotiin (BGM) on the suppression of cancer cachexia was evaluated under in vitro and in vivo conditions to investigate its possible inhibitory effects on the muscle and fat loss. Method: The differentiated C2C12 and 3T3L1 cells were treated with BGM after the induction of cancer-cachexia with pancreatic cancer conditioned media (CM). The expression levels of the various molecules involved in the differentiation and loss of muscle and fat (MuRF-1, Atrogin-1, C/EBPα, and PPARγ) were analyzed by Western blot and oil red O staining. For in vivo experiment, MIA PaCa-2 cells were injected into the mice (n = 6), and then BGM (1 mg/kg) was intraperitoneally administered to analyze muscle and adipose tissue by Hematoxylin and Eosin staining and Western blot. Result: BGM displayed a significant effect on the inhibition of muscle and fat catabolism under both in vitro and in vivo conditions. The results of the in vivo experiment revealed a remarkable suppressive effect of BGM on the weight loss in mice. Conclusions: The potential effects of BGM on the inhibition of muscle and fat catabolism in vitro and in vivo were thus confirmed. Based on the results, the impact of BGM on cancer cachexia could be possibly analyzed in the future clinical studies.
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15
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Farahani H, Mahmoudi T, Asadi A, Nobakht H, Dabiri R, Hamta A. Insulin Resistance and Colorectal Cancer Risk: the Role of Elevated Plasma Resistin Levels. J Gastrointest Cancer 2021; 51:478-483. [PMID: 31168777 DOI: 10.1007/s12029-019-00260-7] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
PURPOSE Given the important role of resistin in insulin resistance (IR) and obesity, as well as the associations between both IR and obesity and increased risk of colorectal cancer (CRC), we investigated whether plasma resistin levels were associated with CRC risk. Furthermore, the possible correlations between resistin and insulin, IR, and obesity in patients with CRC and controls were explored. METHODS This study was conducted as a case-control study and 170 subjects, including 88 controls and 82 cases with CRC, were enrolled and their plasma levels of glucoe, insulin, and resistin were measured using glucose oxidase or ELISA methods. Moreover, IR was calculated according to HOMA-IR index. RESULTS The cases with CRC had a higher HOMA-IR than the controls (1.8 ± 0.4 versus 1.4 ± 0.3, P < 0.001). Additionally, after the stratification of the cases with CRC by tumor site, higher levels of resistin and insulin, and a higher HOMA-IR in the cases with rectal cancer than in the controls were observed (resistin 5.9 ± 1.2 versus 5.4 ± 1.3, P = 0.043; insulin 5.9 ± 1.2 versus 5.4 ± 1.3, P = 0.039; HOMA- IR 1.9 ± 0.4 versus 1.3 ± 0.3, P < 0.001). Furthermore, resistin was positively correlated with insulin in the controls (r = 0.737, P < 0.001), the cases with CRC (r = 0.881, P < 0.001), the cases with colon cancer (r = 0.811, P < 0.001), and the cases with rectal cancer (r = 0.990, P < 0.001). All these differences remained significant after adjustment for confounding factors. CONCLUSIONS The findings of the present study reinforce the hypothesis that higher plasma levels of resistin in connection with insulin resistance play a role in susceptibility to colorectal, notably rectal, cancer. Nevertheless, further studies with bigger sample sizes are required to validate these findings.
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Affiliation(s)
- Hamid Farahani
- Department of Physiology, School of Medicine, Qom University of Medical Sciences, Alqadir Boulevard, 3736175513, Qom, Iran.
| | - Touraj Mahmoudi
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Asadollah Asadi
- Department of Biology, Faculty of Science, University of Mohaghegh Ardabili, Ardabil, Iran
| | - Hossein Nobakht
- Internal Medicine Department, Semnan University of Medical Sciences, Semnan, Iran
| | - Reza Dabiri
- Internal Medicine Department, Semnan University of Medical Sciences, Semnan, Iran
| | - Amir Hamta
- Department of Social Medicine, School of Medicine, Qom University of Medical Sciences, Qom, Iran
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16
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Shen L, Zhu Y, Xiao J, Qian B, Jiang T, Deng J, Peng G, Yu S, Cao S, Zuo Z, Ma X, Zhong Z, Ren Z, Wang Y, Zhou Z, Liu H, Zong X, Hu Y. Relationships between placental adiponectin, leptin, visfatin and resistin and birthweight in cattle. Reprod Fertil Dev 2021; 32:402-408. [PMID: 31739842 DOI: 10.1071/rd18247] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Accepted: 07/01/2019] [Indexed: 01/05/2023] Open
Abstract
Adipokines can affect intrauterine development while calf birthweight (CBW) is a breeding standard of calves, which reflects the status of fetal intrauterine development. To explore the correlation between placental adipokines and CBW, 54 healthy Chinese Holstein cows were used in the present study. The cows were grouped according to the CBW of their calves. Placentas were collected immediately after delivery and enzyme-linked immunosorbent assay and reverse transcription-polymerase chain reaction were used to detect the placental expression levels of adiponectin, leptin, visfatin and resistin. Our results show that the mRNA transcription and blood placental content of adiponectin, leptin, visfatin and resistin increased with increasing CBW. The analysis showed that the mRNA transcription levels of placental adiponectin, leptin and resistin were positively correlated with CBW. The mRNA and protein expression levels of adiponectin, leptin and visfatin between the three groups were significantly correlated. Placental resistin mRNA levels correlated positively with adiponectin mRNA, but not leptin or visfatin. The protein expression levels of resistin were significantly positively correlated with those of adiponectin, leptin and visfatin. These results suggest that placental adipokines play important roles in regulating calf intrauterine growth.
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Affiliation(s)
- Liuhong Shen
- Sichuan Agricultural University, Chengdu Campus, The Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Chengdu, Sichuan, 611130, China
| | - Yingkun Zhu
- Sichuan Agricultural University, Chengdu Campus, The Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Chengdu, Sichuan, 611130, China
| | - Jinbang Xiao
- Sichuan Agricultural University, Chengdu Campus, The Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Chengdu, Sichuan, 611130, China
| | - Bolin Qian
- Sichuan Agricultural University, Chengdu Campus, The Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Chengdu, Sichuan, 611130, China
| | - Tao Jiang
- Sichuan Agricultural University, Chengdu Campus, The Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Chengdu, Sichuan, 611130, China
| | - Junliang Deng
- Sichuan Agricultural University, Chengdu Campus, The Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Chengdu, Sichuan, 611130, China
| | - Guangneng Peng
- Sichuan Agricultural University, Chengdu Campus, The Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Chengdu, Sichuan, 611130, China
| | - Shumin Yu
- Sichuan Agricultural University, Chengdu Campus, The Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Chengdu, Sichuan, 611130, China
| | - Suizhong Cao
- Sichuan Agricultural University, Chengdu Campus, The Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Chengdu, Sichuan, 611130, China; and Corresponding author.
| | - Zhicai Zuo
- Sichuan Agricultural University, Chengdu Campus, The Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Chengdu, Sichuan, 611130, China
| | - Xiaoping Ma
- Sichuan Agricultural University, Chengdu Campus, The Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Chengdu, Sichuan, 611130, China
| | - Zhijun Zhong
- Sichuan Agricultural University, Chengdu Campus, The Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Chengdu, Sichuan, 611130, China
| | - Zhihua Ren
- Sichuan Agricultural University, Chengdu Campus, The Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Chengdu, Sichuan, 611130, China
| | - Ya Wang
- Sichuan Agricultural University, Chengdu Campus, The Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Chengdu, Sichuan, 611130, China
| | - Ziyao Zhou
- Sichuan Agricultural University, Chengdu Campus, The Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Chengdu, Sichuan, 611130, China
| | - Haifeng Liu
- Sichuan Agricultural University, Chengdu Campus, The Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Chengdu, Sichuan, 611130, China
| | - Xiaolan Zong
- Sichuan Agricultural University, Chengdu Campus, Academic Affairs Office, Chengdu, Sichuan, 611130, China
| | - Yanchun Hu
- Sichuan Agricultural University, Chengdu Campus, The Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Chengdu, Sichuan, 611130, China
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Kumar V, Singh J, Bala K, Singh J. Association of resistin (rs3745367) and urotensin II (rs228648 and rs2890565) gene polymorphisms with risk of type 2 diabetes mellitus in Indian population. Mol Biol Rep 2020; 47:9489-9497. [PMID: 33269434 DOI: 10.1007/s11033-020-05991-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Accepted: 11/06/2020] [Indexed: 01/20/2023]
Abstract
Insulin resistance may become the most powerful predictor of future development of type 2 diabetes mellitus (T2DM) and a therapeutic target for the treatment of the same. Both Resistin, an adipose derived peptide hormone and Urotensin II a potent vasoconstrictor, are reported to be involved in the development of insulin resistance and T2DM but the results remain contradictory. Therefore, investigations were carried out to study the association of T2DM and single nucleotide polymorphism (SNP) in Resistin (RETN) gene at rs3745367 (+ 299 G > A) and Urotensin II (UTS2) gene at rs228648 (+ 143 G > A) and rs2890565 (+ 3836 C > T) in a North Indian population. Method: The present case-control study, conducted from August 2017 to July 2020, involved 168 T2DM patients and 102 healthy controls. SNPs rs3745367, rs228648 and rs2890565 were amplified from genomic DNA in the studied samples by polymerase chain reaction (PCR) using specific primers. The amplified products were genotyped by restriction fragment length polymorphism (RFLP) using particular restriction endonucleases. Clinical parameters viz. glycosylated haemoglobin (HbA1c), fasting blood glucose (FBG), high density lipoprotein cholesterol (HDL-C), triglycerides (TG), total cholesterol (CHL) and fasting insulin were determined by enzymatic methods. Result and conclusion: A statistically significant association between T2DM and RETN gene at SNP rs3745367 (p = 0.001) and UTS2 gene at SNP rs2890565 (p = 0.001) was observed. In RETN gene SNP rs3745367, insulin and homeostasis model assessment of insulin resistance (HOMA-IR) were found to be higher in GA + AA combined genotype than in GG genotype for T2DM subjects. Regression analysis revealed that SNP rs2890565 and HOMA-IR were independently associated with the risk of development of T2DM when three SNPs were taken as independent variable adjusted for clinical variables. Among four haplotypes, A/T was found associated with increased risk of T2DM as determined for rs228648 and rs2890565 of UTS2 gene. It can be concluded from these results that polymorphism at rs3745367 of RETN gene and at rs2890565 of UTS2 gene are associated with risk of T2DM in North Indian population.
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Affiliation(s)
- Vikas Kumar
- Department of Biochemistry, Kurukshetra University, Kurukshetra, 136119, India
| | - Jaswinder Singh
- Department of Biochemistry, Kurukshetra University, Kurukshetra, 136119, India
| | - Kiran Bala
- Department of Biochemistry, Kurukshetra University, Kurukshetra, 136119, India
| | - Jasbir Singh
- Department of Biochemistry, Kurukshetra University, Kurukshetra, 136119, India.
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Szychowski KA, Skóra B, Tobiasz J, Gmiński J. Elastin-derived peptide VGVAPG decreases differentiation of mouse embryo fibroblast (3T3-L1) cells into adipocytes. Adipocyte 2020; 9:234-245. [PMID: 32463311 PMCID: PMC7469433 DOI: 10.1080/21623945.2020.1770525] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Revised: 04/30/2020] [Accepted: 05/07/2020] [Indexed: 02/06/2023] Open
Abstract
Elastin is a highly elastic protein present in connective tissue. As a result of protease activity, elastin hydrolysis occurs, and during this process, elastin-derived peptides (EDPs) are released. One of the constitutively repeating elastin and EDP building sequences is the hexapeptide VGVAPG. Therefore, the aim of our research was to define the effect of VGVAPG peptide on adipogenesis in a mouse 3T3-L1 cell line. 3T3-L1 cells were differentiated according to a previously described protocol and exposed to increasing concentrations of VGVAPG or VVGPGA peptide. The obtained results showed that VGVAPG peptide does not stimulate reactive oxygen species (ROS) production, caspase-1 activation, and 3T3-L1 cell proliferation. In the second part of the experiments, it was proved that VGVAPG peptide decreased lipid accumulation as measured by oil red O staining, which was confirmed by the profile of increased expression markers of undifferentiated preadipocytes. In our experiments, 10 nM VGVAPG added for differentiating to adipocytes increased the expression of Pref-1, serpin E1, and adiponectin as compared to rosiglitazone (PPARγ agonist)-treated group and simultaneously decreased the expression of VEGF and resistin as compared to the rosiglitazone-treated group. The obtained results show that VGVAPG peptide sustains 3T3 cells in undifferentiated state. ABBREVIATIONS DMSO: dimethyl sulphoxide; EBP: elastin-binding protein; EDPs: elastin-derived peptides; FBS: foetal bovine serum; Glb1: gene for beta-galactosidase; LDL: low-density-lipoprotein; PAI-1 (Serpin E1): plasminogen activator inhibitor-1; PBS: phosphate-buffered saline; PPARγ: peroxisome proliferator-activated receptor gamma; Pref-1: preadipocyte factor 1; ROS: reactive oxygen species; VEGF-A: vascular endothelial growth factor-A; VGVAPG: Val-Gly-Val-Ala-Pro-Gly; β-Gal: beta-galactosidase; ORO: oil red O; IBMX: 3-isobutyl-1-methylxanthine; H2DCFDA: 2',7'-dichlorodihydrofluorescein diacetate; DMEM: Dulbecco's Modified Eagle's Medium; VVGPGA: Val-Val-Gly-Pro-Gly-Ala.
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Affiliation(s)
- Konrad A. Szychowski
- Department of Lifestyle Disorders and Regenerative Medicine, University of Information Technology and Management in Rzeszow, Rzeszow, Poland
| | - Bartosz Skóra
- Department of Lifestyle Disorders and Regenerative Medicine, University of Information Technology and Management in Rzeszow, Rzeszow, Poland
| | - Jakub Tobiasz
- Department of Lifestyle Disorders and Regenerative Medicine, University of Information Technology and Management in Rzeszow, Rzeszow, Poland
| | - Jan Gmiński
- Department of Lifestyle Disorders and Regenerative Medicine, University of Information Technology and Management in Rzeszow, Rzeszow, Poland
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Rawal K, Purohit KM, Patel TP, Karont N, Gupta S. Resistin mitigates stemness and metabolic profile of human adipose-derived mesenchymal stem cells via insulin resistance. Cytokine 2020; 138:155374. [PMID: 33271386 DOI: 10.1016/j.cyto.2020.155374] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 10/31/2020] [Accepted: 11/15/2020] [Indexed: 01/23/2023]
Abstract
During obesity adipose tissue abundantly secrete pro-inflammatory adipokines like Tumour Necrosis factor-alpha (TNFα), resistin, leptin, etc. but reduced anti-inflammatory adipokines like adiponectin, interleukin (IL)-10, and IL-4. In our recent clinical study, it was observed that both gene expressions and stored levels of resistin were elevated in adipose tissue of metabolically obese Indians. Resistin profoundly increases obesity, mitigates lipid metabolism, and causes peripheral insulin resistance. It dysregulates the metabolism of human adipocytes but, its effects on human adipose-derived mesenchymal stem cells (hADSC) are sparsely explored. Therefore, the present study was designed to explore the repercussion of resistin on stemness and metabolic profile of hADSC. hADSC were isolated from a healthy individual followed by immunophenotyping. Purified cells were treated with resistin and proliferation was monitored by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and Cell Cycle experiments. Gene expressions of pluripotent markers, inflammatory mediators, and lipogenic genes were scrutinized. Insulin sensitivity was examined by western blot and glucose uptake assay. Further, consequences of resistin on differentiation potentials of hADSC were examined by temporal expressions of phospho (p)SMAD1/5/8 protein complex, non-phosphorylated beta (β) catenin, and their dependent adipogenic transcription factors (ATF) and osteogenic transcription factors (OTF). MTT and cell cycle analysis revealed that resistin hampered proliferation of hADSC. Expressions of inflammatory markers and lipogenic genes were elevated. Resistin impaired insulin sensitivity and thus embarked insulin resistance in hADSC. Resistin increased adipogenesis and osteogenesis by altering expressions of activated pSMAD1/5/8 complex, activated β catenin, ATF and OTF temporally. Downregulation of CCAAT/enhancer-binding proteins (C/EBP)α and adiponectin in adipocytes and Sirtuin (SIRT)1 in osteocytes denote that resistin induces immaturity and insulin resistance in adipocytes and osteocytes. This is the first study which, reports that resistin mitigates the stemness of hADSC by reducing proliferation, inducing insulin resistance, and hampering maturation of adipocyte and osteocyte which could lead to metabolic disorders.
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Affiliation(s)
- Komal Rawal
- Molecular Endocrinology and Stem Cell Research Laboratory, Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara 390002, Gujarat, India
| | - Kishan M Purohit
- Molecular Endocrinology and Stem Cell Research Laboratory, Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara 390002, Gujarat, India
| | - Tushar P Patel
- Molecular Endocrinology and Stem Cell Research Laboratory, Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara 390002, Gujarat, India
| | - Neeta Karont
- Molecular Endocrinology and Stem Cell Research Laboratory, Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara 390002, Gujarat, India
| | - Sarita Gupta
- Molecular Endocrinology and Stem Cell Research Laboratory, Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara 390002, Gujarat, India.
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20
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Bléher M, Meshko B, Cacciapuoti I, Gergondey R, Kovacs Y, Duprez D, L'Honoré A, Havis E. Egr1 loss-of-function promotes beige adipocyte differentiation and activation specifically in inguinal subcutaneous white adipose tissue. Sci Rep 2020; 10:15842. [PMID: 32985557 PMCID: PMC7522992 DOI: 10.1038/s41598-020-72698-w] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Accepted: 08/24/2020] [Indexed: 11/12/2022] Open
Abstract
In mice, exercise, cold exposure and fasting lead to the differentiation of inducible-brown adipocytes, called beige adipocytes, within white adipose tissue and have beneficial effects on fat burning and metabolism, through heat production. This browning process is associated with an increased expression of the key thermogenic mitochondrial uncoupling protein 1, Ucp1. Egr1 transcription factor has been described as a regulator of white and beige differentiation programs, and Egr1 depletion is associated with a spontaneous increase of subcutaneous white adipose tissue browning, in absence of external stimulation. Here, we demonstrate that Egr1 mutant mice exhibit a restrained Ucp1 expression specifically increased in subcutaneous fat, resulting in a metabolic shift to a more brown-like, oxidative metabolism, which was not observed in other fat depots. In addition, Egr1 is necessary and sufficient to promote white and alter beige adipocyte differentiation of mouse stem cells. These results suggest that modulation of Egr1 expression could represent a promising therapeutic strategy to increase energy expenditure and to restrain obesity-associated metabolic disorders.
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Affiliation(s)
| | | | | | - Rachel Gergondey
- Sorbonne Université, 75005, Paris, France
- Institute of Biology Paris Seine-Integrative Cellular Ageing and Inflammation, French National Centre for Scientific Research (CNRS) UMR8256, 75005, Paris, France
| | - Yoann Kovacs
- Sorbonne Université, 75005, Paris, France
- Institute of Biology Paris Seine-Integrative Cellular Ageing and Inflammation, French National Centre for Scientific Research (CNRS) UMR8256, 75005, Paris, France
| | - Delphine Duprez
- Sorbonne Université, 75005, Paris, France
- Institute of Biology Paris Seine-Developmental Biology Laboratory, Inserm U1156, French National Centre for Scientific Research (CNRS) UMR7622, 75005, Paris, France
| | - Aurore L'Honoré
- Sorbonne Université, 75005, Paris, France
- Institute of Biology Paris Seine-Integrative Cellular Ageing and Inflammation, French National Centre for Scientific Research (CNRS) UMR8256, 75005, Paris, France
| | - Emmanuelle Havis
- Sorbonne Université, 75005, Paris, France.
- Institute of Biology Paris Seine-Developmental Biology Laboratory, Inserm U1156, French National Centre for Scientific Research (CNRS) UMR7622, 75005, Paris, France.
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21
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Yao H, Fan C, Lu Y, Fan X, Xia L, Li P, Wang R, Tang T, Wang Y, Qi K. Alteration of gut microbiota affects expression of adiponectin and resistin through modifying DNA methylation in high-fat diet-induced obese mice. GENES & NUTRITION 2020; 15:12. [PMID: 32586265 PMCID: PMC7318443 DOI: 10.1186/s12263-020-00671-3] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 06/16/2020] [Indexed: 12/17/2022]
Abstract
BACKGROUND Adiponectin and resistin are typically secreted by the adipose tissue and are abnormally expressed in obesity. However, the underlying influential factors and mechanisms are to be elucidated. It is well known that the expression of genes is regulated by epigenetics while gut microbiota participates in epigenetic processes through its metabolites such as folate, biotin, and short-chain fatty acids (SCFAs). Therefore, we supposed that alteration of gut microbiota might affect the transcriptional expression of adiponectin and resistin through epigenetic regulation in obesity. METHODS C57BL/6J mice were fed either a high-fat diet (34.9% fat by wt., 60% kcal) or a normal-fat diet (4.3% fat by wt., 10% kcal) for 16 weeks, with ampicillin and neomycin delivered via drinking water to interfere with gut microbiota development. Fecal microbiota was analyzed by 16S rRNA high-throughput sequencing. The mRNA expression levels of genes were measured by real-time quantitative RT-PCR. SCFA contents in feces were examined using gas chromatography. RESULTS Alteration of the gut microbiota induced by antibiotic use, characterized by a dramatic reduction of the phylum Firmicutes and Actinobacteria and an increase of Proteobacteria with reductions of genera including Lactobacillus, norank_f_Bacteroidales_S24-7_group, Alistipes, Desulfovibrio, Helicobacter, etc., and increases in Bacteroides, Enterobacter, Klebsiella, inhibited the body weight gain in mice fed the high-fat diet instead of the normal-fat diet. The mRNA expression of adiponectin and resistin was upregulated by antibiotic use in mice fed the high-fat diet, accompanied by increased expression of fat oxidation and thermogenesis-related genes (PPAR-α, Pgc-1α, and Atgl) in the fat and/or liver, whereas no change in the expression of adiponectin and resistin was found in mice fed the normal-fat diet. Furthermore, antibiotic use reduced DNA methylation fractions of the adiponectin and resistin promoters and downregulated the expression of DNA methyltransferase 1 and 3a (DNMT1 and DNMT3a) with the high-fat diet feeding. CONCLUSION Alteration of gut microbiota induced by antibiotic use may affect the expression of adiponectin and resistin in mice fed the high-fat diet by modifying promoter DNA methylation, thus leading to increased fatty acid oxidation and less body weight gain.
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Affiliation(s)
- Hongyang Yao
- grid.24696.3f0000 0004 0369 153XLaboratory of Nutrition and Development, Beijing Pediatric Research Institute, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, 100045 China
| | - Chaonan Fan
- grid.24696.3f0000 0004 0369 153XLaboratory of Nutrition and Development, Beijing Pediatric Research Institute, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, 100045 China
| | - Yuanyuan Lu
- grid.24696.3f0000 0004 0369 153XDepartment of Child Health Care Center, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, 100045 China
| | - Xiuqin Fan
- grid.24696.3f0000 0004 0369 153XLaboratory of Nutrition and Development, Beijing Pediatric Research Institute, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, 100045 China
| | - Lulu Xia
- grid.24696.3f0000 0004 0369 153XDepartment of Diet and Nutrition, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, 100045 China
| | - Ping Li
- grid.24696.3f0000 0004 0369 153XLaboratory of Nutrition and Development, Beijing Pediatric Research Institute, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, 100045 China
| | - Rui Wang
- grid.24696.3f0000 0004 0369 153XLaboratory of Nutrition and Development, Beijing Pediatric Research Institute, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, 100045 China
| | - Tiantian Tang
- grid.24696.3f0000 0004 0369 153XLaboratory of Nutrition and Development, Beijing Pediatric Research Institute, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, 100045 China
| | - Yuanyuan Wang
- grid.24696.3f0000 0004 0369 153XLaboratory of Nutrition and Development, Beijing Pediatric Research Institute, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, 100045 China
| | - Kemin Qi
- grid.24696.3f0000 0004 0369 153XLaboratory of Nutrition and Development, Beijing Pediatric Research Institute, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, 100045 China
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22
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You D, Lyn-Cook LE, Gatti DM, Bell N, Mayeux PR, James LP, Mattes WB, Larson GJ, Harrill AH. Nitrosative Stress and Lipid Homeostasis as a Mechanism for Zileuton Hepatotoxicity and Resistance in Genetically Sensitive Mice. Toxicol Sci 2020; 175:220-235. [PMID: 32170957 PMCID: PMC7253212 DOI: 10.1093/toxsci/kfaa037] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Zileuton is an orally active inhibitor of leukotriene synthesis for maintenance treatment of asthma, for which clinical usage has been associated with idiosyncratic liver injury. Mechanistic understanding of zileuton toxicity is hampered by the rarity of the cases and lack of an animal model. A promising model for mechanistic study of rare liver injury is the Diversity Outbred (J:DO) mouse population, with genetic variation similar to that found in humans. In this study, female DO mice were administered zileuton or vehicle daily for 7 days (i.g.). Serum liver enzymes were elevated in the zileuton group, with marked interindividual variability in response. Zileuton exposure-induced findings in susceptible DO mice included microvesicular fatty change, hepatocellular mitosis, and hepatocellular necrosis. Inducible nitric oxide synthase and nitrotyrosine abundance were increased in livers of animals with necrosis and those with fatty change, implicating nitrosative stress as a possible injury mechanism. Conversely, DO mice lacking adverse liver pathology following zileuton exposure experienced decreased hepatic concentrations of resistin and increased concentrations of insulin and leptin, providing potential clues into mechanisms of toxicity resistance. Transcriptome pathway analysis highlighted mitochondrial dysfunction and altered fatty acid oxidation as key molecular perturbations associated with zileuton exposure, and suggested that interindividual differences in cytochrome P450 metabolism, glutathione-mediated detoxification, and farnesoid X receptor signaling may contribute to zileuton-induced liver injury (ZILI). Taken together, DO mice provided a platform for investigating mechanisms of toxicity and resistance in context of ZILI which may lead to targeted therapeutic interventions.
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Affiliation(s)
- Dahea You
- Division of the National Toxicology Program, The National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709
| | - Lascelles E Lyn-Cook
- Graduate Program in Interdisciplinary Biomedical Sciences, The University of Arkansas for Medical Sciences and Arkansas Children’s Research Institute, Little Rock, Arkansas 72205
| | | | - Natalie Bell
- Division of the National Toxicology Program, The National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709
- East Carolina University, Greenville, North Carolina 27858
| | | | - Laura P James
- Department of Pediatrics, The University of Arkansas for Medical Sciences and Arkansas Children’s Research Institute, Little Rock, Arkansas 27705
| | - William B Mattes
- Division of Systems Biology, The National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas 72079
| | - Gary J Larson
- Social & Scientific Systems, Inc., Durham, North Carolina 27703
| | - Alison H Harrill
- Division of the National Toxicology Program, The National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709
- Department of Environmental and Occupational Health, The University of Arkansas for Medical Sciences and Arkansas Children’s Research Institute, Little Rock, Arkansas 72205
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23
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An F, Zhang L, Gao H, Wang J, Liu C, Tian Y, Ma C, Zhao J, Wang K, Wang J. Variants in RETN gene are associated with steroid-induced osteonecrosis of the femoral head risk among Han Chinese people. J Orthop Surg Res 2020; 15:96. [PMID: 32143662 PMCID: PMC7060642 DOI: 10.1186/s13018-020-1557-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Accepted: 01/14/2020] [Indexed: 12/13/2022] Open
Abstract
Background Gene polymorphism has an important influence on RETN gene expression level, and the increased level of resistin encoded in RETN will lead to metabolic disorder, especially lipid metabolism. Moreover, steroid-induced osteonecrosis of the femoral head (steroid-induced ONFH) is closely related to lipid metabolism level, so this study is intended to explore the relationship of RETN polymorphisms with susceptibility to steroid-induced ONFH in the Chinese Han population. Methods In this case-control study, eight single-nucleotide polymorphisms (SNPs) of RETN were genotyped by the Agena MassARRAY system in 199 steroid-induced ONFH patients and 200 healthy controls. The relationship between RETN polymorphisms and steroid-induced ONFH risk was assessed using genetic models and haplotype analyses. Odds ratio (OR) and 95% confidence intervals (CIs) were obtained by logistic regression adjusted for age. Results We found significant differences in the distribution of HDL-C, TG/HDL-C, and LDL-C/HDL-C between the patients and the control group (p < 0.05). In allele model and genotype model analysis, rs34861192, rs3219175, rs3745368, and rs1477341 could reduce the risk of steroid-induced ONFH. Further stratified analysis showed that rs3745367 was related to the clinical stage of patients, and rs1477341 was significantly correlated with an increased TG level and a decreased TC/HDL-C level. The linkage analysis showed that two SNPs (rs34861192 and rs3219175) in RETN even significant linkage disequilibrium. Conclusions Our results provide the firstly evidence that RETN gene polymorphisms were associated with a reduced risk of steroid-induced ONFH in Chinese Han population.
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Affiliation(s)
- Feimeng An
- Inner Mongolia Medical University, Hohhot, 010050, Inner Mongolia, China.,Department of Trauma Orthopedics, The Second Affiliated Hospital of Inner Mongolia Medical University, Hohhot, 010030, Inner Mongolia, China
| | - Litian Zhang
- Inner Mongolia Medical University, Hohhot, 010050, Inner Mongolia, China.,Department of Trauma Orthopedics, The Second Affiliated Hospital of Inner Mongolia Medical University, Hohhot, 010030, Inner Mongolia, China
| | - Hongyan Gao
- Inner Mongolia Medical University, Hohhot, 010050, Inner Mongolia, China.,Department of Trauma Orthopedics, The Second Affiliated Hospital of Inner Mongolia Medical University, Hohhot, 010030, Inner Mongolia, China
| | - Jiaqi Wang
- Inner Mongolia Medical University, Hohhot, 010050, Inner Mongolia, China.,Department of Trauma Orthopedics, The Second Affiliated Hospital of Inner Mongolia Medical University, Hohhot, 010030, Inner Mongolia, China
| | - Chang Liu
- Inner Mongolia Medical University, Hohhot, 010050, Inner Mongolia, China.,Department of Trauma Orthopedics, The Second Affiliated Hospital of Inner Mongolia Medical University, Hohhot, 010030, Inner Mongolia, China
| | - Ye Tian
- Inner Mongolia Medical University, Hohhot, 010050, Inner Mongolia, China.,Department of Trauma Orthopedics, The Second Affiliated Hospital of Inner Mongolia Medical University, Hohhot, 010030, Inner Mongolia, China
| | - Chao Ma
- Inner Mongolia Medical University, Hohhot, 010050, Inner Mongolia, China.,Department of Trauma Orthopedics, The Second Affiliated Hospital of Inner Mongolia Medical University, Hohhot, 010030, Inner Mongolia, China
| | - Jian Zhao
- Inner Mongolia Medical University, Hohhot, 010050, Inner Mongolia, China.,Department of Trauma Orthopedics, The Second Affiliated Hospital of Inner Mongolia Medical University, Hohhot, 010030, Inner Mongolia, China
| | - Kunzheng Wang
- The Second Affiliated Hospital of Xi'an Jiaotong University, #157 Xi Wu Road, Xi'an, 710004, Shaanxi Province, China.
| | - Jianzhong Wang
- Department of Trauma Orthopedics, The Second Affiliated Hospital of Inner Mongolia Medical University, Hohhot, 010030, Inner Mongolia, China.
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24
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Pesce Viglietti AI, Giambartolomei GH, Quarleri J, Delpino MV. Brucella abortus Infection Modulates 3T3-L1 Adipocyte Inflammatory Response and Inhibits Adipogenesis. Front Endocrinol (Lausanne) 2020; 11:585923. [PMID: 33071987 PMCID: PMC7531218 DOI: 10.3389/fendo.2020.585923] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Accepted: 09/08/2020] [Indexed: 01/18/2023] Open
Abstract
Brucellosis is a prevalent global zoonotic infection but has far more impact in developing countries. The adipocytes are the most abundant cell type of adipose tissue and their secreted factors play an important role in several aspects of the innate and adaptive immune response. Here, we demonstrated the ability of Brucella abortus to infect and replicate in both adipocytes and its precursor cells (pre-adipocytes) derived from 3T3-L1 cell line. Additionally, infection of pre-adipocytes also inhibited adipogenesis in a mechanism independent of bacterial viability and dependent on lipidated outer membrane protein (L-Omp19). B. abortus infection was able to modulate the secretion of IL-6 and the matrix metalloproteases (MMPs) -2 and-9 in pre-adipocytes and adipocytes, and also modulated de transcription of adiponectin, leptin, and resistin in differentiated adipocytes. B. abortus-infected macrophages also modulate adipocyte differentiation involving a TNF-α dependent mechanism, thus suggesting a plausible interplay between B. abortus, adipocytes, and macrophages. In conclusion, B. abortus is able to alter adipogenesis process in adipocytes and its precursors directly after their infection, or merely their exposure to the B. abortus lipoproteins, and indirectly through soluble factors released by B. abortus-infected macrophages.
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Affiliation(s)
- Ayelén Ivana Pesce Viglietti
- Instituto de Inmunología, Genética y Metabolismo (INIGEM), Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires (UBA), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Guillermo Hernán Giambartolomei
- Instituto de Inmunología, Genética y Metabolismo (INIGEM), Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires (UBA), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Jorge Quarleri
- Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), Facultad de Medicina, Universidad de Buenos Aires (UBA), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
- *Correspondence: María Victoria Delpino, ; Jorge Quarleri,
| | - María Victoria Delpino
- Instituto de Inmunología, Genética y Metabolismo (INIGEM), Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires (UBA), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
- *Correspondence: María Victoria Delpino, ; Jorge Quarleri,
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25
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Yaribeygi H, Simental-Mendía LE, Barreto GE, Sahebkar A. Metabolic effects of antidiabetic drugs on adipocytes and adipokine expression. J Cell Physiol 2019; 234:16987-16997. [PMID: 30825205 DOI: 10.1002/jcp.28420] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Revised: 02/05/2019] [Accepted: 02/14/2019] [Indexed: 12/14/2022]
Abstract
Several classes of antidiabetic agents have been developed that achieve their hypoglycemic outcomes via various molecular mechanisms. Adipose tissue is a major metabolic and energy-storing tissue and plays an important role in many metabolic pathways, including insulin signaling and insulin sensitivity. Adipose tissue monitors and regulates whole body homeostasis via production and release of potent proteins, such as adipokine and adiponectin, into the circulation. Therefore, any agent that can modulate adipocyte metabolism can, in turn, affect metabolic and glucose homeostatic pathways. Antidiabetic drugs are not only recognized primarily as hypoglycemic agents but may also alter adipose tissue itself, as well as adipocyte-derived adipokine expression and secretion. In the current review, we present the major evidence concerning routinely used antidiabetic agents on adipocyte metabolism and adipokine expression.
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Affiliation(s)
- Habib Yaribeygi
- Chronic Kidney Disease Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Luis E Simental-Mendía
- Unidad de Investigación Biomédica, Delegación Durango, Instituto Mexicano del Seguro Social, México, México
| | - George E Barreto
- Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá D.C, Colombia.,Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, Santiago, Chile
| | - Amirhossein Sahebkar
- Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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26
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Tsave O, Halevas E, Yavropoulou MP, Yovos E, Hatzidimitriou A, Psycharis V, Ypsilantis K, Stathi P, Salifoglou A. V(v)-Schiff base species induce adipogenesis through structure-specific influence of genetic targets. NEW J CHEM 2019. [DOI: 10.1039/c9nj02520k] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Appropriately designed Schiff-base substrates enhance V(v)-bioavailability and insulin-mimetic biomolecular gene profiling, inducing adipogenesis in a structure-specific manner.
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Affiliation(s)
- O. Tsave
- Laboratory of Inorganic Chemistry and Advanced Materials
- Department of Chemical Engineering
- Aristotle University of Thessaloniki
- Thessaloniki 54124
- Greece
| | - E. Halevas
- Laboratory of Inorganic Chemistry and Advanced Materials
- Department of Chemical Engineering
- Aristotle University of Thessaloniki
- Thessaloniki 54124
- Greece
| | - M. P. Yavropoulou
- Division of Clinical and Molecular Endocrinology
- 1st Department of Internal Medicine
- AHEPA
- University Hospital
- Aristotle University of Thessaloniki
| | - E. Yovos
- Division of Clinical and Molecular Endocrinology
- 1st Department of Internal Medicine
- AHEPA
- University Hospital
- Aristotle University of Thessaloniki
| | - A. Hatzidimitriou
- Laboratory of Inorganic Chemistry
- Department of Chemistry
- Aristotle University of Thessaloniki
- Thessaloniki 54124
- Greece
| | - V. Psycharis
- Institute of Nanoscience and Nanotechnology
- NCSR “Demokritos”
- Aghia Paraskevi 15310
- Greece
| | - K. Ypsilantis
- Department of Chemistry
- University of Ioannina
- Ioannina 45110
- Greece
| | - P. Stathi
- Laboratory of Physical Chemistry of Materials & Environment
- Department of Physics
- University of Ioannina
- Ioannina 45110
- Greece
| | - A. Salifoglou
- Laboratory of Inorganic Chemistry and Advanced Materials
- Department of Chemical Engineering
- Aristotle University of Thessaloniki
- Thessaloniki 54124
- Greece
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27
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Metwally FM, Rashad H, Mahmoud AA. Morus alba L. Diminishes visceral adiposity, insulin resistance, behavioral alterations via regulation of gene expression of leptin, resistin and adiponectin in rats fed a high-cholesterol diet. Physiol Behav 2018; 201:1-11. [PMID: 30552920 DOI: 10.1016/j.physbeh.2018.12.010] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2018] [Revised: 12/04/2018] [Accepted: 12/10/2018] [Indexed: 01/07/2023]
Abstract
Ethanolic extract of leaves of Morus alba L. (M. alba), known as white mulberry, was orally administered (100 mg/kg b.wt) for 8 weeks to female Wistar rats that were fed a high-cholesterol diet (HCD), to investigate the potential of M. alba leaves in attenuation of obesity, dyslipidemia, insulin resistance, and deficits in mood, cognitive as well as motor activity that are linked to the adipokines secretions of visceral adipose tissue. Results showed that M. alba diminished body weight gain, hypercholesterolemia, hypertriglyceridemia, atherogenic (AI) & coronary artery indices (CRI), and ameliorated glucose level and insulin resistance index in rats on HCD, compared with untreated HCD rats. Moreover, M. alba administration significantly decreased serum leptin and resistin contents as well as their mRNA expression in visceral adipose tissue, but significantly increased serum adiponectin level, and its mRNA expression in visceral adipose tissue in rats fed on HCD, compared to those in untreated HCD group. Regarding behavioral alterations, M. alba attenuated motor deficit, declined memory, depression and anxiety-like behavior, as well in rats on HCD, compared to that noticed in untreated HCD rats. The current data showed that serum leptin and resistin showed a positive correlation with and body weight gain, triglycerides (TG), AI as well as CRI, but showed a negative correlation with exploration, declined memory, depression- and anxiety-like behavior. Conversely, serum adiponectin showed a negative correlation with and body weight gain, TG, AI as well as CRI, but showed a positive correlation with locomotor activity, exploration, declined memory, and depression- and anxiety-like behavior. In conclusion, M. alba leaves supplementation could attenuate adiposity, insulin resistance behavioral deficits via down-regulation of regulation of gene expression of leptin, resistin, but up-regulation of adiponectin gene expression in the visceral adipose tissue of rats fed a high-cholesterol diet.
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Affiliation(s)
| | - Hend Rashad
- Environmental and Occupational Medicine, National Research Centre, Giza, Egypt
| | - Asmaa Ahmed Mahmoud
- Department of Zoology, Faculty of Science, Ain Shams University, Cairo, Egypt.
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28
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Iwamoto K, Kamo S, Takada Y, Ieda A, Yamashita T, Sato T, Zaima N, Moriyama T. Soyasapogenols reduce cellular triglyceride levels in 3T3-L1 mouse adipocyte cells by accelerating triglyceride lipolysis. Biochem Biophys Rep 2018; 16:44-49. [PMID: 30294680 PMCID: PMC6171538 DOI: 10.1016/j.bbrep.2018.09.006] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2018] [Revised: 07/27/2018] [Accepted: 09/18/2018] [Indexed: 01/07/2023] Open
Abstract
Soyasapogenol is a soyasaponin aglycone, which has been suggested to exert a more potent function than the glycoside form. In this study, the effect of soyasapogenol A and B on cultured adipocyte cell function was investigated using mouse 3T3-L1 adipocyte cells. 3T3-L1 cells were treated with insulin, dexamethasone, and 3-isobutyl-1-methylxanthine for differentiation to adipocytes, and the cells were then cultured in the presence of soyasapogenol A or B (6.25 or 12.5 µM). The media were harvested and refreshed every 2 d. After a 10 d culture, the cells were harvested and the triglyceride content of the cells was determined. The triglyceride content of soyasapogenol B-treated cells was significantly lower than those of vehicle-treated cells. Glycerol and free fatty acid levels in the soyasapogenol-treated cell media were higher than those in vehicle cells. However, there was no difference in the level of adipose triglyceride lipase among soyasapogenol A-, soyasapogenol B-, and vehicle-treated cells. The secreted adiponectin and resistin levels of soyasapogenol-treated cell media were also different compared with those of vehicle-treated cells. Especially, the secreted resistin level in soyasapogenol B-treated cell media was obviously reduced compared with that of vehicle-treated cells. Taken together, these results suggest that soyasapogenol B exerted an anti-obesity and anti-diabetic effect on adipocytes by lowering the cellular triglyceride level by accelerating triglyceride lipolysis with reduced resistin secretion.
Soyasapogenol A and B exerted an influence on TG accumulation in adipocytes. Soyasapogenol B accelerated lipolysis in adipocyte cells. Soyasapogenol-treated adipocytes significantly decreased resistin secretion.
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Affiliation(s)
- Kazuko Iwamoto
- School of Agriculture, Kindai University, Naka-machi, Nara, Nara 631-8505, Japan
| | - Shuichi Kamo
- Product Development Laboratory, J-OIL MILLS, Inc., 7–41, Daikoku-cho, Tsurumi-ku, Yokohama-city, Kanagawa 230-0053, Japan
| | - Yuichi Takada
- School of Agriculture, Kindai University, Naka-machi, Nara, Nara 631-8505, Japan
| | - Ayana Ieda
- School of Agriculture, Kindai University, Naka-machi, Nara, Nara 631-8505, Japan
| | - Takatoshi Yamashita
- Product Development Laboratory, J-OIL MILLS, Inc., 7–41, Daikoku-cho, Tsurumi-ku, Yokohama-city, Kanagawa 230-0053, Japan
| | - Toshiro Sato
- Fundamental Research Laboratory, J-OIL MILLS, Inc., 7–41, Daikoku-cho, Tsurumi-ku, Yokohama-city, Kanagawa 230-0053, Japan
| | - Nobuhiro Zaima
- School of Agriculture, Kindai University, Naka-machi, Nara, Nara 631-8505, Japan
- KINDAI Research Institute for Agricultural Technology and Innovation, Naka-machi, Nara, Nara 631–8505, Japan
| | - Tatsuya Moriyama
- School of Agriculture, Kindai University, Naka-machi, Nara, Nara 631-8505, Japan
- KINDAI Research Institute for Agricultural Technology and Innovation, Naka-machi, Nara, Nara 631–8505, Japan
- Corresponding author at: School of Agriculture, Kindai University, Naka-machi, Nara, Nara 631-8505, Japan.
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Underrated enemy - from nonalcoholic fatty liver disease to cancers of the gastrointestinal tract. Clin Exp Hepatol 2018; 4:55-71. [PMID: 29904722 PMCID: PMC6000748 DOI: 10.5114/ceh.2018.75955] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Accepted: 04/17/2018] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is intrahepatic ectopic lipid deposition which is present despite a lack of other causes of secondary hepatic fat accumulation. It is the most common chronic liver disorder in the welldeveloped countries. NAFLD is a multidisciplinary disease that affects various systems and organs and is inextricably linked to simple obesity, metabolic syndrome, insulin resistance and overt diabetes mellitus type 2. The positive energy balance related to obesity leads to a variety of systemic changes including modified levels of insulin, insulin- like growth factor-1, adipokines, hepatokines and cytokines. It is strongly linked to carcinogenesis and new evidence proves that NAFLD is associated with higher risk of all-cause mortality and cancer-specific mortality among cancer survivors. This article focuses on the association between NAFLD and extrahepatic gastrointestinal tract cancers, aiming to shed light on the pathomechanism of changes leading to the development of tumors.
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Differential Effect of
cis
‐Eicosenoic Acid Positional Isomers on Adipogenesis and Lipid Accumulation in 3T3‐L1 Cells. EUR J LIPID SCI TECH 2018. [DOI: 10.1002/ejlt.201700512] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
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Identification and expression patterns of adipokine genes during adipocyte differentiation in the Tibetan goat ( Capra hircus ). Gene 2018; 643:17-25. [DOI: 10.1016/j.gene.2017.11.069] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Revised: 11/13/2017] [Accepted: 11/28/2017] [Indexed: 02/08/2023]
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Okazaki H, Takeda S, Ishii H, Takemoto Y, Fujita S, Suyama M, Matsumoto K, Shindo M, Aramaki H. A Novel Bongkrekic Acid Analog-Mediated Modulation of the Size of Lipid Droplets: Evidence for the Appearance of Smaller Adipocytes. Biol Pharm Bull 2017; 40:1192-1198. [PMID: 28769000 DOI: 10.1248/bpb.b16-00915] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Thiazolidinediones (TZDs) are known as peroxisome proliferator-activated receptor γ (PPARγ) activators, and are used in the treatment of diabetes. Although the usefulness of TZDs has been demonstrated, some of their side effects are becoming an obstacle to their clinical applicability; edema is known to be evoked by the "structural characteristics" of TZD, but not by the PPARγ activation. Thus, novel therapeutic modalities (i.e., non-TZD-type PPARγ activators) having different structures to those of TZDs are desired. We previously identified bongkrekic acid (BKA) as a PPARγ activator using the human breast cancer MCF-7 cell line as a model system. In the present study, we newly synthesized BKA analogs and examined the usefulness of BKA and its analogs as PPARγ activators in differentiated adipocyte cells. Among the chemicals investigated, one of the BKA analogs (BKA-#2) strongly stimulated PPARγ and the differentiation of 3T3-L1 cells similar to pioglitazone, a positive control. Furthermore, BKA-#2 reduced the size of lipid droplets in the mature adipocyte cells. The possible modulation mechanism by BKA-#2 is discussed.
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Affiliation(s)
| | - Shuso Takeda
- Laboratory of Xenobiotic Metabolism and Environmental Toxicology, Faculty of Pharmaceutical Sciences, Hiroshima International University (HIU)
| | - Hiroyuki Ishii
- Department of Molecular Biology, Daiichi University of Pharmacy
| | - Yukimi Takemoto
- Department of Molecular Biology, Daiichi University of Pharmacy
| | - Satoshi Fujita
- Institute for Materials Chemistry and Engineering, Kyushu University
| | - Masaki Suyama
- Institute for Materials Chemistry and Engineering, Kyushu University
| | - Kenji Matsumoto
- Institute for Materials Chemistry and Engineering, Kyushu University
| | - Mitsuru Shindo
- Institute for Materials Chemistry and Engineering, Kyushu University
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Richards P, Ourabah S, Montagne J, Burnol AF, Postic C, Guilmeau S. MondoA/ChREBP: The usual suspects of transcriptional glucose sensing; Implication in pathophysiology. Metabolism 2017; 70:133-151. [PMID: 28403938 DOI: 10.1016/j.metabol.2017.01.033] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2017] [Accepted: 01/21/2017] [Indexed: 12/22/2022]
Abstract
Identification of the Mondo glucose-responsive transcription factors family, including the MondoA and MondoB/ChREBP paralogs, has shed light on the mechanism whereby glucose affects gene transcription. They have clearly emerged, in recent years, as key mediators of glucose sensing by multiple cell types. MondoA and ChREBP have overlapping yet distinct expression profiles, which underlie their downstream targets and separate roles in regulating genes involved in glucose metabolism. MondoA can restrict glucose uptake and influences energy utilization in skeletal muscle, while ChREBP signals energy storage through de novo lipogenesis in liver and white adipose tissue. Because Mondo proteins mediate metabolic adaptations to changing glucose levels, a better understanding of cellular glucose sensing through Mondo proteins will likely uncover new therapeutic opportunities in the context of the imbalanced glucose homeostasis that accompanies metabolic diseases such as type 2 diabetes and cancer. Here, we provide an overview of structural homologies, transcriptional partners as well as the nutrient and hormonal mechanisms underlying Mondo proteins regulation. We next summarize their relative contribution to energy metabolism changes in physiological states and the evolutionary conservation of these pathways. Finally, we discuss their possible targeting in human pathologies.
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Affiliation(s)
- Paul Richards
- Inserm, U1016, Institut Cochin, Paris, 75014, France; CNRS, UMR 8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France
| | - Sarah Ourabah
- Inserm, U1016, Institut Cochin, Paris, 75014, France; CNRS, UMR 8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France
| | - Jacques Montagne
- Institut for Integrative Biology of the Cell (I2BC), CNRS, Université Paris-Sud, CEA, UMR 9198, F-91190, Gif-sur-Yvette, France
| | - Anne-Françoise Burnol
- Inserm, U1016, Institut Cochin, Paris, 75014, France; CNRS, UMR 8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France
| | - Catherine Postic
- Inserm, U1016, Institut Cochin, Paris, 75014, France; CNRS, UMR 8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France
| | - Sandra Guilmeau
- Inserm, U1016, Institut Cochin, Paris, 75014, France; CNRS, UMR 8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
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López-Yoldi M, Marcos-Gomez B, Romero-Lozano MA, Sáinz N, Prieto J, Martínez JA, Bustos M, Moreno-Aliaga MJ. Cardiotrophin-1 Regulates Adipokine Production in 3T3-L1 Adipocytes and Adipose Tissue From Obese Mice. J Cell Physiol 2017; 232:2469-2477. [PMID: 27608275 DOI: 10.1002/jcp.25590] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2015] [Accepted: 09/06/2016] [Indexed: 12/19/2022]
Abstract
Cardiotrophin-1 (CT-1) belongs to the IL-6 family of cytokines. Previous studies of our group revealed that CT-1 is a key regulator of glucose and lipid metabolism. The aim of the present study was to analyze the in vitro and in vivo effects of CT-1 on the production of several adipokines involved in body weight regulation, nutrient metabolism, and inflammation. For this purpose, 3T3-L1 adipocytes were incubated with recombinant protein CT-1 (rCT-1) (1-40 ng/ml) for 1 and 18 h. Moreover, the acute effects of rCT-1 administration (0.2 mg/kg, i.v.) for 30 min and 3 h on adipokines levels were also evaluated in high-fat fed obese mice. In 3T3-L1 adipocytes, rCT-1 treatment downregulated the expression and secretion of leptin, resistin, and visfatin. However, rCT-1 significantly stimulated apelin mRNA and secretion. rCT-1 (18 h) also promoted the activation by phosphorylation of AKT, ERK 1/2, and STAT3. Interestingly, pre-treatment with the PI3K inhibitor LY294002 reversed the stimulatory effects of rCT-1 on apelin expression, suggesting that this pathway could be mediating the effects of rCT-1 on apelin production. In contrast, acute administration of rCT-1 (30 min and 3 h) to diet-induced obese mice downregulated leptin and resistin, without significantly modifying apelin or visfatin mRNA in adipose tissue. Furthermore, CT-1 null mice exhibited altered expression of adipokines in adipose tissue. The present study demonstrates that rCT-1 modulates the production of adipokines in vitro and in vivo, suggesting that the regulation of the secretory function of adipocytes could be involved in the metabolic actions of this cytokine. J. Cell. Physiol. 232: 2469-2477, 2017. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Miguel López-Yoldi
- Department of Nutrition, Food Science and Physiology, University of Navarra, Pamplona, Navarra, Spain.,Centre for Nutrition Research, University of Navarra, Pamplona, Navarra, Spain
| | - Beatriz Marcos-Gomez
- Department of Nutrition, Food Science and Physiology, University of Navarra, Pamplona, Navarra, Spain
| | | | - Neira Sáinz
- Department of Nutrition, Food Science and Physiology, University of Navarra, Pamplona, Navarra, Spain.,Centre for Nutrition Research, University of Navarra, Pamplona, Navarra, Spain
| | - Jesús Prieto
- Department of Hepatology and Gene Therapy, CIMA, University of Navarra, Pamplona, Navarra, Spain.,CIBERehd, Institute of Health Carlos III, Madrid, Spain
| | - Jose Alfredo Martínez
- Department of Nutrition, Food Science and Physiology, University of Navarra, Pamplona, Navarra, Spain.,Centre for Nutrition Research, University of Navarra, Pamplona, Navarra, Spain.,CIBERobn, Physiopathology of Obesity and Nutrition, Institute of Health Carlos III, Madrid, Spain.,IdiSNA, Navarra's Health Research Institute, Pamplona, Spain
| | - Matilde Bustos
- Department of Hepatology and Gene Therapy, CIMA, University of Navarra, Pamplona, Navarra, Spain
| | - Maria J Moreno-Aliaga
- Department of Nutrition, Food Science and Physiology, University of Navarra, Pamplona, Navarra, Spain.,Centre for Nutrition Research, University of Navarra, Pamplona, Navarra, Spain.,CIBERobn, Physiopathology of Obesity and Nutrition, Institute of Health Carlos III, Madrid, Spain.,IdiSNA, Navarra's Health Research Institute, Pamplona, Spain
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Hasan M, Tarashima N, Fujikawa K, Ohgita T, Hama S, Tanaka T, Saito H, Minakawa N, Kogure K. The novel functional nucleic acid iRed effectively regulates target genes following cytoplasmic delivery by faint electric treatment. SCIENCE AND TECHNOLOGY OF ADVANCED MATERIALS 2016; 17:554-562. [PMID: 27877903 PMCID: PMC5111564 DOI: 10.1080/14686996.2016.1221726] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/29/2016] [Revised: 08/02/2016] [Accepted: 08/04/2016] [Indexed: 06/06/2023]
Abstract
An intelligent shRNA expression device (iRed) contains the minimum essential components needed for shRNA production in cells, and could be a novel tool to regulate target genes. However, general delivery carriers consisting of cationic polymers/lipids could impede function of a newly generated shRNA via electrostatic interaction in the cytoplasm. Recently, we found that faint electric treatment (fET) of cells enhanced delivery of siRNA and functional nucleic acids into the cytoplasm in the absence of delivery carriers. Here, we examined fET of cells stably expressing luciferase in the presence of iRed encoding anti-luciferase shRNA. Transfection of lipofectamine 2000 (LFN)/iRed lipoplexes showed an RNAi effect, but fET-mediated iRed transfection did not, likely because of the endosomal localization of iRed after delivery. However, fET in the presence of lysosomotropic agent chloroquine significantly improved the RNAi effect of iRed/fET to levels that were higher than those for the LFN/iRed lipoplexes. Furthermore, the amount of lipid droplets in adipocytes significantly decreased following fET with iRed against resistin in the presence of chloroquine. Thus, iRed could be a useful tool to regulate target genes following fET-mediated cytoplasmic delivery with endosomal escape devices.
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Affiliation(s)
- Mahadi Hasan
- Department of Biophysical Chemistry, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Noriko Tarashima
- Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Koki Fujikawa
- Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Takashi Ohgita
- Department of Biophysical Chemistry, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Susumu Hama
- Department of Biophysical Chemistry, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Tamotsu Tanaka
- Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Hiroyuki Saito
- Department of Biophysical Chemistry, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Noriaki Minakawa
- Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Kentaro Kogure
- Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
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Circulating Resistin Levels and Risk of Colorectal Cancer: A Meta-Analysis. BIOMED RESEARCH INTERNATIONAL 2016; 2016:7367485. [PMID: 27642602 PMCID: PMC5013211 DOI: 10.1155/2016/7367485] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/10/2016] [Accepted: 07/20/2016] [Indexed: 12/20/2022]
Abstract
Objectives. Published data on resistin levels in patients with colorectal cancer (CRC) were conflicting and heterogeneous. We conducted a meta-analysis of observational studies to examine the association of circulating resistin levels with carcinogenesis of the CRC. Methods. Potentially eligible studies published up to November 2015 were searched through MEDLINE, EMBASE, Science Citation Index Expanded database, CNKI, and WanFang database. The pooled weighted mean differences (WMDs) with 95% confidence intervals (CIs) calculated by fixed- or random-effect model were used to estimate the effects. Results. A total of 11 studies involving 965 patients were admitted in our meta-analysis. The pooled effects indicated that resistin levels were higher in CRC patients compared to healthy controls (WMD: 1.47 ng/mL; 95% CI: 0.78 to 2.16), with significant heterogeneity across the studies (I2 = 72%, p < 0.0001). Subgroup analyses and sensitivity analyses revealed that study quality, design, sample type, and resistin assays may account for this heterogeneity. No publication bias was observed. Conclusions. Our meta-analysis suggests that increased circulating resistin levels are associated with greater risk of colorectal cancer. Given the limited number of available studies and significant heterogeneity, larger well-designed randomized studies are warranted.
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Huang X, Yang Z. Resistin's, obesity and insulin resistance: the continuing disconnect between rodents and humans. J Endocrinol Invest 2016; 39:607-15. [PMID: 26662574 DOI: 10.1007/s40618-015-0408-2] [Citation(s) in RCA: 78] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2015] [Accepted: 10/24/2015] [Indexed: 02/07/2023]
Abstract
PURPOSE This review aimed to discuss the conflicting findings from resistin research in rodents and humans as well as recent advances in our understanding of resistin's role in obesity and insulin resistance. METHODS A comprehensive review and synthesis of resistin's role in obesity and insulin resistance as well as conflicting findings from resistin research in rodents and humans. RESULTS In rodents, resistin is increased in high-fat/high-carbohydrate-fed, obese states characterized by impaired glucose uptake and insulin sensitivity. Resistin plays a causative role in the development of insulin resistance in rodents via 5' AMP-activated protein kinase (AMPK)-dependent and AMPK-independent suppressor of cytokine signaling-3 (SOCS-3) signaling. In contrast to rodents, human resistin is primarily secreted by peripheral-blood mononuclear cells (PBMCs) as opposed to white adipocytes. Circulating resistin levels have been positively associated with central/visceral obesity (but not BMI) as well as insulin resistance, while other studies show no such association. Human resistin has a role in pro-inflammatory processes that have been conclusively associated with obesity and insulin resistance. PBMCs, as well as vascular cells, have been identified as the primary targets of resistin's pro-inflammatory activity via nuclear factor-κB (NF-κB, p50/p65) and other signaling pathways. CONCLUSION Mounting evidence reveals a continuing disconnect between resistin's role in rodents and humans due to significant differences between these two species with respect to resistin's gene and protein structure, differential gene regulation, tissue-specific distribution, and insulin resistance induction as well as a paucity of evidence regarding the resistin receptor and downstream signaling mechanisms of action.
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Affiliation(s)
- X Huang
- Department of Radiology, College of Basic Medicine, Chongqing Medical University, Chongqing, China
- Department of Internal Medicine, Hechuan Hospital of First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Z Yang
- Department of Internal Medicine, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
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García-Niño WR, Zazueta C. Ellagic acid: Pharmacological activities and molecular mechanisms involved in liver protection. Pharmacol Res 2015; 97:84-103. [DOI: 10.1016/j.phrs.2015.04.008] [Citation(s) in RCA: 158] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2015] [Revised: 04/16/2015] [Accepted: 04/18/2015] [Indexed: 12/23/2022]
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Chang WT, Wu CH, Hsu CL. Diallyl trisulphide inhibits adipogenesis in 3T3-L1 adipocytes through lipogenesis, fatty acid transport, and fatty acid oxidation pathways. J Funct Foods 2015. [DOI: 10.1016/j.jff.2015.05.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
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Antiresistin RNA Oligonucleotide Ameliorates Diet-Induced Nonalcoholic Fatty Liver Disease in Mice through Attenuating Proinflammatory Cytokines. BIOMED RESEARCH INTERNATIONAL 2015; 2015:414860. [PMID: 25922835 PMCID: PMC4397480 DOI: 10.1155/2015/414860] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/13/2015] [Revised: 02/19/2015] [Accepted: 03/10/2015] [Indexed: 02/08/2023]
Abstract
The aim of this study was to determine whether inhibition of resistin by a synthetic antiresistin RNA (oligonucleotide) oligo ameliorates metabolic and histological abnormalities in nonalcoholic fatty liver disease (NAFLD) induced by high-fat diet (HFD) in mice. The antiresistin RNA oligo and a scrambled control oligo (25 mg/kg of body weight) were i.p. injected to HFD mice. Serum metabolic parameters and hepatic enzymes were measured after 4-week treatment. The treatment significantly reduced epididymal fat and attenuated the elevated serum resistin, cholesterol, triglycerides, glucose, and insulin with an improved glucose tolerance test. Antiresistin RNA oligo also normalized serum AST and ALT levels with improved pathohistology of NAFLD. Immunoblotting and qRT-PCR revealed that decreased protein and mRNA expression of resistin in fat and liver tissues of the treated mice were associated with reduction of adipose TNF-α and IL-6 expression and secretion into circulation. mRNA and protein expression of hepatic phosphoenolpyruvate carboxykinase (PEPCK) and sterol regulatory element-binding protein-1c (SREBP-1c) were also significantly decreased in the treated mice. Our results suggest that resistin may exacerbate NAFLD in metabolic syndrome through upregulating inflammatory cytokines and hepatic PEPCK and SREBP-1c. Antiresistin RNA oligo ameliorated metabolic abnormalities and histopathology of NAFLD through attenuating proinflammatory cytokines.
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Chen N, Zhou L, Zhang Z, Xu J, Wan Z, Qin L. Resistin induces lipolysis and suppresses adiponectin secretion in cultured human visceral adipose tissue. ACTA ACUST UNITED AC 2014; 194-195:49-54. [DOI: 10.1016/j.regpep.2014.10.001] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2014] [Revised: 10/08/2014] [Accepted: 10/09/2014] [Indexed: 01/19/2023]
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Asterholm IW, Rutkowski JM, Fujikawa T, Cho YR, Fukuda M, Tao C, Wang ZV, Gupta RK, Elmquist JK, Scherer PE. Elevated resistin levels induce central leptin resistance and increased atherosclerotic progression in mice. Diabetologia 2014; 57:1209-18. [PMID: 24623101 PMCID: PMC4106234 DOI: 10.1007/s00125-014-3210-3] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2013] [Accepted: 02/14/2014] [Indexed: 01/24/2023]
Abstract
AIMS/HYPOTHESIS Resistin was originally identified as an adipocyte-derived factor upregulated during obesity and as a contributor to obesity-associated insulin resistance. Clinically, resistin has also been implicated in cardiovascular disease in a number of different patient populations. Our aim was to simultaneously address these phenomena. METHODS We generated mice with modest adipocyte-specific resistin overexpression. These mice were crossed with mice deficient in the LDL receptor (Ldlr (-/-)) to probe the physiological role of resistin. Both metabolic and atherosclerotic assessments were performed. RESULTS Resistin overexpression led to increased atherosclerotic progression in Ldlr (-/-) mice. This was in part related to elevated serum triacylglycerol levels and a reduced ability to clear triacylglycerol upon a challenge. Additional phenotypic changes, such as increased body weight and reduced glucose clearance, independent of the Ldlr (-/-) background, confirmed increased adiposity associated with a more pronounced insulin resistance. A hallmark of elevated resistin was the disproportionate increase in circulating leptin levels. These mice thus recapitulated both the proposed negative cardiovascular correlation and the insulin resistance. A unifying mechanism for this complex phenotype was a resistin-mediated central leptin resistance, which we demonstrate directly both in vivo and in organotypic brain slices. In line with reduced sympathetic nervous system outflow, we found decreased brown adipose tissue (BAT) activity. The resulting elevated triacylglycerol levels provide a likely explanation for accelerated atherosclerosis. CONCLUSIONS/INTERPRETATION Resistin overexpression leads to a complex metabolic phenotype driven by resistin-mediated central leptin resistance and reduced BAT activity. Hypothalamic leptin resistance thus provides a unifying mechanism for both resistin-mediated insulin resistance and enhanced atherosclerosis.
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Affiliation(s)
- Ingrid W. Asterholm
- Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-8549, USA
| | - Joseph M. Rutkowski
- Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-8549, USA
| | - Teppei Fujikawa
- Division of Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - You-Ree Cho
- Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-8549, USA
| | - Makoto Fukuda
- Division of Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Caroline Tao
- Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-8549, USA
| | - Zhao V. Wang
- Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-8549, USA
| | - Rana K. Gupta
- Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-8549, USA
| | - Joel K. Elmquist
- Division of Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Philipp E. Scherer
- Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-8549, USA
- Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA
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Riondino S, Roselli M, Palmirotta R, Della-Morte D, Ferroni P, Guadagni F. Obesity and colorectal cancer: Role of adipokines in tumor initiation and progression. World J Gastroenterol 2014; 20:5177-5190. [PMID: 24833848 PMCID: PMC4017033 DOI: 10.3748/wjg.v20.i18.5177] [Citation(s) in RCA: 143] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2013] [Revised: 01/20/2014] [Accepted: 03/06/2014] [Indexed: 02/06/2023] Open
Abstract
Obesity-associated diseases account for a large portion of public health challenges. Among obesity-related disorders, a direct and independent relationship has been ascertained for colorectal cancer (CRC). The evidence that adipocyte hypertrophy and excessive adipose tissue accumulation (mainly visceral) can promote pathogenic adipocyte and adipose tissue-related diseases, has led to formulate the concept of “adiposopathy”, defined as adipocyte and adipose tissue dysfunction that contributes to metabolic syndrome. Adipose tissue can, indeed, be regarded as an important and highly active player of the innate immune response, in which cytokine/adipokine secretion is responsible for a paracrine loop between adipocytes and macrophages, thus contributing to the systemic chronic low-grade inflammation associated with visceral obesity, which represents a favorable niche for tumor development. The adipocyte itself participates as a central mediator of this inflammatory response in obese individuals by secreting hormones, growth factors and proinflammatory cytokines, which are of particular relevance for the pathogenesis of CRC. Among adipocyte-secreted hormones, the most relevant to colorectal tumorigenesis are adiponectin, leptin, resistin and ghrelin. All these molecules have been involved in cell growth and proliferation, as well as tumor angiogenesis and it has been demonstrated that their expression changes from normal colonic mucosa to adenoma and adenocarcinoma, suggesting their involvement in multistep colorectal carcinogenesis. These findings have led to the hypothesis that an unfavorable adipokine profile, with a reduction of those with an anti-inflammatory and anti-cancerous activity, might serve as a prognostic factor in CRC patients and that adipokines or their analogues/antagonists might become useful agents in the management or chemoprevention of CRC.
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Ikeda Y, Tsuchiya H, Hama S, Kajimoto K, Kogure K. Resistin regulates the expression of plasminogen activator inhibitor-1 in 3T3-L1 adipocytes. Biochem Biophys Res Commun 2014; 448:129-33. [PMID: 24667608 DOI: 10.1016/j.bbrc.2014.03.076] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2014] [Accepted: 03/17/2014] [Indexed: 11/27/2022]
Abstract
Resistin and plasminogen activator inhibitor-1 (PAI-1) are adipokines, which are secreted from adipocytes. Increased plasma resistin and PAI-1 levels aggravate metabolic syndrome through exacerbation of insulin resistance and induction of chronic inflammation. However, the relationship between resistin and PAI-1 gene expression remains unclear. Previously, we found that resistin regulates lipid metabolism via carbohydrate responsive element-binding protein (ChREBP) during adipocyte maturation (Ikeda et al., 2013) [6]. In this study, to clarify the relationship between expression of resistin and PAI-1, PAI-1 expression in differentiated 3T3-L1 adipocytes was measured after transfection with anti-resistin siRNA. We found that PAI-1 gene expression and secreted PAI-1 protein were significantly decreased by resistin knockdown. Furthermore, phosphorylation of Akt, which can inhibit PAI-1 expression, was accelerated and the activity of protein phosphatase 2A (PP2A) was suppressed in resistin knockdown 3T3-L1 adipocytes. In addition, the expression of glucose transporter type 4, a ChREBP target gene, was reduced and was associated with inhibition of PP2A. The addition of culture medium collected from COS7 cells transfected with a resistin expression plasmid rescued the suppression of PAI-1 expression in resistin knockdown 3T3-L1 adipocytes. Our findings suggest that resistin regulates PAI-1 expression in 3T3-L1 adipocytes via Akt phosphorylation.
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Affiliation(s)
- Yoshito Ikeda
- Department of Biophysical Chemistry, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan
| | - Hiroyuki Tsuchiya
- Department of Biophysical Chemistry, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan
| | - Susumu Hama
- Department of Biophysical Chemistry, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan
| | - Kazuaki Kajimoto
- Laboratory of Innovative Nanomedicine, Graduate School of Pharmaceutical Sciences, Hokkaido University, Hokkaido 060-0808, Japan
| | - Kentaro Kogure
- Department of Biophysical Chemistry, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan.
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Nieva-Vazquez A, Pérez-Fuentes R, Torres-Rasgado E, López-López JG, Romero JR. Serum resistin levels are associated with adiposity and insulin sensitivity in obese Hispanic subjects. Metab Syndr Relat Disord 2013; 12:143-8. [PMID: 24266722 DOI: 10.1089/met.2013.0118] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND AND AIMS Resistin is involved in the development of obesity and insulin resistance (IR) in mice and may play a similar role in humans through mechanisms that remain unresolved. The objective of this study was to characterize the relationship between resistin levels in obese subjects with and without IR among Hispanic subjects. MATERIAL AND METHODS A cross-sectional study was performed on 117 nondiabetic Hispanic subjects of both genders that were allocated into three study groups: A control group (n=47) of otherwise healthy individuals in metabolic balance, a group with obesity (OB) (n=36), and a group with obesity and IR (OB-IR) (n=34). Anthropometric and clinical characterization was carried out, and resistin levels were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS We found that resistin levels were higher in OB and OB-IR groups when compared to the control group (1331.79±142.15 pg/mL, 1266.28±165.97 pg/mL vs. 959.21±171.43 pg/mL; P<0.05), an effect that was not confounded by age (control, 34.04±10.00 years; OB, 37.30±10.78 years; and OB-IR, 35.67±10.15 years). In addition, we observed a significant correlation (P<0.001) between resistin levels and higher adiposity and insulin sensitivity (IS) in our cohort. CONCLUSIONS Our results suggest that higher resistin levels are associated with higher adiposity and lower IS among obese Hispanic subjects.
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Affiliation(s)
- Adriana Nieva-Vazquez
- 1 Posgrado en Ciencias Químicas, Benemérita Universidad Autónoma de Puebla (BUAP) , Puebla, México
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