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Hade MD, Butsch BL, Palacio PL, Nguyen KT, Shantaram D, Noria S, Brethauer SA, Needleman BJ, Hsueh W, Reategui E, Magana SM. Human differentiated adipocytes can serve as surrogate mature adipocytes for adipocyte-derived extracellular vesicle analysis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.02.05.636729. [PMID: 39974962 PMCID: PMC11839020 DOI: 10.1101/2025.02.05.636729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/21/2025]
Abstract
Obesity is a growing global health concern, contributing to diseases such as cancer, autoimmune disorders, and neurodegenerative conditions. Adipose tissue dysfunction, characterized by abnormal adipokine secretion and chronic inflammation, plays a key role in these conditions. Adipose-derived extracellular vesicles (ADEVs) have emerged as critical mediators in obesity-related diseases. However, the study of mature adipocyte-derived EVs (mAdipo-EVs) is limited due to the short lifespan of mature adipocytes in culture, low EV yields, and the low abundance of these EV subpopulations in the circulation. Additionally, most studies rely on rodent models, which have differences in adipose tissue biology compared to humans. To overcome these challenges, we developed a standardized approach for differentiating human preadipocytes (preAdipos) into mature differentiated adipocytes (difAdipos), which produce high-yield, human adipocyte EVs (Adipo-EVs). Using visceral adipose tissue from bariatric surgical patients, we isolated the stromal vascular fraction (SVF) and differentiated preAdipos into difAdipos. Brightfield microscopy revealed that difAdipos exhibited morphological characteristics comparable to mature adipocytes (mAdipos) directly isolated from visceral adipose tissue, confirming their structural similarity. Additionally, qPCR analysis demonstrated decreased preadipocyte markers and increased mature adipocyte markers, further validating successful differentiation. Functionally, difAdipos exhibited lipolytic activity comparable to mAdipos, supporting their functional resemblance to native adipocytes. We then isolated preAdipo-EVs and difAdipo-EVs using tangential flow filtration and characterized them using bulk and single EV analysis. DifAdipo-EVs displayed classical EV and adipocyte-specific markers, with significant differences in biomarker expression compared to preAdipo-EVs. These findings demonstrate that difAdipos serve as a reliable surrogate for mature adipocytes, offering a consistent and scalable source of adipocyte-derived EVs for studying obesity and its associated disorders. Keywords: extracellular vesicles, adipocyte, adipose, adipocyte-derived extracellular vesicles, obesity.
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Elfeky M, Tsubota A, Shimozuru M, Tsubota T, Kimura K, Okamatsu-Ogura Y. Regulation of mitochondrial metabolism by hibernating bear serum: Insights into seasonal metabolic adaptations. Biochem Biophys Res Commun 2024; 736:150510. [PMID: 39121671 DOI: 10.1016/j.bbrc.2024.150510] [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: 05/09/2024] [Revised: 08/01/2024] [Accepted: 08/05/2024] [Indexed: 08/12/2024]
Abstract
Hibernating animals undergo a unique and reversible decrease in their whole-body metabolism, which is often accompanied by a suppression of mitochondrial respiration. However, the precise mechanisms underlying these seasonal shifts in mitochondrial metabolism remain unclear. In this study, the effect of the serum from active and hibernating Japanese black bears on mitochondrial respiration was assessed. Stromal-vascular cells were obtained from bear white adipose tissue and cultured with or without an adipocyte differentiation cocktail. When the oxygen consumption was measured in the presence of bear serum, the hibernating bear serum reduced maximal respiration by 15.5 % (p < 0.05) and spare respiratory capacity by 46.0 % (p < 0.01) in the differentiated adipocytes in comparison to the active bear serum. Similar reductions of 23.4 % (p = 0.06) and 40.6 % (p < 0.05) respectively were observed in undifferentiated cells, indicating the effect is cell type-independent. Blue native PAGE analysis revealed that hibernating bear serum suppressed cellular metabolism independently of the assembly of mitochondrial respiratory chain complexes. RNA-seq analysis identified 1094 differentially expressed genes (fold change>1.5, FDR<0.05) related to insulin signaling and glucose metabolism pathways. These findings suggest that the rapid alterations in mitochondrial metabolism during hibernation are likely induced by a combination of reduced insulin signaling and suppressed mitochondrial function, rather than changes in respiratory complex assembly.
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Affiliation(s)
- Mohamed Elfeky
- Laboratory of Biochemistry, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, 060-0818, Japan; Department of Biochemistry, Faculty of Veterinary Medicine, Alexandria University, Alexandria, 21526, Egypt.
| | - Ayumi Tsubota
- Laboratory of Biochemistry, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, 060-0818, Japan
| | - Michito Shimozuru
- Laboratory of Wildlife Biology and Medicine, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, 060-0818, Japan
| | - Toshio Tsubota
- Laboratory of Wildlife Biology and Medicine, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, 060-0818, Japan
| | - Kazuhiro Kimura
- Laboratory of Biochemistry, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, 060-0818, Japan
| | - Yuko Okamatsu-Ogura
- Laboratory of Biochemistry, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, 060-0818, Japan
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Zhou J, Wang S, Shen L, Song Y, Cao Z, Li Y, Luan P, Li H, Bai X, Zhang H. CTGF Inhibits the Differentiation of Chicken Preadipocytes via the TGFβ/Smad3 Signaling Pathway or by Inducing the Expression of ACTG2. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:19413-19423. [PMID: 39178398 DOI: 10.1021/acs.jafc.4c04233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/25/2024]
Abstract
Chicken is the main source of protein for humans in most parts of the world. However, excessive fat deposition in chickens has become a serious problem. This adversely affects the growth of chickens and causes economic losses. Fat formation mainly occurs through preadipocyte differentiation, and excessive fat deposition results from the accumulation of preadipocytes after differentiation. Our previous studies have found that the connective tissue growth factor (CTGF) may be an important candidate gene for fat deposition. However, its function and mechanism in preadipocyte differentiation are still unclear. In this study, the RT-qPCR and Western blot results showed that the expression of CTGF mRNA and protein in the abdominal adipose of lean chickens was significantly higher than that of fat chickens. Therefore, we studied the function and mechanism of the CTGF in the differentiation of chicken preadipocytes. Functionally, the CTGF inhibited the differentiation of chicken preadipocytes. Mechanistically, the CTGF mediated the TGFβ1/Smad3 signaling pathway, thereby inhibiting the differentiation of chicken preadipocytes. In addition, we used the unique molecular identifier (UMI) RNA-Seq technology to detect genes that can be regulated by the CTGF in the whole genome. Through transcriptome data analysis, we selected actin gamma 2 (ACTG2) as a candidate gene. Regarding the function of the ACTG2 gene, we found that it inhibited the differentiation of chicken preadipocytes. Furthermore, we found that the CTGF can inhibit the differentiation of preadipocytes through the ACTG2 gene. In summary, this study found the CTGF as a new negative regulator of chicken preadipocyte differentiation. The results of this study help improve the understanding of the molecular genetic mechanism of chicken adipose tissue growth and development and also have reference significance for the study of human obesity.
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Affiliation(s)
- Jiamei Zhou
- College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, P. R. China
- Key Laboratory of Chicken Genetics and Breeding, Ministry of Agriculture and Rural Affairs, Harbin 150030, P. R. China
- Key Laboratory of Animal Genetics, Breeding and Reproduction, Education Department of Heilongjiang Province, Harbin 150030, P. R. China
| | - Shuping Wang
- College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, P. R. China
- Key Laboratory of Chicken Genetics and Breeding, Ministry of Agriculture and Rural Affairs, Harbin 150030, P. R. China
- Key Laboratory of Animal Genetics, Breeding and Reproduction, Education Department of Heilongjiang Province, Harbin 150030, P. R. China
| | - Linyong Shen
- College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, P. R. China
- Key Laboratory of Chicken Genetics and Breeding, Ministry of Agriculture and Rural Affairs, Harbin 150030, P. R. China
- Key Laboratory of Animal Genetics, Breeding and Reproduction, Education Department of Heilongjiang Province, Harbin 150030, P. R. China
| | - Yan Song
- College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, P. R. China
- Key Laboratory of Chicken Genetics and Breeding, Ministry of Agriculture and Rural Affairs, Harbin 150030, P. R. China
- Key Laboratory of Animal Genetics, Breeding and Reproduction, Education Department of Heilongjiang Province, Harbin 150030, P. R. China
| | - Zhiping Cao
- College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, P. R. China
- Key Laboratory of Chicken Genetics and Breeding, Ministry of Agriculture and Rural Affairs, Harbin 150030, P. R. China
- Key Laboratory of Animal Genetics, Breeding and Reproduction, Education Department of Heilongjiang Province, Harbin 150030, P. R. China
| | - Yumao Li
- College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, P. R. China
- Key Laboratory of Chicken Genetics and Breeding, Ministry of Agriculture and Rural Affairs, Harbin 150030, P. R. China
- Key Laboratory of Animal Genetics, Breeding and Reproduction, Education Department of Heilongjiang Province, Harbin 150030, P. R. China
| | - Peng Luan
- College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, P. R. China
- Key Laboratory of Chicken Genetics and Breeding, Ministry of Agriculture and Rural Affairs, Harbin 150030, P. R. China
- Key Laboratory of Animal Genetics, Breeding and Reproduction, Education Department of Heilongjiang Province, Harbin 150030, P. R. China
| | - Hui Li
- College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, P. R. China
- Key Laboratory of Chicken Genetics and Breeding, Ministry of Agriculture and Rural Affairs, Harbin 150030, P. R. China
- Key Laboratory of Animal Genetics, Breeding and Reproduction, Education Department of Heilongjiang Province, Harbin 150030, P. R. China
| | - Xue Bai
- College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, P. R. China
- Key Laboratory of Chicken Genetics and Breeding, Ministry of Agriculture and Rural Affairs, Harbin 150030, P. R. China
- Key Laboratory of Animal Genetics, Breeding and Reproduction, Education Department of Heilongjiang Province, Harbin 150030, P. R. China
| | - Hui Zhang
- College of Animal Science and Technology, Northeast Agricultural University, Harbin 150030, P. R. China
- Key Laboratory of Chicken Genetics and Breeding, Ministry of Agriculture and Rural Affairs, Harbin 150030, P. R. China
- Key Laboratory of Animal Genetics, Breeding and Reproduction, Education Department of Heilongjiang Province, Harbin 150030, P. R. China
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Galal MA, Alouch SS, Alsultan BS, Dahman H, Alyabis NA, Alammar SA, Aljada A. Insulin Receptor Isoforms and Insulin Growth Factor-like Receptors: Implications in Cell Signaling, Carcinogenesis, and Chemoresistance. Int J Mol Sci 2023; 24:15006. [PMID: 37834454 PMCID: PMC10573852 DOI: 10.3390/ijms241915006] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 09/22/2023] [Accepted: 09/26/2023] [Indexed: 10/15/2023] Open
Abstract
This comprehensive review thoroughly explores the intricate involvement of insulin receptor (IR) isoforms and insulin-like growth factor receptors (IGFRs) in the context of the insulin and insulin-like growth factor (IGF) signaling (IIS) pathway. This elaborate system encompasses ligands, receptors, and binding proteins, giving rise to a wide array of functions, including aspects such as carcinogenesis and chemoresistance. Detailed genetic analysis of IR and IGFR structures highlights their distinct isoforms, which arise from alternative splicing and exhibit diverse affinities for ligands. Notably, the overexpression of the IR-A isoform is linked to cancer stemness, tumor development, and resistance to targeted therapies. Similarly, elevated IGFR expression accelerates tumor progression and fosters chemoresistance. The review underscores the intricate interplay between IRs and IGFRs, contributing to resistance against anti-IGFR drugs. Consequently, the dual targeting of both receptors could present a more effective strategy for surmounting chemoresistance. To conclude, this review brings to light the pivotal roles played by IRs and IGFRs in cellular signaling, carcinogenesis, and therapy resistance. By precisely modulating these receptors and their complex signaling pathways, the potential emerges for developing enhanced anti-cancer interventions, ultimately leading to improved patient outcomes.
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Affiliation(s)
- Mariam Ahmed Galal
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
- Department of Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol BS8 1QU, UK
| | - Samhar Samer Alouch
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
| | - Buthainah Saad Alsultan
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
| | - Huda Dahman
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
| | - Nouf Abdullah Alyabis
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
| | - Sarah Ammar Alammar
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
| | - Ahmad Aljada
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
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Santos MM, Costa TC, Silva W, Pistillo LZ, Junior DTV, Verardo LL, Paulino PVR, Sampaio CB, Gionbelli MP, Du M, Duarte MS. Nutrient supplementation of beef female calves at pre-weaning enhances the commitment of fibro-adipogenic progenitor cells to preadipocytes. Meat Sci 2023; 204:109286. [PMID: 37494740 DOI: 10.1016/j.meatsci.2023.109286] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 07/13/2023] [Accepted: 07/18/2023] [Indexed: 07/28/2023]
Abstract
We aimed to evaluate the impact of nutrient supplementation of beef female calves at pre-weaning on adipogenic determination. Thirty-four female calves were assigned to two experimental treatments: Control (CON, n = 17), where animals were supplemented only with mineral mixture; Supplemented (SUP, n = 17), where animals received energy-protein supplement containing minerals (5 g/kg of BW per day) of their body weight. Animals were supplemented from 100 to 250 days of age, and muscle samples were biopsied at the end of the supplementation period. Regarding the performance variables, there were no differences between treatments for initial body weight (P = 0.75). The final body weight (P = 0.07), average daily gain (P = 0.07), rib eye area (P = 0.03), and rib fat thickness (P = 0.08) were greater in SUP female calves compared with CON treatment. The number of fibro-adipogenic progenitor cells (P = 0.69) did not differ between treatments, while a greater number of intramuscular pre-adipocytes were observed in SUP than CON female calves (P = 0.01). The expression of miRNA-4429 (P = 0.20) did not differ between treatments, while the expression of miRNA-129-5p (P = 0.09) and miRNA-129-2-3p (P = 0.05) was greater in CON than SUP female calves. Our results suggest that nutrient supplementation at early postnatal stages of development enhances the commitment of fibro-adipogenic progenitor cells into the adipogenic lineages allowing to an increase in intramuscular fat deposition potential of the animals later in life.
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Affiliation(s)
- M M Santos
- Department of Animal Science, Universidade Federal de Viçosa, Viçosa, Brazil; Muscle Biology and Nutrigenomics Laboratory, Universidade Federal de Viçosa, Viçosa, Brazil
| | - T C Costa
- Muscle Biology and Nutrigenomics Laboratory, Universidade Federal de Viçosa, Viçosa, Brazil; Department of Animal Science, Universidade Federal de Lavras, Lavras, MG, Brazil
| | - W Silva
- Department of Animal Science, Universidade Federal de Viçosa, Viçosa, Brazil; Department of Animal Biosciences, University of Guelph, Guelph, ON, Canada
| | - L Z Pistillo
- Department of Animal Science, Universidade Federal de Viçosa, Viçosa, Brazil
| | - D T Valente Junior
- Department of Animal Science, Universidade Federal de Viçosa, Viçosa, Brazil; Muscle Biology and Nutrigenomics Laboratory, Universidade Federal de Viçosa, Viçosa, Brazil; Department of Animal Biosciences, University of Guelph, Guelph, ON, Canada
| | - L L Verardo
- Department of Animal Science, Universidade Federal dos Vales do Jequitinhonha e Mucuri, Diamantina, Brazil
| | | | - C B Sampaio
- Department of Animal Science, Universidade Federal de Viçosa, Viçosa, Brazil
| | - M P Gionbelli
- Department of Animal Science, Universidade Federal de Lavras, Lavras, MG, Brazil
| | - M Du
- Department of Animal Sciences, Washington State University, Pullman, WA, USA
| | - M S Duarte
- Department of Animal Biosciences, University of Guelph, Guelph, ON, Canada.
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Ayache L, Bushell A, Lee J, Salminen I, Crespi B. Mother's warmth from maternal genes: genomic imprinting of brown adipose tissue. Evol Med Public Health 2023; 11:379-385. [PMID: 37928960 PMCID: PMC10621903 DOI: 10.1093/emph/eoad031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 08/04/2023] [Indexed: 11/07/2023] Open
Abstract
Background and objectives Brown adipose tissue (BAT) plays key roles in mammalian physiology, most notably with regard to thermoregulation in infants and juveniles. Previous studies have suggested that intragenomic conflict, in the form of genomic imprinting, mediates BAT thermogenesis, because it represents a public good for groups of siblings, or a mother with her offspring, who huddle together to conserve warmth. By this hypothesis, maternally expressed imprinted genes should promote BAT, while paternally expressed genes should repress it. Methodology We systematically searched the literature using two curated lists of genes imprinted in humans and/or mice, in association with evidence regarding effects of perturbation to imprinted gene expression on BAT development or activity. Results Overall, enhanced BAT was associated with relatively higher expression of maternally expressed imprinted genes, and relatively lower expression of paternally expressed imprinted genes; this pattern was found for 16 of the 19 genes with sufficient information for robust ascertainment (Binomial test, P < 0.005, 2-tailed). Conclusions and implications These results support the kinship theory of imprinting and indicate that future studies of BAT, and its roles in human health and disease, may usefully focus on effects of imprinted genes and associated genomic conflicts.
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Affiliation(s)
- Lynn Ayache
- Department of Biological Sciences, Simon Fraser University, 8888 University Drive, Burnaby, British Columbia V5A 1S6, Canada
| | - Aiden Bushell
- Department of Biological Sciences, Simon Fraser University, 8888 University Drive, Burnaby, British Columbia V5A 1S6, Canada
| | - Jessica Lee
- Department of Biological Sciences, Simon Fraser University, 8888 University Drive, Burnaby, British Columbia V5A 1S6, Canada
| | - Iiro Salminen
- Department of Biological Sciences, Simon Fraser University, 8888 University Drive, Burnaby, British Columbia V5A 1S6, Canada
| | - Bernard Crespi
- Department of Biological Sciences, Simon Fraser University, 8888 University Drive, Burnaby, British Columbia V5A 1S6, Canada
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Xu S, Xi J, Wu T, Wang Z. The Role of Adipocyte Endoplasmic Reticulum Stress in Obese Adipose Tissue Dysfunction: A Review. Int J Gen Med 2023; 16:4405-4418. [PMID: 37789878 PMCID: PMC10543758 DOI: 10.2147/ijgm.s428482] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Accepted: 09/19/2023] [Indexed: 10/05/2023] Open
Abstract
Adipose tissue dysfunction plays an important role in metabolic diseases associated with chronic inflammation, insulin resistance and lipid ectopic deposition in obese patients. In recent years, it has been found that under the stimulation of adipocyte endoplasmic reticulum stress (ERS), the over-activated ER unfolded protein response (UPR) exacerbates the inflammatory response of adipose tissue by interfering with the normal metabolism of adipose tissue, promotes the secretion of adipokines, and affects the browning and thermogenic pathways of adipose tissue, ultimately leading to the manifestation of metabolic syndrome such as ectopic lipid deposition and disorders of glucolipid metabolism in obese patients. This paper mainly summarizes the relationship between adipocyte ERS and obese adipose tissue dysfunction and provides an overview of the mechanisms by which ERS induces metabolic disorders such as catabolism, thermogenesis and inflammation in obese adipose tissue through the regulation of molecules and pathways such as NF-κB, ADPN, STAMP2, LPIN1, TRIP-Br2, NF-Y and SIRT2 and briefly describes the current mechanisms targeting adipocyte endoplasmic reticulum stress to improve obesity and provide ideas for intervention and treatment of obese adipose tissue dysfunction.
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Affiliation(s)
- Shengjie Xu
- The First Clinical College, Shandong University of Traditional Chinese Medicine, Jinan, 250000, People’s Republic of China
| | - Jiaqiu Xi
- Shandong University of Traditional Chinese Medicine, Jinan, 250000, People’s Republic of China
| | - Tao Wu
- The First Clinical College, Shandong University of Traditional Chinese Medicine, Jinan, 250000, People’s Republic of China
| | - Zhonglin Wang
- Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, 250014, People’s Republic of China
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Monmai C, Kim JS, Baek SH. Germinated Rice Seeds Improved Resveratrol Production to Suppress Adipogenic and Inflammatory Molecules in 3T3-L1 Adipocytes. Molecules 2023; 28:5750. [PMID: 37570719 PMCID: PMC10420918 DOI: 10.3390/molecules28155750] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Revised: 07/21/2023] [Accepted: 07/28/2023] [Indexed: 08/13/2023] Open
Abstract
Obesity is a major risk factor for a variety of diseases and contributes to chronic inflammation. Resveratrol is a naturally occurring antioxidant that can reduce adipogenesis. In this study, the antiadipogenic and anti-inflammatory activities of resveratrol-enriched rice were investigated in 3T3-L1 adipocyte cells. Cotreatment of dexamethasone and isobutylmethylxanthin upregulated adipogenic transcription factors and signaling pathways. Subsequent treatment of adipocytes with rice seed extracts suppressed the differentiation of 3T3-L1 by downregulating adipogenic transcription factors (peroxisome proliferator-activated receptor γ and CCAAT/enhancer-binding protein α) and signaling pathways (extracellular signal-regulated kinase 1/2 and protein kinase B Akt), this was especially observed in cells treated with germinated resveratrol-enriched rice seed extract (DJ526_5). DJ526_5 treatment also markedly reduced lipid accumulation in the cells and expression of adipogenic genes. Lipopolysaccharide (LPS)-induced inflammatory cytokines (prostaglandin-endoperoxide synthase 2 (COX-2), tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6) decreased in cells treated with DJ526_5. Collectively, DJ526_5 exerts antiadipogenic effects by suppressing the expression of adipogenesis transcription factors. Moreover, DJ526_5 ameliorates anti-inflammatory effects in 3T3-L1 adipocytes by inhibiting the activation of phosphorylation NF-κB p65 and ERK ½ (MAPK). These results highlight the potential of resveratrol-enriched rice as an alternative obesity-reducing and anti-inflammatory agent.
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Affiliation(s)
| | | | - So-Hyeon Baek
- Department of Agricultural Life Science, Sunchon National University, Suncheon 59722, Republic of Korea; (C.M.); (J.-S.K.)
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Hoang AC, Sasi-Szabó L, Pál T, Szabó T, Diedrich V, Herwig A, Landgraf K, Körner A, Röszer T. Mitochondrial RNA stimulates beige adipocyte development in young mice. Nat Metab 2022; 4:1684-1696. [PMID: 36443525 PMCID: PMC9771821 DOI: 10.1038/s42255-022-00683-w] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 10/10/2022] [Indexed: 11/30/2022]
Abstract
Childhood obesity is a serious public health crisis and a critical factor that determines future obesity prevalence. Signals affecting adipocyte development in early postnatal life have a strong potential to trigger childhood obesity; however, these signals are still poorly understood. We show here that mitochondrial (mt)RNA efflux stimulates transcription of nuclear-encoded genes for mitobiogenesis and thermogenesis in adipocytes of young mice and human infants. While cytosolic mtRNA is a potential trigger of the interferon (IFN) response, young adipocytes lack such a response to cytosolic mtRNA due to the suppression of IFN regulatory factor (IRF)7 expression by vitamin D receptor signalling. Adult and obese adipocytes, however, strongly express IRF7 and mount an IFN response to cytosolic mtRNA. In turn, suppressing IRF7 expression in adult adipocytes restores mtRNA-induced mitobiogenesis and thermogenesis and eventually mitigates obesity. Retrograde mitochondrion-to-nucleus signalling by mtRNA is thus a mechanism to evoke thermogenic potential during early adipocyte development and to protect against obesity.
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Affiliation(s)
| | - László Sasi-Szabó
- Institute of Pediatrics, Clinical Centre, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Tibor Pál
- Institute of Pediatrics, Clinical Centre, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Tamás Szabó
- Institute of Pediatrics, Clinical Centre, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | | | - Annika Herwig
- Institute of Neurobiology, Ulm University, Ulm, Germany
| | - Kathrin Landgraf
- Center for Pediatric Research, University Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany
| | - Antje Körner
- Center for Pediatric Research, University Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany
- Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Center München at the University of Leipzig and University Hospital Leipzig, Leipzig, Germany
| | - Tamás Röszer
- Institute of Neurobiology, Ulm University, Ulm, Germany.
- Institute of Pediatrics, Clinical Centre, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
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10
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Huang J, Chen M, Liang Y, Hu Y, Xia W, Zhang Y, Zhao C, Wu L. Integrative metabolic analysis of orbital adipose/connective tissue in patients with thyroid-associated ophthalmopathy. Front Endocrinol (Lausanne) 2022; 13:1001349. [PMID: 36465658 PMCID: PMC9718489 DOI: 10.3389/fendo.2022.1001349] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Accepted: 11/04/2022] [Indexed: 11/19/2022] Open
Abstract
Objective Thyroid-associated ophthalmopathy (TAO) is a disfiguring autoimmune disease, which destroys the structure of orbital tissues and even threatens vision. Metabolic reprograming is critical in autoimmune diseases; however, the metabolic basis of TAO remains to be clarified. Our study aimed to reveal the metabolic profile of TAO. Methods Orbital adipose/connective tissues from eleven TAO patients and twelve control subjects were collected during surgeries and analyzed with liquid chromatograph-mass spectrometer. Orthogonal partial least-squares discrimination analysis (OPLS-DA), variable importance in projection (VIP), heat map, and volcano plot were used to reveal metabolic profile in TAO. Pathway analysis and metabolites-gene analysis were utilized to explore potential metabolic metabolism in TAO. Results 3038 metabolites were detected in samples from the TAO patients and the controls. OPLS-DA analysis of the metabolomics results showed two distinguished groups, demonstrating that TAO has a unique metabolome. Univariate tests identified 593 dysregulated metabolites (P < 0.05), including 367 increased metabolites and 226 decreased metabolites. Pathway analysis showed that changed metabolites were enriched in cholesterol metabolism, choline metabolism in cancer, fat digestion and absorption, regulation of lipolysis in adipocytes, and insulin resistance. In addition, metabolites-gene analysis illustrated that cholesterol metabolism was involved in the pathogenesis of TAO. Endoplasmic reticulum stress-related genes (ATF6, PERK, and IRE1α) expressions were higher in TAO orbital tissues than in control orbital tissues verified by western blot. Additionally, the expression level of diacylglycerol acyltransferase 1 (DGAT1), a key metabolic protein for triacylglycerol synthesis, was increased in orbital tissues of TAO detected by qRT-PCR, indicating disrupted cholesterol metabolism in TAO. Conclusion The present study demonstrated different metabolite profiles and potential metabolic mechanisms in TAO.
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Affiliation(s)
- Jiancheng Huang
- Eye Institute, Eye and Ear, Nose & Throat (ENT) Hospital, Shanghai Medical College, Fudan University, Shanghai, China
- National Healthcare (NHC) Key Laboratory of Myopia, Fudan University, Shanghai, China
- Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, China
- Shanghai Key Laboratory of Visual Impairment and Restoration, Fudan University, Shanghai, China
| | - Meng Chen
- Eye Institute, Eye and Ear, Nose & Throat (ENT) Hospital, Shanghai Medical College, Fudan University, Shanghai, China
- National Healthcare (NHC) Key Laboratory of Myopia, Fudan University, Shanghai, China
- Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, China
| | - Yu Liang
- Eye Institute, Eye and Ear, Nose & Throat (ENT) Hospital, Shanghai Medical College, Fudan University, Shanghai, China
- National Healthcare (NHC) Key Laboratory of Myopia, Fudan University, Shanghai, China
- Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, China
- Shanghai Key Laboratory of Visual Impairment and Restoration, Fudan University, Shanghai, China
| | - Yuxiang Hu
- Eye Institute, Eye and Ear, Nose & Throat (ENT) Hospital, Shanghai Medical College, Fudan University, Shanghai, China
- National Healthcare (NHC) Key Laboratory of Myopia, Fudan University, Shanghai, China
- Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, China
- Shanghai Key Laboratory of Visual Impairment and Restoration, Fudan University, Shanghai, China
| | - Weiyi Xia
- Eye Institute, Eye and Ear, Nose & Throat (ENT) Hospital, Shanghai Medical College, Fudan University, Shanghai, China
- National Healthcare (NHC) Key Laboratory of Myopia, Fudan University, Shanghai, China
- Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, China
- Shanghai Key Laboratory of Visual Impairment and Restoration, Fudan University, Shanghai, China
| | - Yihan Zhang
- Eye Institute, Eye and Ear, Nose & Throat (ENT) Hospital, Shanghai Medical College, Fudan University, Shanghai, China
- National Healthcare (NHC) Key Laboratory of Myopia, Fudan University, Shanghai, China
- Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, China
- Shanghai Key Laboratory of Visual Impairment and Restoration, Fudan University, Shanghai, China
| | - Chen Zhao
- Eye Institute, Eye and Ear, Nose & Throat (ENT) Hospital, Shanghai Medical College, Fudan University, Shanghai, China
- National Healthcare (NHC) Key Laboratory of Myopia, Fudan University, Shanghai, China
- Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, China
- Shanghai Key Laboratory of Visual Impairment and Restoration, Fudan University, Shanghai, China
| | - Lianqun Wu
- Eye Institute, Eye and Ear, Nose & Throat (ENT) Hospital, Shanghai Medical College, Fudan University, Shanghai, China
- National Healthcare (NHC) Key Laboratory of Myopia, Fudan University, Shanghai, China
- Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, China
- Shanghai Key Laboratory of Visual Impairment and Restoration, Fudan University, Shanghai, China
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11
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Ramón-Landreau M, Sánchez-Puelles C, López-Sánchez N, Lozano-Ureña A, Llabrés-Mas AM, Frade JM. E2F4DN Transgenic Mice: A Tool for the Evaluation of E2F4 as a Therapeutic Target in Neuropathology and Brain Aging. Int J Mol Sci 2022; 23:ijms232012093. [PMID: 36292945 PMCID: PMC9603043 DOI: 10.3390/ijms232012093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Revised: 10/04/2022] [Accepted: 10/05/2022] [Indexed: 12/03/2022] Open
Abstract
E2F4 was initially described as a transcription factor with a key function in the regulation of cell quiescence. Nevertheless, a number of recent studies have established that E2F4 can also play a relevant role in cell and tissue homeostasis, as well as tissue regeneration. For these non-canonical functions, E2F4 can also act in the cytoplasm, where it is able to interact with many homeostatic and synaptic regulators. Since E2F4 is expressed in the nervous system, it may fulfill a crucial role in brain function and homeostasis, being a promising multifactorial target for neurodegenerative diseases and brain aging. The regulation of E2F4 is complex, as it can be chemically modified through acetylation, from which we present evidence in the brain, as well as methylation, and phosphorylation. The phosphorylation of E2F4 within a conserved threonine motif induces cell cycle re-entry in neurons, while a dominant negative form of E2F4 (E2F4DN), in which the conserved threonines have been substituted by alanines, has been shown to act as a multifactorial therapeutic agent for Alzheimer’s disease (AD). We generated transgenic mice neuronally expressing E2F4DN. We have recently shown using this mouse strain that expression of E2F4DN in 5xFAD mice, a known murine model of AD, improved cognitive function, reduced neuronal tetraploidization, and induced a transcriptional program consistent with modulation of amyloid-β (Aβ) peptide proteostasis and brain homeostasis recovery. 5xFAD/E2F4DN mice also showed reduced microgliosis and astrogliosis in both the cerebral cortex and hippocampus at 3-6 months of age. Here, we analyzed the immune response in 1 year-old 5xFAD/E2F4DN mice, concluding that reduced microgliosis and astrogliosis is maintained at this late stage. In addition, the expression of E2F4DN also reduced age-associated microgliosis in wild-type mice, thus stressing its role as a brain homeostatic agent. We conclude that E2F4DN transgenic mice represent a promising tool for the evaluation of E2F4 as a therapeutic target in neuropathology and brain aging.
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Affiliation(s)
- Morgan Ramón-Landreau
- Department of Molecular, Cellular and Developmental Neurobiology, Cajal Institute, Consejo Superior de Investigaciones Científicas, 28002 Madrid, Spain
| | - Cristina Sánchez-Puelles
- Department of Molecular, Cellular and Developmental Neurobiology, Cajal Institute, Consejo Superior de Investigaciones Científicas, 28002 Madrid, Spain
| | - Noelia López-Sánchez
- Department of Molecular, Cellular and Developmental Neurobiology, Cajal Institute, Consejo Superior de Investigaciones Científicas, 28002 Madrid, Spain
| | - Anna Lozano-Ureña
- Department of Molecular, Cellular and Developmental Neurobiology, Cajal Institute, Consejo Superior de Investigaciones Científicas, 28002 Madrid, Spain
| | - Aina M. Llabrés-Mas
- Department of Molecular, Cellular and Developmental Neurobiology, Cajal Institute, Consejo Superior de Investigaciones Científicas, 28002 Madrid, Spain
| | - José M. Frade
- Department of Molecular, Cellular and Developmental Neurobiology, Cajal Institute, Consejo Superior de Investigaciones Científicas, 28002 Madrid, Spain
- Cajal International Neuroscience Center, Consejo Superior de Investigaciones Científicas, UAH Science and Technology Campus, Avenida León 1, 28805 Alcalá de Henares, Spain
- Correspondence: ; Tel.: +34-91-585-4740
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12
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A Mutant Variant of E2F4 Triggers Multifactorial Therapeutic Effects in 5xFAD Mice. Mol Neurobiol 2022; 59:3016-3039. [PMID: 35254651 PMCID: PMC9016056 DOI: 10.1007/s12035-022-02764-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 01/28/2022] [Indexed: 11/25/2022]
Abstract
Alzheimer’s disease (AD) has a complex etiology, which requires a multifactorial approach for an efficient treatment. We have focused on E2 factor 4 (E2F4), a transcription factor that regulates cell quiescence and tissue homeostasis, controls gene networks affected in AD, and is upregulated in the brains of Alzheimer’s patients and of APPswe/PS1dE9 and 5xFAD transgenic mice. E2F4 contains an evolutionarily conserved Thr-motif that, when phosphorylated, modulates its activity, thus constituting a potential target for intervention. In this study, we generated a knock-in mouse strain with neuronal expression of a mouse E2F4 variant lacking this Thr-motif (E2F4DN), which was mated with 5xFAD mice. Here, we show that neuronal expression of E2F4DN in 5xFAD mice potentiates a transcriptional program consistent with the attenuation of the immune response and brain homeostasis. This correlates with reduced microgliosis and astrogliosis, modulation of amyloid-β peptide proteostasis, and blocking of neuronal tetraploidization. Moreover, E2F4DN prevents cognitive impairment and body weight loss, a known somatic alteration associated with AD. We also show that our finding is significant for AD, since E2F4 is expressed in cortical neurons from Alzheimer patients in association with Thr-specific phosphorylation, as evidenced by an anti-E2F4/anti-phosphoThr proximity ligation assay. We propose E2F4DN-based gene therapy as a promising multifactorial approach against AD.
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13
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Ha YS, Kim TK, Park KS, Hwang S, Kim J, Kim SJ. Inhibitory effects of Rocaglamide-A on PPARγ-driven adipogenesis through regulation of mitotic clonal expansion involving the JAK2/STAT3 pathway. Biochim Biophys Acta Mol Cell Biol Lipids 2022; 1867:159148. [PMID: 35248800 DOI: 10.1016/j.bbalip.2022.159148] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 02/20/2022] [Accepted: 02/27/2022] [Indexed: 11/15/2022]
Abstract
Inhibition of adipogenesis is an important strategy for obesity treatment. Rocaglamide-A (Roc-A) is a natural herbal medicine isolated from the genus Aglaia (family Meliaceae), which has a cyclopenta[b]benzofuran core structure. Roc-A exhibits various pharmacological effects against diverse human cancer cells. However, the exact role of Roc-A during adipogenesis in adipocytes has not been studied at all. In this study, we demonstrate that Roc-A is crucial for reducing adipogenesis via downregulating PPARγ transcriptional activity. Consistently, Western-blot and RT-PCR analyses clearly showed that Roc-A inhibits the expression of PPARγ target genes and lipogenic markers in a dose-dependent manner along with suppression of lipid accumulation, in both 3T3-L1 cells and mouse adipose-derived stem cells. Mechanistically, Roc-A significantly decreased JAK2/STAT3 phosphorylation in a dose-dependent manner in 3T3-L1 adipocytes. In particular, we confirmed that Roc-A effectively suppressed the expression of genes involved in cell-cycle regulation, such as cyclin A, B, D1, and E1, early during mitotic clonal expansion in 3T3-L1 adipocytes, and this effect was abolished by the JAK2/STAT3 activator FGF2. Taken together, our results demonstrated that Roc-A reduces adipogenesis by inhibiting PPARγ transactivation and JAK2/STAT3 phosphorylation and thus may serve as a therapeutic target in obesity.
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Affiliation(s)
- Yoon-Su Ha
- Department of Biochemistry, College of Natural Sciences, and Kangwon Institute of Inclusive Technology, Kangwon National University, 24341 Chuncheon, Republic of Korea; Global/Gangwon Innovative Biologics-Regional Leading Research Center (GIB-RLRC), Kangwon National University, 24341 Chuncheon, Republic of Korea
| | - Taek-Kyong Kim
- Department of Biochemistry, College of Natural Sciences, and Kangwon Institute of Inclusive Technology, Kangwon National University, 24341 Chuncheon, Republic of Korea; Global/Gangwon Innovative Biologics-Regional Leading Research Center (GIB-RLRC), Kangwon National University, 24341 Chuncheon, Republic of Korea
| | - Ki-Sun Park
- KM Science Research Division, Korea Institute of Oriental Medicine, Daejeon 34054, Republic of Korea
| | - Seonghwan Hwang
- College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, 46241, South Korea
| | - Jeongkyu Kim
- Department of Life Science, Chung-Ang University, Seoul 06974, Republic of Korea.
| | - Seung-Jin Kim
- Department of Biochemistry, College of Natural Sciences, and Kangwon Institute of Inclusive Technology, Kangwon National University, 24341 Chuncheon, Republic of Korea; Global/Gangwon Innovative Biologics-Regional Leading Research Center (GIB-RLRC), Kangwon National University, 24341 Chuncheon, Republic of Korea.
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14
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Kirschner KM, Foryst-Ludwig A, Gohlke S, Li C, Flores RE, Kintscher U, Schupp M, Schulz TJ, Scholz H. Wt1 haploinsufficiency induces browning of epididymal fat and alleviates metabolic dysfunction in mice on high-fat diet. Diabetologia 2022; 65:528-540. [PMID: 34846543 PMCID: PMC8803700 DOI: 10.1007/s00125-021-05621-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Accepted: 09/24/2021] [Indexed: 11/26/2022]
Abstract
AIMS/HYPOTHESIS Despite a similar fat storing function, visceral (intra-abdominal) white adipose tissue (WAT) is detrimental, whereas subcutaneous WAT is considered to protect against metabolic disease. Recent findings indicate that thermogenic genes, expressed in brown adipose tissue (BAT), can be induced primarily in subcutaneous WAT. Here, we investigate the hypothesis that the Wilms tumour gene product (WT1), which is expressed in intra-abdominal WAT but not in subcutaneous WAT and BAT, suppresses a thermogenic program in white fat cells. METHODS Heterozygous Wt1 knockout mice and their wild-type littermates were examined in terms of thermogenic and adipocyte-selective gene expression. Glucose tolerance and hepatic lipid accumulation in these mice were assessed under normal chow and high-fat diet conditions. Pre-adipocytes isolated from the stromal vascular fraction of BAT were transduced with Wt1-expressing retrovirus, induced to differentiate and analysed for the expression of thermogenic and adipocyte-selective genes. RESULTS Expression of the thermogenic genes Cpt1b and Tmem26 was enhanced and transcript levels of Ucp1 were on average more than tenfold higher in epididymal WAT of heterozygous Wt1 knockout mice compared with wild-type mice. Wt1 heterozygosity reduced epididymal WAT mass, improved whole-body glucose tolerance and alleviated severe hepatic steatosis upon diet-induced obesity in mice. Retroviral expression of WT1 in brown pre-adipocytes, which lack endogenous WT1, reduced mRNA levels of Ucp1, Ppargc1a, Cidea, Prdm16 and Cpt1b upon in vitro differentiation by 60-90%. WT1 knockdown in epididymal pre-adipocytes significantly lowered Aldh1a1 and Zfp423 transcripts, two key suppressors of the thermogenic program. Conversely, Aldh1a1 and Zfp423 mRNA levels were increased approximately five- and threefold, respectively, by retroviral expression of WT1 in brown pre-adipocytes. CONCLUSION/INTERPRETATION WT1 functions as a white adipocyte determination factor in epididymal WAT by suppressing thermogenic genes. Reducing Wt1 expression in this and other intra-abdominal fat depots may represent a novel treatment strategy in metabolic disease.
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Affiliation(s)
- Karin M Kirschner
- Institut für Vegetative Physiologie, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Anna Foryst-Ludwig
- Institut für Pharmakologie, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), partner site Berlin, Berlin, Germany
| | - Sabrina Gohlke
- Department of Adipocyte Development and Nutrition, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany
| | - Chen Li
- Institut für Pharmakologie, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Roberto E Flores
- Institut für Pharmakologie, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Ulrich Kintscher
- Institut für Pharmakologie, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), partner site Berlin, Berlin, Germany
| | - Michael Schupp
- Institut für Pharmakologie, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Tim J Schulz
- Department of Adipocyte Development and Nutrition, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany
- Institute of Nutritional Science, University of Potsdam, Potsdam-Rehbrücke, Nuthetal, Germany
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Holger Scholz
- Institut für Vegetative Physiologie, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
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15
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Pei J, Wang B, Wang D. Current Studies on Molecular Mechanisms of Insulin Resistance. J Diabetes Res 2022; 2022:1863429. [PMID: 36589630 PMCID: PMC9803571 DOI: 10.1155/2022/1863429] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 06/06/2022] [Accepted: 12/12/2022] [Indexed: 12/24/2022] Open
Abstract
Diabetes is a metabolic disease that raises the risk of microvascular and neurological disorders. Insensitivity to insulin is a characteristic of type II diabetes, which accounts for 85-90 percent of all diabetic patients. The fundamental molecular factor of insulin resistance may be impaired cell signal transduction mediated by the insulin receptor (IR). Several cell-signaling proteins, including IR, insulin receptor substrate (IRS), and phosphatidylinositol 3-kinase (PI3K), have been recognized as being important in the impaired insulin signaling pathway since they are associated with a large number of proteins that are strictly regulated and interact with other signaling pathways. Many studies have found a correlation between IR alternative splicing, IRS gene polymorphism, the complicated regulatory function of IRS serine/threonine phosphorylation, and the negative regulatory role of p85 in insulin resistance and diabetes mellitus. This review brings up-to-date knowledge of the roles of signaling proteins in insulin resistance in order to aid in the discovery of prospective targets for insulin resistance treatment.
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Affiliation(s)
- Jinli Pei
- Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Baochun Wang
- The First Department of Gastrointestinal Surgery, Hainan General Hospital, Haikou, Hainan 570228, China
| | - Dayong Wang
- Laboratory of Biopharmaceuticals and Molecular Pharmacology, School of Pharmaceutical Sciences, Hainan University, Hainan 570228, China
- State Key Laboratory of Tropical Biological Resources of the Ministry of Education of China, Hainan University, Hainan 570228, China
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16
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Peng H, Tian X, Gan L, Yang X. Nobiletin promotes adipogenesis in 3T3-L1 cells through the activation of Akt. ADVANCES IN TRADITIONAL MEDICINE 2021. [DOI: 10.1007/s13596-021-00614-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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17
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Abou Azar F, Lim GE. Metabolic Contributions of Wnt Signaling: More Than Controlling Flight. Front Cell Dev Biol 2021; 9:709823. [PMID: 34568323 PMCID: PMC8458764 DOI: 10.3389/fcell.2021.709823] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Accepted: 08/16/2021] [Indexed: 12/12/2022] Open
Abstract
The canonical Wnt signaling pathway is ubiquitous throughout the body and influences a diverse array of physiological processes. Following the initial discovery of the Wnt signaling pathway during wing development in Drosophila melanogaster, it is now widely appreciated that active Wnt signaling in mammals is necessary for the development and growth of various tissues involved in whole-body metabolism, such as brain, liver, pancreas, muscle, and adipose. Moreover, elegant gain- and loss-of-function studies have dissected the tissue-specific roles of various downstream effector molecules in the regulation of energy homeostasis. This review attempts to highlight and summarize the contributions of the Wnt signaling pathway and its downstream effectors on whole-body metabolism and their influence on the development of metabolic diseases, such as diabetes and obesity. A better understanding of the Wnt signaling pathway in these tissues may aid in guiding the development of future therapeutics to treat metabolic diseases.
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Affiliation(s)
- Frederic Abou Azar
- 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
| | - Gareth E 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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18
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Ruiz-Cantos M, Hutchison CE, Shoulders CC. Musings from the Tribbles Research and Innovation Network. Cancers (Basel) 2021; 13:cancers13184517. [PMID: 34572744 PMCID: PMC8467127 DOI: 10.3390/cancers13184517] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2021] [Revised: 09/02/2021] [Accepted: 09/04/2021] [Indexed: 11/16/2022] Open
Abstract
This commentary integrates historical and modern findings that underpin our understanding of the cell-specific functions of the Tribbles (TRIB) proteins that bear on tumorigenesis. We touch on the initial discovery of roles played by mammalian TRIB proteins in a diverse range of cell-types and pathologies, for example, TRIB1 in regulatory T-cells, TRIB2 in acute myeloid leukaemia and TRIB3 in gliomas; the origins and diversity of TRIB1 transcripts; microRNA-mediated (miRNA) regulation of TRIB1 transcript decay and translation; the substantial conformational changes that ensue on binding of TRIB1 to the transcription factor C/EBPα; and the unique pocket formed by TRIB1 to sequester its C-terminal motif bearing a binding site for the E3 ubiquitin ligase COP1. Unashamedly, the narrative is relayed through the perspective of the Tribbles Research and Innovation Network, and its establishment, progress and future ambitions: the growth of TRIB and COP1 research to hasten discovery of their cell-specific contributions to health and obesity-related cancers.
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Yoshikawa K. Necdin: A purposive integrator of molecular interaction networks for mammalian neuron vitality. Genes Cells 2021; 26:641-683. [PMID: 34338396 PMCID: PMC9290590 DOI: 10.1111/gtc.12884] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 06/27/2021] [Accepted: 06/29/2021] [Indexed: 12/29/2022]
Abstract
Necdin was originally found in 1991 as a hypothetical protein encoded by a neural differentiation‐specific gene transcript in murine embryonal carcinoma cells. Virtually all postmitotic neurons and their precursor cells express the necdin gene (Ndn) during neuronal development. Necdin mRNA is expressed only from the paternal allele through genomic imprinting, a placental mammal‐specific epigenetic mechanism. Necdin and its homologous MAGE (melanoma antigen) family, which have evolved presumedly from a subcomplex component of the SMC5/6 complex, are expressed exclusively in placental mammals. Paternal Ndn‐mutated mice totally lack necdin expression and exhibit various types of neuronal abnormalities throughout the nervous system. Ndn‐null neurons are vulnerable to detrimental stresses such as DNA damage. Necdin also suppresses both proliferation and apoptosis of neural stem/progenitor cells. Functional analyses using Ndn‐manipulated cells reveal that necdin consistently exerts antimitotic, anti‐apoptotic and prosurvival effects. Necdin interacts directly with a number of regulatory proteins including E2F1, p53, neurotrophin receptors, Sirt1 and PGC‐1α, which serve as major hubs of protein–protein interaction networks for mitosis, apoptosis, differentiation, neuroprotection and energy homeostasis. This review focuses on necdin as a pleiotropic protein that integrates molecular interaction networks to promote neuronal vitality in modern placental mammals.
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Zhang Z, Yang D, Xiang J, Zhou J, Cao H, Che Q, Bai Y, Guo J, Su Z. Non-shivering Thermogenesis Signalling Regulation and Potential Therapeutic Applications of Brown Adipose Tissue. Int J Biol Sci 2021; 17:2853-2870. [PMID: 34345212 PMCID: PMC8326120 DOI: 10.7150/ijbs.60354] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Accepted: 06/23/2021] [Indexed: 12/25/2022] Open
Abstract
In mammals, thermogenic organs exist in the body that increase heat production and enhance energy regulation. Because brown adipose tissue (BAT) consumes energy and generates heat, increasing energy expenditure via BAT might be a potential strategy for new treatments for obesity and obesity-related diseases. Thermogenic differentiation affects normal adipose tissue generation, emphasizing the critical role that common transcriptional regulation factors might play in common characteristics and sources. An understanding of thermogenic differentiation and related factors could help in developing ways to improve obesity indirectly or directly through targeting of specific signalling pathways. Many studies have shown that the active components of various natural products promote thermogenesis through various signalling pathways. This article reviews recent major advances in this field, including those in the cyclic adenosine monophosphate-protein kinase A (cAMP-PKA), cyclic guanosine monophosphate-GMP-dependent protein kinase G (cGMP-AKT), AMP-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), transforming growth factor-β/bone morphogenic protein (TGF-β/BMP), transient receptor potential (TRP), Wnt, nuclear factor-κ-light-chain-enhancer of activated B cells (NF-κΒ), Notch and Hedgehog (Hh) signalling pathways in brown and brown-like adipose tissue. To provide effective information for future research on weight-loss nutraceuticals or drugs, this review also highlights the natural products and their active ingredients that have been reported in recent years to affect thermogenesis and thus contribute to weight loss via the above signalling pathways.
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Affiliation(s)
- Zhengyan Zhang
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China.,Guangdong Metabolic Diseases Research Centre of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Di Yang
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China.,Guangdong Metabolic Diseases Research Centre of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Junwei Xiang
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China.,Guangdong Metabolic Diseases Research Centre of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Jingwen Zhou
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China.,Guangdong Metabolic Diseases Research Centre of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Hua Cao
- Guangdong Cosmetics Engineering & Technology Research Center, School of Chemistry and Chemical Engneering, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Qishi Che
- Guangzhou Rainhome Pharm & Tech Co., Ltd., Guangzhou 510663, China
| | - Yan Bai
- School of Public Health, Guangdong Pharmaceutical University, Guangzhou 510310, China
| | - Jiao Guo
- Guangdong Metabolic Diseases Research Centre of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Zhengquan Su
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China.,Guangdong Metabolic Diseases Research Centre of Integrated Chinese and Western Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
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21
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Nie X, Wei X, Ma H, Fan L, Chen WD. The complex role of Wnt ligands in type 2 diabetes mellitus and related complications. J Cell Mol Med 2021; 25:6479-6495. [PMID: 34042263 PMCID: PMC8278111 DOI: 10.1111/jcmm.16663] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 05/02/2021] [Accepted: 05/10/2021] [Indexed: 12/15/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) is one of the major chronic diseases, whose prevalence is increasing dramatically worldwide and can lead to a range of serious complications. Wnt ligands (Wnts) and their activating Wnt signalling pathways are closely involved in the regulation of various processes that are important for the occurrence and progression of T2DM and related complications. However, our understanding of their roles in these diseases is quite rudimentary due to the numerous family members of Wnts and conflicting effects via activating the canonical and/or non-canonical Wnt signalling pathways. In this review, we summarize the current findings on the expression pattern and exact role of each human Wnt in T2DM and related complications, including Wnt1, Wnt2, Wnt2b, Wnt3, Wnt3a, Wnt4, Wnt5a, Wnt5b, Wnt6, Wnt7a, Wnt7b, Wnt8a, Wnt8b, Wnt9a, Wnt9b, Wnt10a, Wnt10b, Wnt11 and Wnt16. Moreover, the role of main antagonists (sFRPs and WIF-1) and coreceptor (LRP6) of Wnts in T2DM and related complications and main challenges in designing Wnt-based therapeutic approaches for these diseases are discussed. We hope a deep understanding of the mechanistic links between Wnt signalling pathways and diabetic-related diseases will ultimately result in a better management of these diseases.
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Affiliation(s)
- Xiaobo Nie
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Basic Medical Sciences, People's Hospital of Hebi, Henan University, Kaifeng, China
| | - Xiaoyun Wei
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Basic Medical Sciences, People's Hospital of Hebi, Henan University, Kaifeng, China
| | - Han Ma
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Basic Medical Sciences, People's Hospital of Hebi, Henan University, Kaifeng, China
| | - Lili Fan
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Basic Medical Sciences, People's Hospital of Hebi, Henan University, Kaifeng, China
| | - Wei-Dong Chen
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Basic Medical Sciences, People's Hospital of Hebi, Henan University, Kaifeng, China.,Key Laboratory of Molecular Pathology, School of Basic Medical Science, Inner Mongolia Medical University, Hohhot, China
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22
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Li N, Chen K, Dong H, Yang J, Yoshizawa M, Kagami H, Li X. Alliin inhibits adipocyte differentiation by downregulating Akt expression: Implications for metabolic disease. Exp Ther Med 2021; 21:563. [PMID: 33850535 PMCID: PMC8027764 DOI: 10.3892/etm.2021.9995] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Accepted: 07/23/2020] [Indexed: 12/13/2022] Open
Abstract
Obesity is currently an important health problem and is associated with an increased likelihood of various diseases. The efficacies of various natural treatments have been assessed for their utility in treating obesity. Alliin (S-allyl-L-cysteine sulfoxides) is considered the major component of garlic and has a wide range of natural antioxidant properties. However, the direct effects of alliin on obesity have not been well clarified. The present study investigated the effects and possible mechanisms of alliin on adipocyte differentiation. The 3T3-L1 cells were treated with alliin (0-40 µg/ml) during adipogenic differentiation. The effect of alliin on lipid accumulation was evaluated by Oil red O staining. Reverse transcription-quantitative PCR was performed to investigate the expression levels of adipogenic differentiation-related genes. The accumulation of lipid droplets was markedly inhibited following alliin treatment. The expression levels of multiple adipogenic transcription markers, such as CCAAT/enhancer-binding protein (C/EBP) β, C/EBP α and peroxisome proliferation-activity receptor γ, were markedly decreased following treatment with alliin during adipogenic differentiation. Expression levels of several adipocyte-related genes were subsequently suppressed. Additionally, alliin suppressed PKB/Akt and PI3K expression. These results suggested that alliin exhibits anti-adipogenic activity by downregulating major adipogenic differentiation-related genes and Akt/PI3K expression. Alliin may have a potential therapeutic effect on metabolic disease.
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Affiliation(s)
- Ni Li
- Department of Stomatology, Zhongshan Hospital, Fudan University, Shanghai 200031, P.R. China.,Department of Hard Tissue Research, Graduate School of Oral Medicine, Matsumoto Dental University, Shiojiri, Nagano 399-0781, Japan
| | - Kai Chen
- Department of Stomatology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, P.R. China
| | - Hongwei Dong
- Department of Hard Tissue Research, Graduate School of Oral Medicine, Matsumoto Dental University, Shiojiri, Nagano 399-0781, Japan
| | - Jing Yang
- Department of Hard Tissue Research, Institute for Oral Science, Matsumoto Dental University, Shiojiri, Nagano 399-0781, Japan
| | - Michiko Yoshizawa
- Department of Hard Tissue Research, Graduate School of Oral Medicine, Matsumoto Dental University, Shiojiri, Nagano 399-0781, Japan.,Department of Oral and Maxillofacial Surgery, School of Dentistry, Matsumoto Dental University, Shiojiri, Nagano 399-0781, Japan
| | - Hideaki Kagami
- Department of Hard Tissue Research, Graduate School of Oral Medicine, Matsumoto Dental University, Shiojiri, Nagano 399-0781, Japan.,Department of Hard Tissue Research, Institute for Oral Science, Matsumoto Dental University, Shiojiri, Nagano 399-0781, Japan
| | - Xianqi Li
- Department of Hard Tissue Research, Graduate School of Oral Medicine, Matsumoto Dental University, Shiojiri, Nagano 399-0781, Japan.,Department of Hard Tissue Research, Institute for Oral Science, Matsumoto Dental University, Shiojiri, Nagano 399-0781, Japan.,Department of Oral and Maxillofacial Surgery, School of Dentistry, Matsumoto Dental University, Shiojiri, Nagano 399-0781, Japan
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23
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Obesity-induced TRB3 negatively regulates Brown adipose tissue function in mice. Biochem Biophys Res Commun 2021; 547:29-35. [PMID: 33592376 DOI: 10.1016/j.bbrc.2021.01.103] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Accepted: 01/28/2021] [Indexed: 12/26/2022]
Abstract
Brown adipose tissue (BAT) and stimulating adaptive thermogenesis have been implicated as anti-obese and anti-diabetic tissues due to their ability to dissipate energy as heat by the expression of UCP1. We have recently demonstrated that TRB3 impairs differentiation of brown preadipocytes via inhibiting insulin signaling. However, the roles of the protein in BAT function and thermogenesis in vivo have not yet been established. For this study we tested the hypothesis that TRB3 mediates obesity- and diabetes-induced impairments in BAT differentiation and function, and that inhibition of TRB3 improves BAT function. TRB3 expression was increased in BAT from high-fat fed mice and ob/ob mice, which was associated with decreased UCP1 expression. Incubation of brown adipocytes with palmitate increased TRB3 expression and decreased UCP1. Knockout of TRB3 in mice displayed higher UCP1 expression in BAT and cold resistance. Incubation of brown adipocytes with ER stressors increased TRB3 but decreased UCP1 and ER stress markers were elevated in BAT from high-fat fed mice and ob/ob mice. Finally, high-fat feeding in TRB3KO mice were protected from obesity-induced glucose intolerance and displayed cold resistance and higher expression of BAT-specific markers. These data demonstrate that high-fat feeding and obesity increase TRB3 in BAT, resulting in impaired tissue function.
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24
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Abstract
Prader-Willi syndrome (PWS) is a neurodevelopmental disorder characterized by hyperphagia, hypotonia, learning disability, as well as a range of psychiatric conditions. The conservation of the PWS genetic interval on chromosome 15q11-q13 in human, and a cluster of genes on mouse chromosome 7, has facilitated the use of mice as animal models for PWS. Some models faithfully mimic the loss of all gene expression from the paternally inherited PWS genetic interval, whereas others target smaller regions or individual genes. Collectively, these models have provided insight into the mechanisms, many of which lead to alterations in hypothalamic function, underlying the core symptoms of PWS, including growth retardation, hyperphagia and metabolism, reproductive maturation and endophenotypes of relevance to behavioral and psychiatric problems. Here we review and summarize these studies.
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Affiliation(s)
- Simona Zahova
- Neuroscience and Mental Health Research Institute, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - Anthony R Isles
- Neuroscience and Mental Health Research Institute, School of Medicine, Cardiff University, Cardiff, United Kingdom.
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25
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Puckett D, Alquraishi M, Alani DS, Chahed S, Frankel VD, Donohoe D, Voy B, Whelan J, Bettaieb A. Zyflamend, a unique herbal blend, induces cell death and inhibits adipogenesis through the coordinated regulation of PKA and JNK. Adipocyte 2020; 9:454-471. [PMID: 32779962 PMCID: PMC7469463 DOI: 10.1080/21623945.2020.1803642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
The prevalence of obesity and its comorbidities has sparked a worldwide concern to address rates of adipose tissue accrual. Recent studies have demonstrated a novel role of Zyflamend, a blend of natural herbal extracts, in regulating lipid metabolism in several cancer cell lines through the activation of the AMPK signalling pathway. Yet, the role of Zyflamend in adipogenic differentiation and lipid metabolism remains largely unexplored. The objective of this study is to investigate the effects of Zyflamend on white 3T3-MBX pre-adipocyte differentiation and elucidate the molecular mechanisms. We demonstrate that Zyflamend treatment altered cell cycle progression, attenuated proliferation, and increased cell death of 3T3-MBX pre-adipocytes. In addition, treatment with Zyflamend inhibited lipid accumulation during the differentiation of 3T3-MBX cells, consistent with decreased expression of lipogenic genes and increased lipolysis. Mechanistically, Zyflamend-induced alterations in adipogenesis were mediated, at least in part, through the activation of AMPK, PKA, and JNK. Inhibition of AMPK partially reversed Zyflamend-induced inhibition of differentiation, whereas the inhibition of either JNK or PKA fully restored adipocyte differentiation and decreased lipolysis. Taken together, the present study demonstrates that Zyflamend, as a novel anti-adipogenic bioactive mix, inhibits adipocyte differentiation through the activation of the PKA and JNK pathways. Abbreviation: 7-AAD: 7-amino-actinomycin D; ACC: acetyl-CoA carboxylase; AKT: protein kinase B; AMPK: AMP-activated protein kinase; ATGL: adipose triglyceride lipase; C/EBPα: CCAAT-enhancer binding protein alpha; DMEM: Dulbecco’s Modified Eagle Medium; DMSO: dimethyl sulphoxide; DTT: dithiothreitol; EGTA: ethylene glycol-bis-(2-aminoethyl)-N,N,N’,N’-tetraacetic acid; ERK: extracellular signal–regulated kinases; FASN: fatty acid synthase; FBS: foetal bovine serum; GLUT: glucose transporter; HSL: hormone-sensitive lipase; IR: insulin receptor; IRS: insulin receptor substrate; JNK: c-JUN N-terminal kinase; MGL: monoacylglycerol lipase; NaF: sodium fluoride; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; PBS: phosphate buffered- saline; PCB: pyruvate carboxylase; PDE: phosphodiesterase; PKA: protein kinase cAMP-dependent; PMSF: phenylmethylsulfonyl fluoride; PPARγ: perilipin peroxisome proliferator-activated receptor gamma; PREF-1: pre-adipocyte factor 1; PVDF: polyvinylidene fluoride; RIPA: radio-immunoprecipitation assay; SDS-PAGE: sodium dodecyl sulphate polyacrylamide gel electrophoresis; SEM: standard error of the mean; SOX9: suppressor of cytokine signalling 9; TGs: triacylglycerols.
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Affiliation(s)
- Dexter Puckett
- Department of Nutrition, University of Tennessee Knoxville, Knoxville, TN, USA
| | - Mohammed Alquraishi
- Department of Nutrition, University of Tennessee Knoxville, Knoxville, TN, USA
| | - Dina S. Alani
- Department of Nutrition, University of Tennessee Knoxville, Knoxville, TN, USA
| | - Samah Chahed
- Department of Nutrition, University of Tennessee Knoxville, Knoxville, TN, USA
| | - Victoria D. Frankel
- Department of Nutrition, University of Tennessee Knoxville, Knoxville, TN, USA
| | - Dallas Donohoe
- Department of Nutrition, University of Tennessee Knoxville, Knoxville, TN, USA
| | - Brynn Voy
- Tennessee Agricultural Experiment Station, University of Tennessee Institute of Agriculture, Knoxville, TN, USA
- Graduate School of Genome Science and Technology, University of Tennessee, Knoxville, TN, USA
| | - Jay Whelan
- Department of Nutrition, University of Tennessee Knoxville, Knoxville, TN, USA
- Tennessee Agricultural Experiment Station, University of Tennessee Institute of Agriculture, Knoxville, TN, USA
| | - Ahmed Bettaieb
- Department of Nutrition, University of Tennessee Knoxville, Knoxville, TN, USA
- Graduate School of Genome Science and Technology, University of Tennessee, Knoxville, TN, USA
- Department of Biochemistry, Cellular and Molecular Biology, University of Tennessee, Knoxville, TN, USA
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26
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Geng R, Zheng Y, Zhou D, Li Q, Li R, Guo X. ZBTB7A, a potential biomarker for prognosis and immune infiltrates, inhibits progression of endometrial cancer based on bioinformatics analysis and experiments. Cancer Cell Int 2020; 20:542. [PMID: 33292231 PMCID: PMC7654049 DOI: 10.1186/s12935-020-01600-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Accepted: 10/06/2020] [Indexed: 12/24/2022] Open
Abstract
Backgroud ZBTB protein is an important member of the C2H2 zinc finger protein family. As a transcription factor, it is widely involved in the transcriptional regulation of genes, cell proliferation, differentiation, and apoptosis. The ZBTB7A has been largely linked to different kinds of tumors due to its diverse function. However, the value for ZBTB7A in uterine corpus endometrial carcinoma (UCEC) is unclear. Methods In our work, we assessed the importance of ZBTB7A in UCEC. Firstly, Using Oncomine and Tumor Immunoassay Resource (TIMER) databases to evaluate the expression of ZBTB7A. Secondly, we explored the co-expression network of ZBTB7A through the cBioPortal online tool, Metascape, and LinkedOmics. TIMER was also used to explore the relationship between ZBTB7A and tumor immune invasion, and to detect the correlation between the ZBTB7A and the marker genes related to immune infiltration. Finally, CCK8, migration, ChIP assays were introduced to partly validate ZBTB7A function in endometrial cancer cells. Results We found the ZBTB7A expression in TIMER was associated with various cancers, especially UCEC. The decreased expression of ZBTB7A was markedly related to the stage and prognosis of UCEC. Furthermore, ZBTB7A was also related to the expression of various immune markers such as Neutrophils, Dendritic cell, T cell (general), Th1, Th2, and Treg. Finally, we verified that ZBTB7A repressed E2F4 transcription and inhibited cells proliferation and migration. These results indicate that ZBTB7A may play a vital role in regulating immune cell infiltration in UCEC, and is a valuable prognostic marker. Conclusions In summary, we demonstrate that ZBTB7A is notably downregulated in UCEC, plays a vital role in regulating immune cell infiltration, possesses diagnostic and prognostic values and attenuates E2F4 transcription and cell proliferation, migration in vitro.
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Affiliation(s)
- Rong Geng
- Department of Gynecology, Affiliated Foshan Maternity & Child Healthcare Hospital, Southern Medical University, Foshan, 52800, China.,Department of Gynecology and Obstetrics, The First Affiliated Hospital, Jinan University, Guangzhou, 510632, China.,Foshan Maternal and Children Healthy Research Institute, Affiliated Foshan Maternity & Child Healthcare Hospital, Southern Medical University, Foshan, China
| | - Yuhua Zheng
- Department of Gynecology, Affiliated Foshan Maternity & Child Healthcare Hospital, Southern Medical University, Foshan, 52800, China
| | - Donghua Zhou
- Department of Pathology, Affiliated Foshan Maternity & Child Healthcare Hospital, Southern Medical University, Foshan, China
| | - Qingdong Li
- Department of Gynecology, Affiliated Foshan Maternity & Child Healthcare Hospital, Southern Medical University, Foshan, 52800, China
| | - Ruiman Li
- Department of Gynecology and Obstetrics, The First Affiliated Hospital, Jinan University, Guangzhou, 510632, China.
| | - Xiaoling Guo
- Department of Gynecology, Affiliated Foshan Maternity & Child Healthcare Hospital, Southern Medical University, Foshan, 52800, China.
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27
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Xu H, Yang X, Huang W, Ma Y, Ke H, Zou L, Yang Q, Jiao B. Single-cell profiling of long noncoding RNAs and their cell lineage commitment roles via RNA-DNA-DNA triplex formation in mammary epithelium. Stem Cells 2020; 38:1594-1611. [PMID: 32930441 DOI: 10.1002/stem.3274] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 07/21/2020] [Accepted: 08/03/2020] [Indexed: 06/11/2023]
Abstract
Long noncoding RNAs (lncRNAs), which are crucial for organ development, exhibit cell-specific expression. Thus, transcriptomic analysis based on total tissue (bulk-seq) cannot accurately reflect the expression pattern of lncRNAs. Here, we used high-throughput single-cell RNA-seq data to investigate the role of lncRNAs using the hierarchical model of mammary epithelium. With our comprehensive annotation of the mammary epithelium, lncRNAs showed much greater cell-lineage specific expression than coding genes. The lineage-specific lncRNAs were functionally correlated with lineage commitment through the coding genes via the cis- and trans-effects of lncRNAs. For the working mechanism, lncRNAs formed a triplex structure with the DNA helix to regulate downstream lineage-specific marker genes. We used lncRNA-Carmn as an example to validate the above findings. Carmn, which is specifically expressed in mammary gland stem cells (MaSCs) and basal cells, positively regulated the Wnt signaling ligand Wnt10a through formation of a lncRNA-DNA-DNA triplex, and thus controlled the stemness of MaSCs. Our study suggests that lncRNAs play essential roles in cell-lineage commitment and provides an approach to decipher lncRNA functions based on single-cell RNA-seq data.
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Affiliation(s)
- Haibo Xu
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, People's Republic of China
- Department of Urology, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, People's Republic of China
- International Cancer Center, Shenzhen University School of Medicine, Shenzhen, People's Republic of China
| | - Xing Yang
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, People's Republic of China
- Yan'an Hospital Affiliated to Kunming Medical University, Kunming, Yunnan, People's Republic of China
- Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming, Yunnan, People's Republic of China
| | - Weiren Huang
- Department of Urology, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, People's Republic of China
- International Cancer Center, Shenzhen University School of Medicine, Shenzhen, People's Republic of China
| | - Yujie Ma
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, People's Republic of China
| | - Hao Ke
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, People's Republic of China
| | - Li Zou
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, People's Republic of China
| | - Qin Yang
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, People's Republic of China
| | - Baowei Jiao
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, People's Republic of China
- KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, People's Republic of China
- Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, Yunnan, People's Republic of China
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28
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Zhang K, Yang X, Zhao Q, Li Z, Fu F, Zhang H, Zheng M, Zhang S. Molecular Mechanism of Stem Cell Differentiation into Adipocytes and Adipocyte Differentiation of Malignant Tumor. Stem Cells Int 2020; 2020:8892300. [PMID: 32849880 PMCID: PMC7441422 DOI: 10.1155/2020/8892300] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 07/07/2020] [Accepted: 07/27/2020] [Indexed: 02/07/2023] Open
Abstract
Adipogenesis is the process through which preadipocytes differentiate into adipocytes. During this process, the preadipocytes cease to proliferate, begin to accumulate lipid droplets, and develop morphologic and biochemical characteristics of mature adipocytes. Mesenchymal stem cells (MSCs) are a type of adult stem cells known for their high plasticity and capacity to generate mesodermal and nonmesodermal tissues. Many mature cell types can be generated from MSCs, including adipocyte, osteocyte, and chondrocyte. The differentiation of stem cells into multiple mature phenotypes is at the basis for tissue regeneration and repair. Cancer stem cells (CSCs) play a very important role in tumor development and have the potential to differentiate into multiple cell lineages. Accumulating evidence has shown that cancer cells can be induced to differentiate into various benign cells, such as adipocytes, fibrocytes, osteoblast, by a variety of small molecular compounds, which may provide new strategies for cancer treatment. Recent studies have reported that tumor cells undergoing epithelial-to-mesenchymal transition can be induced to differentiate into adipocytes. In this review, molecular mechanisms, signal pathways, and the roles of various biological processes in adipose differentiation are summarized. Understanding the molecular mechanism of adipogenesis and adipose differentiation of cancer cells may contribute to cancer treatments that involve inducing differentiation into benign cells.
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Affiliation(s)
- Kexin Zhang
- Department of Pathology, Tianjin Union Medical Center, Tianjin, China
- Nankai University School of Medicine, Nankai University, Tianjin, China
| | - Xudong Yang
- Tianjin Rehabilitation Center, Tianjin, China
| | - Qi Zhao
- Department of Pathology, Tianjin Union Medical Center, Tianjin, China
| | - Zugui Li
- Department of Pathology, Tianjin Union Medical Center, Tianjin, China
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Fangmei Fu
- Department of Pathology, Tianjin Union Medical Center, Tianjin, China
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Hao Zhang
- Department of Pathology, Tianjin Union Medical Center, Tianjin, China
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Minying Zheng
- Department of Pathology, Tianjin Union Medical Center, Tianjin, China
| | - Shiwu Zhang
- Department of Pathology, Tianjin Union Medical Center, Tianjin, China
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29
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Comas F, Latorre J, Ortega F, Oliveras-Cañellas N, Lluch A, Ricart W, Fernández-Real JM, Moreno-Navarrete JM. Permanent cystathionine-β-Synthase gene knockdown promotes inflammation and oxidative stress in immortalized human adipose-derived mesenchymal stem cells, enhancing their adipogenic capacity. Redox Biol 2020; 42:101668. [PMID: 32800520 PMCID: PMC8113015 DOI: 10.1016/j.redox.2020.101668] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Accepted: 07/29/2020] [Indexed: 12/12/2022] Open
Abstract
In the present study, we aimed to investigate the impact of permanent cystathionine-β-Synthase (CBS) gene knockdown in human telomerase reverse transcriptase (hTERT) immortalized human adipose-derived mesenchymal stem cells (ASC52telo) and in their capacity to differentiate into adipocytes. CBS gene KD in ASC52telo cells led to increased cellular inflammation (IL6, CXCL8, TNF) and oxidative stress markers (increased intracellular reactive oxygen species and decreased reduced glutathione levels) in parallel to decreased H2S production and rejuvenation (LC3 and SIRT1)-related gene expression. In addition, CBS gene KD in ASC52telo cells resulted in altered mitochondrial respiratory function, characterised by decreased basal respiration (specifically proton leak) and spare respiratory capacity, without significant effects on cell viability and proliferation. In this context, shCBS-ASC52telo cells displayed enhanced adipogenic (FABP4, ADIPOQ, SLC2A4, CEBPA, PPARG)-, lipogenic (FASN, DGAT1)- and adipocyte (LEP, LBP)-related gene expression markers, decreased expression of proinflammatory cytokines, and increased intracellular lipid accumulation during adipocyte differentiation compared to control ASC52telo cells. Otherwise, the increased adipogenic potential of shCBS-ASC52telo cells was detrimental to the ability to differentiate into osteogenic linage. In conclusion, this study demonstrated that permanent CBS gene KD in ASC52telo cells promotes a cellular senescence phenotype with a very increased adipogenic potential, promoting a non-physiological enhanced adipocyte differentiation with excessive lipid storage.
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Affiliation(s)
- Ferran Comas
- Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), Girona, Spain
| | - Jèssica Latorre
- Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), Girona, Spain
| | - Francisco Ortega
- Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), Girona, Spain
| | - Núria Oliveras-Cañellas
- Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), Girona, Spain
| | - Aina Lluch
- Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), Girona, Spain
| | - Wifredo Ricart
- Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), Girona, Spain
| | - José Manuel Fernández-Real
- Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), Girona, Spain; Department of Medicine, Universitat de Girona, Girona, Spain.
| | - José María Moreno-Navarrete
- Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010) and Instituto de Salud Carlos III (ISCIII), Girona, Spain; Department of Medicine, Universitat de Girona, Girona, Spain.
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30
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Man XF, Hu N, Tan SW, Tang HN, Guo Y, Tang CY, Liu YQ, Tang J, Zhou CL, Wang F, Zhou HD. Insulin receptor substrate-1 inhibits high-fat diet-induced obesity by browning of white adipose tissue through miR-503. FASEB J 2020; 34:12308-12323. [PMID: 32721050 DOI: 10.1096/fj.201903283rr] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 06/13/2020] [Accepted: 07/01/2020] [Indexed: 12/18/2022]
Abstract
Genetic variation of insulin receptor substrate 1 (IRS-1) was found to modulate the insulin resistance of adipose tissues, but the underlying mechanism was not clear. To investigate how the IRS-1 was involved in the browning of white adipose tissue through miRNA, we identified a mutated Irs-1 (Irs-1-/- ) mice model and found that this mice had a reduced subcutaneous WAT (sWAT) and increased brown adipose tissue (BAT) in the interscapular region. So we isolated the bone marrow stromal cells and analyzed differentially expressed miRNAs and adipogenesis-related genes with miRNA arrays and PCR arrays. Irs-1-/- mice showed decreased miR-503 expression, but increased expression of its target, bone morphogenetic protein receptor type 1a (BMPR1a). Overexpression of miR-503 in preadipocytes downregulated BMPR1a and impaired adipogenic activity through the phosphotidylinositol 3-kinase (PI3K/Akt) pathway, while the inhibitor had the opposite effect. In both Irs-1-/- and cold-induced models, sWAT exhibited BAT features, and showed tissue-specific increased BMPR1a expression, PI3K expression, and Akt phosphorylation. Thus, our results showed that IRS-1 regulated brown preadipocyte differentiation and induced browning in sWAT through the miR-503-BMPR1a pathway, which played important roles in high-fat diet-induced obesity.
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Affiliation(s)
- Xiao-Fei Man
- Hunan Provincial Key Laboratory For Metabolic Bone Diseases, Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, China.,Department of Nephrology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Nan Hu
- Hunan Provincial Key Laboratory For Metabolic Bone Diseases, Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Shu-Wen Tan
- Hunan Provincial Key Laboratory For Metabolic Bone Diseases, Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Hao-Neng Tang
- Hunan Provincial Key Laboratory For Metabolic Bone Diseases, Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Yue Guo
- Hunan Provincial Key Laboratory For Metabolic Bone Diseases, Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Chen-Yi Tang
- Hunan Provincial Key Laboratory For Metabolic Bone Diseases, Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Ya-Qing Liu
- Hunan Provincial Key Laboratory For Metabolic Bone Diseases, Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Jun Tang
- Hunan Provincial Key Laboratory For Metabolic Bone Diseases, Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Ci-La Zhou
- Hunan Provincial Key Laboratory For Metabolic Bone Diseases, Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Fang Wang
- Hunan Provincial Key Laboratory For Metabolic Bone Diseases, Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Hou-De Zhou
- Hunan Provincial Key Laboratory For Metabolic Bone Diseases, Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, China
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Boucher P, Matz RL, Terrand J. atherosclerosis: gone with the Wnt? Atherosclerosis 2020; 301:15-22. [PMID: 32289618 DOI: 10.1016/j.atherosclerosis.2020.03.024] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Revised: 02/19/2020] [Accepted: 03/26/2020] [Indexed: 12/11/2022]
Abstract
Atherosclerosis, a pathology affecting large and medium-sized arteries, is the major cause of cardiovascular morbidity/mortality in industrialized countries. During atherosclerosis, cells accumulate large amounts of cholesterol through the uptake of modified low-density lipoprotein particles to form foam cells. This accumulation forms the basis for the development of the disease and for a large spectrum of other diseases in various organs. Massive research efforts have yielded valuable information about the underlying molecular mechanisms of atherosclerosis. In particular, newer discoveries on the early stage of lesion formation, cholesterol accumulation, reverse cholesterol transport, and local inflammation in the vascular wall have opened unanticipated horizons of understanding and raised novel questions and therapeutic opportunities. In this review, we focus on Wnt signaling, which has received little attention so far, yet affects lysosomal function and signalling pathways that limit cholesterol accumulation. This occurs in different tissues and cell types, including smooth muscle cells, endothelial cells and macrophages in the arterial wall, and thus profoundly impacts on atherosclerotic disease development and progression.
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Affiliation(s)
- Philippe Boucher
- CNRS, UMR 7021, University of Strasbourg, 67401, Illkirch, France.
| | - Rachel L Matz
- CNRS, UMR 7021, University of Strasbourg, 67401, Illkirch, France
| | - Jérôme Terrand
- CNRS, UMR 7021, University of Strasbourg, 67401, Illkirch, France
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32
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Adipose Tissue and FoxO1: Bridging Physiology and Mechanisms. Cells 2020; 9:cells9040849. [PMID: 32244542 PMCID: PMC7226803 DOI: 10.3390/cells9040849] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 03/23/2020] [Accepted: 03/30/2020] [Indexed: 12/22/2022] Open
Abstract
Forkhead box O class proteins (FoxOs) are expressed nearly in all tissues and are involved in different functions such as energy metabolism, redox homeostasis, differentiation, and cell cycle arrest. The plasticity of FoxOs is demonstrated by post-translational modifications that determine diverse levels of transcriptional regulations also controlled by their subcellular localization. Among the different members of the FoxO family, we will focus on FoxO1 in adipose tissue, where it is abundantly expressed and is involved in differentiation and transdifferentiation processes. The capability of FoxO1 to respond differently in dependence of adipose tissue subtype underlines the specific involvement of the transcription factor in energy metabolism and the “browning” process of adipocytes. FoxO1 can localize to nuclear, cytoplasm, and mitochondrial compartments of adipocytes responding to different availability of nutrients and source of reactive oxygen species (ROS). Specifically, fasted state produced-ROS enhance the nuclear activity of FoxO1, triggering the transcription of lipid catabolism and antioxidant response genes. The enhancement of lipid catabolism, in combination with ROS buffering, allows systemic energetic homeostasis and metabolic adaptation of white/beige adipocytes. On the contrary, a fed state induces FoxO1 to accumulate in the cytoplasm, but also in the mitochondria where it affects mitochondrial DNA gene expression. The importance of ROS-mediated signaling in FoxO1 subcellular localization and retrograde communication will be discussed, highlighting key aspects of FoxO1 multifaceted regulation in adipocytes.
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33
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Theodosiou T, Papanikolaou N, Savvaki M, Bonetto G, Maxouri S, Fakoureli E, Eliopoulos AG, Tavernarakis N, Amoutzias GD, Pavlopoulos GA, Aivaliotis M, Nikoletopoulou V, Tzamarias D, Karagogeos D, Iliopoulos I. UniProt-Related Documents (UniReD): assisting wet lab biologists in their quest on finding novel counterparts in a protein network. NAR Genom Bioinform 2020; 2:lqaa005. [PMID: 33575553 PMCID: PMC7671407 DOI: 10.1093/nargab/lqaa005] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Revised: 01/20/2020] [Accepted: 01/31/2020] [Indexed: 02/04/2023] Open
Abstract
The in-depth study of protein–protein interactions (PPIs) is of key importance for understanding how cells operate. Therefore, in the past few years, many experimental as well as computational approaches have been developed for the identification and discovery of such interactions. Here, we present UniReD, a user-friendly, computational prediction tool which analyses biomedical literature in order to extract known protein associations and suggest undocumented ones. As a proof of concept, we demonstrate its usefulness by experimentally validating six predicted interactions and by benchmarking it against public databases of experimentally validated PPIs succeeding a high coverage. We believe that UniReD can become an important and intuitive resource for experimental biologists in their quest for finding novel associations within a protein network and a useful tool to complement experimental approaches (e.g. mass spectrometry) by producing sorted lists of candidate proteins for further experimental validation. UniReD is available at http://bioinformatics.med.uoc.gr/unired/
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Affiliation(s)
- Theodosios Theodosiou
- University of Crete, School of Medicine, Department of Basic Sciences, Heraklion 71003, Crete, Greece
| | - Nikolaos Papanikolaou
- University of Crete, School of Medicine, Department of Basic Sciences, Heraklion 71003, Crete, Greece
| | - Maria Savvaki
- University of Crete, School of Medicine, Department of Basic Sciences, Heraklion 71003, Crete, Greece.,Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Nikolaou Plastira 100, 70013 Heraklion, Crete, Greece
| | - Giulia Bonetto
- University of Crete, School of Medicine, Department of Basic Sciences, Heraklion 71003, Crete, Greece
| | - Stella Maxouri
- University of Crete, School of Medicine, Department of Basic Sciences, Heraklion 71003, Crete, Greece.,Medical School of Patras University, Laboratory of General Biology, Asklipiou 1, 26500 Rio Patras, Greece
| | - Eirini Fakoureli
- University of Crete, School of Medicine, Department of Basic Sciences, Heraklion 71003, Crete, Greece
| | - Aristides G Eliopoulos
- Department of Biology, Medical School, National and Kapodistrian University of Athens, Mikras Asias 75, 11527 Athens, Greece
| | - Nektarios Tavernarakis
- University of Crete, School of Medicine, Department of Basic Sciences, Heraklion 71003, Crete, Greece.,Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Nikolaou Plastira 100, 70013 Heraklion, Crete, Greece
| | - Grigoris D Amoutzias
- Bioinformatics Laboratory, Department of Biochemistry and Biotechnology, University of Thessaly, Larisa 41500, Greece
| | - Georgios A Pavlopoulos
- Institute for Fundamental Biomedical Research, BSRC "Alexander Fleming", 34 Fleming Street, 16672 Vari, Greece
| | - Michalis Aivaliotis
- Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Nikolaou Plastira 100, 70013 Heraklion, Crete, Greece.,Laboratory of Biological Chemistry, Faculty of Health Sciences, School of Medicine, Aristotle University of Thessaloniki, GR-54124, Thessaloniki, Greece.,Functional Proteomics and Systems Biology (FunPATh), Center for Interdisciplinary Research and Innovation (CIRI-AUTH), Balkan Center, Thessaloniki, 10th km Thessaloniki-Thermi Rd, P.O.Box 8318, GR 57001, Greece
| | - Vasiliki Nikoletopoulou
- Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Nikolaou Plastira 100, 70013 Heraklion, Crete, Greece
| | - Dimitris Tzamarias
- Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Nikolaou Plastira 100, 70013 Heraklion, Crete, Greece
| | - Domna Karagogeos
- University of Crete, School of Medicine, Department of Basic Sciences, Heraklion 71003, Crete, Greece.,Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Nikolaou Plastira 100, 70013 Heraklion, Crete, Greece
| | - Ioannis Iliopoulos
- University of Crete, School of Medicine, Department of Basic Sciences, Heraklion 71003, Crete, Greece
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He QJ, Wang P, Liu QQ, Wu QG, Li YF, Wang J, Lee SC. Secreted Wnt6 mediates diabetes-associated centrosome amplification via its receptor FZD4. Am J Physiol Cell Physiol 2020; 318:C48-C62. [DOI: 10.1152/ajpcell.00091.2019] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
We recently published that type 2 diabetes promotes cell centrosome amplification via upregulation of Rho-associated protein kinase 1 (ROCK1) and 14-3-3 protein-σ (14-3-3σ). This study further investigates the molecular mechanisms underlying diabetes-associated centrosome amplification. We found that treatment of cells with high glucose, insulin, and palmitic acid levels increased the intracellular and extracellular protein levels of Wingless-type MMTV integration site family member 6 (Wnt6) as well as the cellular level of β-catenin. The treatment also activated β-catenin and promoted its nuclear translocation. Treatment of cells with siRNA species for Wnt6, Frizzled-4 (FZD4), or β-catenin as well as introduction of antibodies against Wnt6 or FZD4 to the cell culture medium could all attenuate the treatment-triggered centrosome amplification. Moreover, we showed that secreted Wnt6-FZD4-β-catenin was the signaling pathway that was upstream of ROCK1 and 14-3-3σ. We found that advanced glycation end products (AGEs) were also able to increase the cellular and extracellular levels of Wnt6, the cellular protein level of β-catenin, and centrosome amplification. Treatment of the cells with siRNA species for Wnt6 or FZD4 as well as introduction of antibodies against Wnt6 or FZD4 to the cell culture could all inhibit the AGEs-elicited centrosome amplification. In colon tissues from a diabetic mouse model, the protein levels of Wnt6 and 14-3-3σ were increased. In conclusion, our results showed that the pathophysiological factors in type 2 diabetes, including AGEs, were able to induce centrosome amplification. It is suggested that secreted Wnt6 binds to FZD4 to activate the canonical Wnt6 signaling pathway, which is upstream of ROCK1 and 14-3-3σ, and that this is the cell signaling pathway underlying diabetes-associated centrosome amplification.
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Affiliation(s)
- Qin Ju He
- School of Life Sciences, Shanxi University, Taiyuan, People’s Republic of China
| | - Pu Wang
- School of Life Sciences, Shanxi University, Taiyuan, People’s Republic of China
| | - Qin Qin Liu
- School of Life Sciences, Shanxi University, Taiyuan, People’s Republic of China
| | - Qi Gui Wu
- School of Life Sciences, Shanxi University, Taiyuan, People’s Republic of China
| | - Yuan Fei Li
- Department of Oncology, First Clinical Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China
| | - Jie Wang
- Shanxi College of Traditional Chinese Medicine, Taiyuan, People’s Republic of China
| | - Shao Chin Lee
- School of Life Sciences, Shanxi University, Taiyuan, People’s Republic of China
- School of Life Sciences, Jiangsu Normal University, Xuzhou, People’s Republic of China
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Liang Q, Zheng Q, Zuo Y, Chen Y, Ma J, Ni P, Cheng J. SENP2 Suppresses Necdin Expression to Promote Brown Adipocyte Differentiation. Cell Rep 2019; 28:2004-2011.e4. [DOI: 10.1016/j.celrep.2019.07.083] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Revised: 06/15/2019] [Accepted: 07/23/2019] [Indexed: 11/28/2022] Open
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Jing R, Feng H, Jiang N, Zhang H, Fang W, Ni Z, Yuan J. Visceral adipogenesis inhibited by Pref-1 is associated with peritoneal angiogenesis. Nephrology (Carlton) 2019; 25:248-254. [PMID: 31090987 DOI: 10.1111/nep.13604] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Revised: 02/20/2019] [Accepted: 05/12/2019] [Indexed: 01/04/2023]
Abstract
AIM Studies showed an increased visceral adipose tissue and peritoneal angiogenesis in peritoneal dialysis (PD) patients. However, the relationship between the visceral adipose expands and peritoneal angiogenesis remains unclear. METHODS Pref-1 (preadipocyte factor-1) recombinant adeno-associated virus (AAV) and control AAV were constructed. Mice were divided into four groups, mice in control and PD group were injected intraperitoneally with PBS, mice in control-AAV-PD were injected intraperitoneally with plaque-forming unit (PFU) control AAV and mice in pref-1-AAV-PD group were injected with PFU recombinant AAV. Two weeks later, control group was injected intraperitoneally with normal saline while other groups were injected intraperitoneally with 4.25% peritoneal dialysis fluid (PDF). Thirty days later, viscerall adipose tissue was collected and weighed. Pref-1 protein expression was measured by Western blot, and peritoneal permeability was measured by Evans blue. Cluster of differentiation 31(CD31) immunohistochemical staining was used to detect mesenteric blood vessel number, and vascular endothelial growth factor (VEGF) in serum were measured by enzyme-linked immunosorbent assay. RESULTS Pref-1 protein expression increased in pref-1-AAV-PD group. Visceral adipose expanded in PD and control-AAV-PD group while decreased in pref-1-AAV-PD group, which approves PD fluid enhance visceral adipogensis, and the process could be inhibited by Pref-1 recombinant AAV. The reduction of peritoneal vessel number and the decrease of vascular permeability as well as down-regulation of serum vascular endothelial growth factor observed in pref-1-AAV-PD group suggested peritoneal angiogenesis could be inhibited following visceral adipose tissue reduction. CONCLUSION Visceral adipose expands is associated with peritoneal angiogenesis in PD treatment, and prevention of visceral adipogenesis may be an alternative way to protect the validity of peritoneum. Copyright © 2019 John Wiley & Sons, Ltd.
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Affiliation(s)
- Ran Jing
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Center for Peritoneal Dialysis Research, Shanghai, China
| | - Hao Feng
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Center for Peritoneal Dialysis Research, Shanghai, China
| | - Na Jiang
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Center for Peritoneal Dialysis Research, Shanghai, China
| | - He Zhang
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Center for Peritoneal Dialysis Research, Shanghai, China
| | - Wei Fang
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Center for Peritoneal Dialysis Research, Shanghai, China
| | - Zhaohui Ni
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Center for Peritoneal Dialysis Research, Shanghai, China
| | - Jiangzi Yuan
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Center for Peritoneal Dialysis Research, Shanghai, China
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37
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Pitrone M, Pizzolanti G, Coppola A, Tomasello L, Martorana S, Pantuso G, Giordano C. Knockdown of NANOG Reduces Cell Proliferation and Induces G0/G1 Cell Cycle Arrest in Human Adipose Stem Cells. Int J Mol Sci 2019; 20:ijms20102580. [PMID: 31130693 PMCID: PMC6566573 DOI: 10.3390/ijms20102580] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Revised: 05/21/2019] [Accepted: 05/23/2019] [Indexed: 11/19/2022] Open
Abstract
The core components of regenerative medicine are stem cells with high self-renewal and tissue regeneration potentials. Adult stem cells can be obtained from many organs and tissues. NANOG, SOX2 and OCT4 represent the core regulatory network that suppresses differentiation-associated genes, maintaining the pluripotency of mesenchymal stem cells. The roles of NANOG in maintaining self-renewal and undifferentiated status of adult stem cells are still not perfectly established. In this study we define the effects of downregulation of NANOG in maintaining self-renewal and undifferentiated state in mesenchymal stem cells (MSCs) derived from subcutaneous adipose tissue (hASCs). hASCs were expanded and transfected in vitro with short hairpin Lentivirus targeting NANOG. Gene suppressions were achieved at both transcript and proteome levels. The effect of NANOG knockdown on proliferation after 10 passages and on the cell cycle was evaluated by proliferation assay, colony forming unit (CFU), qRT-PCR and cell cycle analysis by flow-cytometry. Moreover, NANOG involvement in differentiation ability was evaluated. We report that downregulation of NANOG revealed a decrease in the proliferation and differentiation rate, inducing cell cycle arrest by increasing p27/CDKN1B (Cyclin-dependent kinase inhibitor 1B) and p21/CDKN1A (Cyclin-dependent kinase inhibitor 1A) through p53 and regulate DLK1/PREF1. Furthermore, NANOG induced downregulation of DNMT1, a major DNA methyltransferase responsible for maintaining methylation status during DNA replication probably involved in cell cycle regulation. Our study confirms that NANOG regulates the complex transcription network of plasticity of the cells, inducing cell cycle arrest and reducing differentiation potential.
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Affiliation(s)
- Maria Pitrone
- Aldo Galluzzo Laboratory of Regenerative Medicine, Department of Health Promotion Sciences, Maternal and infant Care, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, 90127 Palermo, Italy.
| | - Giuseppe Pizzolanti
- Aldo Galluzzo Laboratory of Regenerative Medicine, Department of Health Promotion Sciences, Maternal and infant Care, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, 90127 Palermo, Italy.
- ATeN (Advanced Technologies Network Center), University of Palermo, 90127 Palermo, Italy.
| | - Antonina Coppola
- Aldo Galluzzo Laboratory of Regenerative Medicine, Department of Health Promotion Sciences, Maternal and infant Care, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, 90127 Palermo, Italy.
| | - Laura Tomasello
- Aldo Galluzzo Laboratory of Regenerative Medicine, Department of Health Promotion Sciences, Maternal and infant Care, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, 90127 Palermo, Italy.
| | - Stefania Martorana
- Department of Surgical, Oncological and Oral Sciences, Division of General and Oncological Surgery, University of Palermo, 90127 Palermo, Italy.
| | - Gianni Pantuso
- Department of Surgical, Oncological and Oral Sciences, Division of General and Oncological Surgery, University of Palermo, 90127 Palermo, Italy.
| | - Carla Giordano
- Aldo Galluzzo Laboratory of Regenerative Medicine, Department of Health Promotion Sciences, Maternal and infant Care, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, 90127 Palermo, Italy.
- ATeN (Advanced Technologies Network Center), University of Palermo, 90127 Palermo, Italy.
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Gohlke S, Zagoriy V, Cuadros Inostroza A, Méret M, Mancini C, Japtok L, Schumacher F, Kuhlow D, Graja A, Stephanowitz H, Jähnert M, Krause E, Wernitz A, Petzke KJ, Schürmann A, Kleuser B, Schulz TJ. Identification of functional lipid metabolism biomarkers of brown adipose tissue aging. Mol Metab 2019; 24:1-17. [PMID: 31003944 PMCID: PMC6531832 DOI: 10.1016/j.molmet.2019.03.011] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Revised: 03/22/2019] [Accepted: 03/28/2019] [Indexed: 12/23/2022] Open
Abstract
OBJECTIVE Aging is accompanied by loss of brown adipocytes and a decline in their thermogenic potential, which may exacerbate the development of adiposity and other metabolic disorders. Presently, only limited evidence exists describing the molecular alterations leading to impaired brown adipogenesis with aging and the contribution of these processes to changes of systemic energy metabolism. METHODS Samples of young and aged murine brown and white adipose tissue were used to compare age-related changes of brown adipogenic gene expression and thermogenesis-related lipid mobilization. To identify potential markers of brown adipose tissue aging, non-targeted proteomic and metabolomic as well as targeted lipid analyses were conducted on young and aged tissue samples. Subsequently, the effects of several candidate lipid classes on brown adipocyte function were examined. RESULTS Corroborating previous reports of reduced expression of uncoupling protein-1, we observe impaired signaling required for lipid mobilization in aged brown fat after adrenergic stimulation. Omics analyses additionally confirm the age-related impairment of lipid homeostasis and reveal the accumulation of specific lipid classes, including certain sphingolipids, ceramides, and dolichols in aged brown fat. While ceramides as well as enzymes of dolichol metabolism inhibit brown adipogenesis, inhibition of sphingosine 1-phosphate receptor 2 induces brown adipocyte differentiation. CONCLUSIONS Our functional analyses show that changes in specific lipid species, as observed during aging, may contribute to reduced thermogenic potential. They thus uncover potential biomarkers of aging as well as molecular mechanisms that could contribute to the degradation of brown adipocytes, thereby providing potential treatment strategies of age-related metabolic conditions.
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Affiliation(s)
- Sabrina Gohlke
- Department of Adipocyte Development and Nutrition, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany
| | | | | | | | - Carola Mancini
- Department of Adipocyte Development and Nutrition, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany
| | - Lukasz Japtok
- Department of Toxicology, Institute of Nutritional Science, University of Potsdam, Potsdam-Rehbrücke, Nuthetal, Germany
| | - Fabian Schumacher
- Department of Toxicology, Institute of Nutritional Science, University of Potsdam, Potsdam-Rehbrücke, Nuthetal, Germany; Department of Molecular Biology, University of Duisburg-Essen, Essen, Germany
| | - Doreen Kuhlow
- Department of Adipocyte Development and Nutrition, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany
| | - Antonia Graja
- Department of Adipocyte Development and Nutrition, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany
| | | | - Markus Jähnert
- Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany; German Center for Diabetes Research (DZD), München, Neuherberg, Germany
| | - Eberhard Krause
- Leibniz Institute for Molecular Pharmacology, Berlin, Germany
| | - Andreas Wernitz
- Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany
| | - Klaus-Jürgen Petzke
- Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany
| | - Annette Schürmann
- Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany; German Center for Diabetes Research (DZD), München, Neuherberg, Germany
| | - Burkhard Kleuser
- Department of Toxicology, Institute of Nutritional Science, University of Potsdam, Potsdam-Rehbrücke, Nuthetal, Germany; NutriAct - Competence Cluster Nutrition Research, Berlin, Potsdam, Germany
| | - Tim J Schulz
- Department of Adipocyte Development and Nutrition, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany; German Center for Diabetes Research (DZD), München, Neuherberg, Germany; Institute of Nutritional Science, University of Potsdam, Potsdam-Rehbrücke, Nuthetal, Germany.
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Wang N, Li Y, Li Z, Ma J, Wu X, Pan R, Wang Y, Gao L, Bao X, Xue P. IRS-1 targets TAZ to inhibit adipogenesis of rat bone marrow mesenchymal stem cells through PI3K-Akt and MEK-ERK pathways. Eur J Pharmacol 2019; 849:11-21. [PMID: 30716312 DOI: 10.1016/j.ejphar.2019.01.064] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Revised: 01/30/2019] [Accepted: 01/31/2019] [Indexed: 01/07/2023]
Abstract
Gene modification of mesenchymal stem cells (MSCs) offers a promising approach for clinical stem cell therapy. Transcriptional co-activator with PDZ-binding motif (TAZ) plays a vital role in MSCs' differentiation. We aim to explore the interaction of insulin receptor substrate-1 (IRS-1) with TAZ to regulate MSCs' adipogenesis in this study. Initially, IRS-1 and TAZ followed similar decreasing expression pattern at the early stage of adipogenesis. And, overexpression of IRS-1 decreased the CCAAT/enhancer binding protein β (C/EBPβ) and peroxi-some proliferator-activated receptor gamma (PPARγ) expression with TAZ upregulation. Accordingly, knockdown of IRS-1 induced the upexpression of C/EBPβ and PPARγ with TAZ downregulation. Indeed, IRS-1 targeted TAZ to downregulate the C/EBPβ and PPARγ expression, while knockdown of TAZ attenuated the IRS-1 inhibited adipogenesis. Furthermore, both LY294002 (the PI3K-Akt inhibitor) and U0126 (the MEK-ERK inhibitor) blocked the regulation of IRS-1 on TAZ during adipogenesis. Additionally, IRS-1 and TAZ influenced the cell proliferation in the above process. Taken together, this study suggests for the first time that IRS-1 is a key regulator of the MSCs' adipogenesis and may serve as a potential therapeutic target for differential alterations in bone marrow.
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Affiliation(s)
- Na Wang
- Department of Endocrinology, The Third Hospital of Hebei Medical University, 139 Ziqiang Road, Shijiazhuang 050051, Hebei Province, PR China; Key Orthopaedic Biomechanics Laboratory of Hebei Province, 139 Ziqiang Road, Shijiazhuang 050051, Hebei Province, PR China
| | - Yukun Li
- Department of Endocrinology, The Third Hospital of Hebei Medical University, 139 Ziqiang Road, Shijiazhuang 050051, Hebei Province, PR China; Key Orthopaedic Biomechanics Laboratory of Hebei Province, 139 Ziqiang Road, Shijiazhuang 050051, Hebei Province, PR China
| | - Ziyi Li
- Department of Endocrinology, The Third Hospital of Hebei Medical University, 139 Ziqiang Road, Shijiazhuang 050051, Hebei Province, PR China; Key Orthopaedic Biomechanics Laboratory of Hebei Province, 139 Ziqiang Road, Shijiazhuang 050051, Hebei Province, PR China
| | - Jianxia Ma
- Department of Endocrinology, The Third Hospital of Hebei Medical University, 139 Ziqiang Road, Shijiazhuang 050051, Hebei Province, PR China; Key Orthopaedic Biomechanics Laboratory of Hebei Province, 139 Ziqiang Road, Shijiazhuang 050051, Hebei Province, PR China
| | - Xuelun Wu
- Department of Endocrinology, The Third Hospital of Hebei Medical University, 139 Ziqiang Road, Shijiazhuang 050051, Hebei Province, PR China; Key Orthopaedic Biomechanics Laboratory of Hebei Province, 139 Ziqiang Road, Shijiazhuang 050051, Hebei Province, PR China
| | - Runzhou Pan
- Department of Endocrinology, The Third Hospital of Hebei Medical University, 139 Ziqiang Road, Shijiazhuang 050051, Hebei Province, PR China; Key Orthopaedic Biomechanics Laboratory of Hebei Province, 139 Ziqiang Road, Shijiazhuang 050051, Hebei Province, PR China
| | - Yan Wang
- Department of Endocrinology, The Third Hospital of Hebei Medical University, 139 Ziqiang Road, Shijiazhuang 050051, Hebei Province, PR China; Key Orthopaedic Biomechanics Laboratory of Hebei Province, 139 Ziqiang Road, Shijiazhuang 050051, Hebei Province, PR China
| | - Liu Gao
- Department of Endocrinology, The Third Hospital of Hebei Medical University, 139 Ziqiang Road, Shijiazhuang 050051, Hebei Province, PR China; Key Orthopaedic Biomechanics Laboratory of Hebei Province, 139 Ziqiang Road, Shijiazhuang 050051, Hebei Province, PR China
| | - Xiaoxue Bao
- Department of Endocrinology, The Third Hospital of Hebei Medical University, 139 Ziqiang Road, Shijiazhuang 050051, Hebei Province, PR China; Key Orthopaedic Biomechanics Laboratory of Hebei Province, 139 Ziqiang Road, Shijiazhuang 050051, Hebei Province, PR China
| | - Peng Xue
- Department of Endocrinology, The Third Hospital of Hebei Medical University, 139 Ziqiang Road, Shijiazhuang 050051, Hebei Province, PR China; Key Orthopaedic Biomechanics Laboratory of Hebei Province, 139 Ziqiang Road, Shijiazhuang 050051, Hebei Province, PR China.
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Goody D, Pfeifer A. MicroRNAs in brown and beige fat. Biochim Biophys Acta Mol Cell Biol Lipids 2019; 1864:29-36. [DOI: 10.1016/j.bbalip.2018.05.003] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2017] [Revised: 02/05/2018] [Accepted: 05/04/2018] [Indexed: 12/27/2022]
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Lo PK, Wolfson B, Zhou Q. Adipogenesis and Noncoding RNAs. HANDBOOK OF NUTRITION, DIET, AND EPIGENETICS 2019:623-645. [DOI: 10.1007/978-3-319-55530-0_41] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Sequence variation of necdin gene in Bovidae. JOURNAL OF ANIMAL SCIENCE AND TECHNOLOGY 2018; 60:32. [PMID: 30598832 PMCID: PMC6302488 DOI: 10.1186/s40781-018-0191-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/24/2018] [Accepted: 12/10/2018] [Indexed: 11/28/2022]
Abstract
Background Necdin (NDN), a member of the melanoma antigen family showing imprinted pattern of expression, has been implicated as causing Prader-Willi symptoms, and known to participate in cellular growth, cellular migration and differentiation. The region where NDN is located has been associated to QTLs affecting reproduction and early growth in cattle, but location and functional analysis of the molecular mechanisms have not been established. Methods Here we report the sequence variation of the entire coding sequence from 72 samples of cattle, yak, buffalo, goat and sheep, and discuss its variation in Bovidae. Median-joining network analysis was used to analyze the variation found in the species. Synonymous and non-synonymous substitution rates were determined for the analysis of all the polymorphic sites. Phylogenetic analysis were carried out among the species of Bovidae to reconstruct their relationships. Results From the phylogenetic analysis with the consensus sequences of the studied Bovidae species, we found that only 11 of the 26 nucleotide changes that differentiate them produced amino acid changes. All the SNPs found in the cattle breeds were novel and showed similar percentages of nucleotides with non-synonymous substitutions at the N-terminal, MHD and C-terminal (12.3, 12.8 and 12.5%, respectively), and were much higher than the percentage of synonymous substitutions (2.5, 2.6 and 4.9%, respectively). Three mutations in cattle and one in sheep, detected in heterozygous individuals were predicted to be deleterious. Additionally, the analysis of the biochemical characteristics in the most common form of the proteins in each species show very little difference in molecular weight, pI, net charge, instability index, aliphatic index and GRAVY (Table 4) in the Bovidae species, except for sheep, which had a higher molecular weight, instability index and GRAVY. Conclusions There is sufficient variation in this gene within and among the studied species, and because NDN carry key functions in the organism, it can have effects in economically important traits in the production of these species. NDN sequence is phylogenetically informative in this group, thus we propose this gene as a phylogenetic marker to study the evolution and conservation in Bovidae.
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Abstract
During the last decades, research on adipose tissues has spread in parallel with the extension of obesity. Several observations converged on the idea that adipose tissues are organized in a large organ with endocrine and plastic properties. Two parenchymal components: white (WATs) and brown adipose tissues (BATs) are contained in subcutaneous and visceral compartments. Although both have endocrine properties, their function differs: WAT store lipids to allow intervals between meals, BAT burns lipids for thermogenesis. In spite of these opposite functions, they share the ability for reciprocal reversible transdifferentiation to tackle special physiologic needs. Thus, chronic need for thermogenesis induces browning and chronic positive energy balance induce whitening. Lineage tracing and data from explant studies strongly suggest other remodeling properties of this organ. During pregnancy and lactation breast WAT transdifferentiates into milk-secreting glands, composed by cells with abundant cytoplasmic lipids (pink adipocytes) and in the postlactation period pink adipocytes transdifferentiate back into WAT and BAT. The plastic properties of mature adipocytes are supported also by a liposecretion process in vitro where adult cell in culture transdifferentiate to differentiated fibroblast-like elements able to give rise to different phenotypes (rainbow adipocytes). In addition, the inflammasome system is activated in stressed adipocytes from obese adipose tissue. These adipocytes die and debris are reabsorbed by macrophages inducing a chronic low-grade inflammation, potentially contributing to insulin resistance and T2 diabetes. Thus, the plastic properties of this organ could open new therapeutic perspectives in the obesity-related metabolic disease and in breast pathologies. © 2018 American Physiological Society. Compr Physiol 8:1357-1431, 2018.
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Affiliation(s)
- Saverio Cinti
- Professor of Human Anatomy, Director, Center of Obesity, University of Ancona (Politecnica delle Marche), Ancona, Italy
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LincRNA H19 protects from dietary obesity by constraining expression of monoallelic genes in brown fat. Nat Commun 2018; 9:3622. [PMID: 30190464 PMCID: PMC6127097 DOI: 10.1038/s41467-018-05933-8] [Citation(s) in RCA: 104] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2017] [Accepted: 07/31/2018] [Indexed: 01/22/2023] Open
Abstract
Increasing brown adipose tissue (BAT) thermogenesis in mice and humans improves metabolic health and understanding BAT function is of interest for novel approaches to counteract obesity. The role of long noncoding RNAs (lncRNAs) in these processes remains elusive. We observed maternally expressed, imprinted lncRNA H19 increased upon cold-activation and decreased in obesity in BAT. Inverse correlations of H19 with BMI were also observed in humans. H19 overexpression promoted, while silencing of H19 impaired adipogenesis, oxidative metabolism and mitochondrial respiration in brown but not white adipocytes. In vivo, H19 overexpression protected against DIO, improved insulin sensitivity and mitochondrial biogenesis, whereas fat H19 loss sensitized towards HFD weight gains. Strikingly, paternally expressed genes (PEG) were largely absent from BAT and we demonstrated that H19 recruits PEG-inactivating H19-MBD1 complexes and acts as BAT-selective PEG gatekeeper. This has implications for our understanding how monoallelic gene expression affects metabolism in rodents and, potentially, humans. Brown adipose tissue (BAT) thermogenesis counteracts obesity and promotes metabolic health. The role of long non-coding RNAs (lncRNAs) in the regulation of this process is not well understood. Here the authors identify a maternally expressed lncRNA, H19, that increases BAT oxidative metabolism and energy expenditure.
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Rabiee A, Krüger M, Ardenkjær-Larsen J, Kahn CR, Emanuelli B. Distinct signalling properties of insulin receptor substrate (IRS)-1 and IRS-2 in mediating insulin/IGF-1 action. Cell Signal 2018; 47:1-15. [PMID: 29550500 DOI: 10.1016/j.cellsig.2018.03.003] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Revised: 03/09/2018] [Accepted: 03/12/2018] [Indexed: 12/21/2022]
Abstract
Insulin/IGF-1 action is driven by a complex and highly integrated signalling network. Loss-of-function studies indicate that the major insulin/IGF-1 receptor substrate (IRS) proteins, IRS-1 and IRS-2, mediate different biological functions in vitro and in vivo, suggesting specific signalling properties despite their high degree of homology. To identify mechanisms contributing to the differential signalling properties of IRS-1 and IRS-2 in the mediation of insulin/IGF-1 action, we performed comprehensive mass spectrometry (MS)-based phosphoproteomic profiling of brown preadipocytes from wild type, IRS-1-/- and IRS-2-/- mice in the basal and IGF-1-stimulated states. We applied stable isotope labeling by amino acids in cell culture (SILAC) for the accurate quantitation of changes in protein phosphorylation. We found ~10% of the 6262 unique phosphorylation sites detected to be regulated by IGF-1. These regulated sites included previously reported substrates of the insulin/IGF-1 signalling pathway, as well as novel substrates including Nuclear Factor I X and Semaphorin-4B. In silico prediction suggests the protein kinase B (PKB), protein kinase C (PKC), and cyclin-dependent kinase (CDK) as the main mediators of these phosphorylation events. Importantly, we found preferential phosphorylation patterns depending on the presence of either IRS-1 or IRS-2, which was associated with specific sets of kinases involved in signal transduction downstream of these substrates such as PDHK1, MAPK3, and PKD1 for IRS-1, and PIN1 and PKC beta for IRS-2. Overall, by generating a comprehensive phosphoproteomic profile from brown preadipocyte cells in response to IGF-1 stimulation, we reveal both common and distinct insulin/IGF-1 signalling events mediated by specific IRS proteins.
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Affiliation(s)
- Atefeh Rabiee
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Faculty of Health and Medical Sciences, Copenhagen, Denmark
| | - Marcus Krüger
- Institute for Genetics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
| | - Jacob Ardenkjær-Larsen
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Faculty of Health and Medical Sciences, Copenhagen, Denmark
| | - C Ronald Kahn
- Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA
| | - Brice Emanuelli
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Faculty of Health and Medical Sciences, Copenhagen, Denmark.
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Supra-pharmacological concentration of capsaicin stimulates brown adipogenesis through induction of endoplasmic reticulum stress. Sci Rep 2018; 8:845. [PMID: 29339762 PMCID: PMC5770457 DOI: 10.1038/s41598-018-19223-2] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Accepted: 12/18/2017] [Indexed: 01/12/2023] Open
Abstract
We previously showed that brown (pre)adipocytes express Trpv1, a capsaicin receptor, and that capsaicin stimulates differentiation of brown preadipocytes in the late stages of brown adipogenesis. The present study revealed that treatment with 100 μM capsaicin stimulates brown adipogenesis by inducing endoplasmic reticulum (ER) stress. Treatment with capsaicin (100 μM) during brown adipogenesis enhanced lipid accumulation and the expression of Ucp1, a gene selectively expressed in brown adipocytes. Capsaicin treatment also caused an increase in the cytosolic calcium concentration even when extracellular calcium was removed. I-RTX, a Trpv1 inhibitor, did not modulate the increase in cytosolic calcium concentration, lipid accumulation or Ucp1 expression. Previous studies revealed that the release of calcium from the ER induces ER stress, leading to the conversion of X-box binding protein 1 (Xbp1) pre-mRNA to spliced Xbp1 (sXbp1) as well as the up-regulation of Chop expression. Capsaicin treatment increased the expression of sXbp1 and Chop in brown preadipocytes and did not enhance lipid accumulation or Ucp1 expression in Xbp1 knockdown cells. The present results describe a novel mechanism of brown adipogenesis regulation via ER stress that is induced by a supra-pharmacological concentration of capsaicin.
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Brandão BB, Guerra BA, Mori MA. Shortcuts to a functional adipose tissue: The role of small non-coding RNAs. Redox Biol 2017; 12:82-102. [PMID: 28214707 PMCID: PMC5312655 DOI: 10.1016/j.redox.2017.01.020] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Accepted: 01/30/2017] [Indexed: 12/20/2022] Open
Abstract
Metabolic diseases such as type 2 diabetes are a major public health issue worldwide. These diseases are often linked to a dysfunctional adipose tissue. Fat is a large, heterogenic, pleiotropic and rather complex tissue. It is found in virtually all cavities of the human body, shows unique plasticity among tissues, and harbors many cell types in addition to its main functional unit - the adipocyte. Adipose tissue function varies depending on the localization of the fat depot, the cell composition of the tissue and the energy status of the organism. While the white adipose tissue (WAT) serves as the main site for triglyceride storage and acts as an important endocrine organ, the brown adipose tissue (BAT) is responsible for thermogenesis. Beige adipocytes can also appear in WAT depots to sustain heat production upon certain conditions, and it is becoming clear that adipose tissue depots can switch phenotypes depending on cell autonomous and non-autonomous stimuli. To maintain such degree of plasticity and respond adequately to changes in the energy balance, three basic processes need to be properly functioning in the adipose tissue: i) adipogenesis and adipocyte turnover, ii) metabolism, and iii) signaling. Here we review the fundamental role of small non-coding RNAs (sncRNAs) in these processes, with focus on microRNAs, and demonstrate their importance in adipose tissue function and whole body metabolic control in mammals.
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Affiliation(s)
- Bruna B Brandão
- Program in Molecular Biology, Universidade Federal de São Paulo, São Paulo, Brazil; Department of Biochemistry and Tissue Biology, Universidade Estadual de Campinas, Campinas, Brazil
| | - Beatriz A Guerra
- Program in Molecular Biology, Universidade Federal de São Paulo, São Paulo, Brazil; Department of Biochemistry and Tissue Biology, Universidade Estadual de Campinas, Campinas, Brazil
| | - Marcelo A Mori
- Program in Molecular Biology, Universidade Federal de São Paulo, São Paulo, Brazil; Department of Biochemistry and Tissue Biology, Universidade Estadual de Campinas, Campinas, Brazil; Program in Genetics and Molecular Biology, Universidade Estadual de Campinas, Campinas, Brazil.
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Abstract
Guarana (Paullinia cupana) is a plant originated in Brazil that presents a beneficial effect on body weight control and metabolic alterations. The aim of this study was to evaluate the effects of guarana on genes and miRNAs related to adipogenesis in 3T3L1 cells. The anti-adipogenic effect of guarana was evaluated by Oil Red-O staining. Gene and miRNA expression levels were determined by real time PCR. The Cebpα and β-catenin nuclear translocation were evaluated using immunocytochemistry. Our data indicated that the triglyceride-reducing effect of guarana was dose-dependent from 100 to 300 µg/mL (−12%, −20%, −24% and −40%, respectively, p < 0.0001). An up-regulation of the anti-adipogenic genes Wnt10b, Wnt3a, Wnt1, Gata3 and Dlk1 and a down-regulation of pro-adipogenic genes Cebpα, Pparγ and Creb1 were also observed. Furthermore, guarana repressed mmu-miR-27b-3p, mmu-miR-34b-5p and mmu-miR-760-5p, that contributed for up-regulation of their molecular targets Wnt3a, Wnt1 and Wnt10b. Additionally, cells treated with guarana presented an increase on β-catenin nuclear translocation (p < 0.0018). In summary, our data indicate that guarana has an anti-adipogenic potential due to its ability to modulate miRNAs and genes related to this process. Together our data demonstrate the important role of guarana as a putative therapeutic agent.
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Paniagua JA. Nutrition, insulin resistance and dysfunctional adipose tissue determine the different components of metabolic syndrome. World J Diabetes 2016; 7:483-514. [PMID: 27895819 PMCID: PMC5107710 DOI: 10.4239/wjd.v7.i19.483] [Citation(s) in RCA: 113] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Revised: 08/16/2016] [Accepted: 09/07/2016] [Indexed: 02/05/2023] Open
Abstract
Obesity is an excessive accumulation of body fat that may be harmful to health. Today, obesity is a major public health problem, affecting in greater or lesser proportion all demographic groups. Obesity is estimated by body mass index (BMI) in a clinical setting, but BMI reports neither body composition nor the location of excess body fat. Deaths from cardiovascular diseases, cancer and diabetes accounted for approximately 65% of all deaths, and adiposity and mainly abdominal adiposity are associated with all these disorders. Adipose tissue could expand to inflexibility levels. Then, adiposity is associated with a state of low-grade chronic inflammation, with increased tumor necrosis factor-α and interleukin-6 release, which interfere with adipose cell differentiation, and the action pattern of adiponectin and leptin until the adipose tissue begins to be dysfunctional. In this state the subject presents insulin resistance and hyperinsulinemia, probably the first step of a dysfunctional metabolic system. Subsequent to central obesity, insulin resistance, hyperglycemia, hypertriglyceridemia, hypoalphalipoproteinemia, hypertension and fatty liver are grouped in the so-called metabolic syndrome (MetS). In subjects with MetS an energy balance is critical to maintain a healthy body weight, mainly limiting the intake of high energy density foods (fat). However, high-carbohydrate rich (CHO) diets increase postprandial peaks of insulin and glucose. Triglyceride-rich lipoproteins are also increased, which interferes with reverse cholesterol transport lowering high-density lipoprotein cholesterol. In addition, CHO-rich diets could move fat from peripheral to central deposits and reduce adiponectin activity in peripheral adipose tissue. All these are improved with monounsaturated fatty acid-rich diets. Lastly, increased portions of ω-3 and ω-6 fatty acids also decrease triglyceride levels, and complement the healthy diet that is recommended in patients with MetS.
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Yanagihara K, Liu Y, Kanie K, Takayama K, Kokunugi M, Hirata M, Fukuda T, Suga M, Nikawa H, Mizuguchi H, Kato R, Furue MK. Prediction of Differentiation Tendency Toward Hepatocytes from Gene Expression in Undifferentiated Human Pluripotent Stem Cells. Stem Cells Dev 2016; 25:1884-1897. [PMID: 27733097 PMCID: PMC5165660 DOI: 10.1089/scd.2016.0099] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Functional hepatocytes derived from human pluripotent stem cells (hPSCs) have potential as tools for predicting drug-induced hepatotoxicity in the early phases of drug development. However, the propensity of hPSC lines to differentiate into specific lineages is reported to differ. The ability to predict low propensity of hPSCs to differentiate into hepatocytes would facilitate the selection of useful hPSC clones and substantially accelerate development of hPSC-derived hepatocytes for pharmaceutical research. In this study, we compared the expression of genes associated with hepatic differentiation in five hPSC lines including human ES cell line, H9, which is known to differentiate into hepatocytes, and an hPSC line reported with a poor propensity for hepatic differentiation. Genes distinguishing between undifferentiated hPSCs, hPSC-derived hepatoblast-like differentiated cells, and primary human hepatocytes were drawn by two-way cluster analysis. The order of expression levels of genes in undifferentiated hPSCs was compared with that in hPSC-derived hepatoblast-like cells. Three genes were selected as predictors of low propensity for hepatic differentiation. Expression of these genes was investigated in 23 hPSC clones. Review of representative cells by induction of hepatic differentiation suggested that low prediction scores were linked with low hepatic differentiation. Thus, our model using gene expression ranking and bioinformatic analysis could reasonably predict poor differentiation propensity of hPSC lines.
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Affiliation(s)
- Kana Yanagihara
- 1 Laboratory of Stem Cell Cultures, National Institutes of Biomedical Innovation , Health and Nutrition, Osaka, Japan
| | - Yujung Liu
- 1 Laboratory of Stem Cell Cultures, National Institutes of Biomedical Innovation , Health and Nutrition, Osaka, Japan
| | - Kei Kanie
- 2 Department of Basic Medicinal Sciences, Graduate School of Pharmaceutical Sciences, Nagoya University , Nagoya, Japan
| | - Kazuo Takayama
- 3 Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University , Osaka, Japan .,4 The Keihanshin Consortium for Fostering the Next Generation of Global Leaders in Research (K-CONNEX), Kyoto University , Kyoto, Japan .,5 Laboratory of Hepatocyte Regulation, National Institutes of Biomedical Innovation , Health and Nutrition, Osaka, Japan
| | - Minako Kokunugi
- 1 Laboratory of Stem Cell Cultures, National Institutes of Biomedical Innovation , Health and Nutrition, Osaka, Japan .,6 Department of Oral Biology & Engineering Integrated Health Sciences, Institute of Biomedical and Health Sciences, Hiroshima University , Hiroshima, Japan
| | - Mitsuhi Hirata
- 1 Laboratory of Stem Cell Cultures, National Institutes of Biomedical Innovation , Health and Nutrition, Osaka, Japan
| | - Takayuki Fukuda
- 1 Laboratory of Stem Cell Cultures, National Institutes of Biomedical Innovation , Health and Nutrition, Osaka, Japan
| | - Mika Suga
- 1 Laboratory of Stem Cell Cultures, National Institutes of Biomedical Innovation , Health and Nutrition, Osaka, Japan
| | - Hiroki Nikawa
- 6 Department of Oral Biology & Engineering Integrated Health Sciences, Institute of Biomedical and Health Sciences, Hiroshima University , Hiroshima, Japan
| | - Hiroyuki Mizuguchi
- 3 Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University , Osaka, Japan .,5 Laboratory of Hepatocyte Regulation, National Institutes of Biomedical Innovation , Health and Nutrition, Osaka, Japan .,7 Global Center for Medical Engineering and Informatics, Osaka University , Osaka, Japan
| | - Ryuji Kato
- 2 Department of Basic Medicinal Sciences, Graduate School of Pharmaceutical Sciences, Nagoya University , Nagoya, Japan
| | - Miho K Furue
- 1 Laboratory of Stem Cell Cultures, National Institutes of Biomedical Innovation , Health and Nutrition, Osaka, Japan
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