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The scaffold protein p62 regulates adaptive thermogenesis through ATF2 nuclear target activation.
Fischer K, Fenzl A, Liu D, Dyar KA, Kleinert M, Brielmeier M, Clemmensen C, Fedl A, Finan B, Gessner A, Jastroch M, Huang J, Keipert S, Klingenspor M, Brüning JC, Kneilling M, Maier FC, Othman AE, Pichler BJ, Pramme-Steinwachs I, Sachs S, Scheideler A, Thaiss WM, Uhlenhaut H, Ussar S, Woods SC, Zorn J, Stemmer K, Collins S, Diaz-Meco M, Moscat J, Tschöp MH, Müller TD
(2020) Nat Commun 11: 2306
MeSH Terms: Activating Transcription Factor 2, Adipogenesis, Adipose Tissue, Brown, Adipose Tissue, White, Animals, Cell Nucleus, Magnetic Resonance Imaging, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Obesity, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Positron Emission Tomography Computed Tomography, Protein Binding, Sequestosome-1 Protein, Uncoupling Protein 1, p38 Mitogen-Activated Protein Kinases
Show Abstract · Added July 22, 2020
During β-adrenergic stimulation of brown adipose tissue (BAT), p38 phosphorylates the activating transcription factor 2 (ATF2) which then translocates to the nucleus to activate the expression of Ucp1 and Pgc-1α. The mechanisms underlying ATF2 target activation are unknown. Here we demonstrate that p62 (Sqstm1) binds to ATF2 to orchestrate activation of the Ucp1 enhancer and Pgc-1α promoter. P62 mice show reduced expression of Ucp1 and Pgc-1α with impaired ATF2 genomic binding. Modulation of Ucp1 and Pgc-1α expression through p62 regulation of ATF2 signaling is demonstrated in vitro and in vivo in p62 mice, global p62 and Ucp1-Cre p62 mice. BAT dysfunction resulting from p62 deficiency is manifest after birth and obesity subsequently develops despite normal food intake, intestinal nutrient absorption and locomotor activity. In summary, our data identify p62 as a master regulator of BAT function in that it controls the Ucp1 pathway through regulation of ATF2 genomic binding.
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18 MeSH Terms
HDAC11 suppresses the thermogenic program of adipose tissue via BRD2.
Bagchi RA, Ferguson BS, Stratton MS, Hu T, Cavasin MA, Sun L, Lin YH, Liu D, Londono P, Song K, Pino MF, Sparks LM, Smith SR, Scherer PE, Collins S, Seto E, McKinsey TA
(2018) JCI Insight 3:
MeSH Terms: Adipose Tissue, Brown, Adipose Tissue, White, Adult, Aged, Aged, 80 and over, Animals, Diet, High-Fat, Disease Models, Animal, Energy Metabolism, Epigenesis, Genetic, Fatty Liver, Female, Gene Expression Regulation, Histone Deacetylases, Humans, Insulin Resistance, Male, Mice, Mice, Knockout, Middle Aged, Obesity, Thermogenesis, Transcription Factors
Show Abstract · Added July 22, 2020
Little is known about the biological function of histone deacetylase 11 (HDAC11), which is the lone class IV HDAC. Here, we demonstrate that deletion of HDAC11 in mice stimulates brown adipose tissue (BAT) formation and beiging of white adipose tissue (WAT). Consequently, HDAC11-deficient mice exhibit enhanced thermogenic potential and, in response to high-fat feeding, attenuated obesity, improved insulin sensitivity, and reduced hepatic steatosis. Ex vivo and cell-based assays revealed that HDAC11 catalytic activity suppresses the BAT transcriptional program, in both the basal state and in response to β-adrenergic receptor signaling, through a mechanism that is dependent on physical association with BRD2, a bromodomain and extraterminal (BET) acetyl-histone-binding protein. These findings define an epigenetic pathway for the regulation of energy homeostasis and suggest the potential for HDAC11-selective inhibitors for the treatment of obesity and diabetes.
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MeSH Terms
Microsomal triglyceride transfer protein contributes to lipid droplet maturation in adipocytes.
Swift LL, Love JD, Harris CM, Chang BH, Jerome WG
(2017) PLoS One 12: e0181046
MeSH Terms: 3T3-L1 Cells, Adipocytes, Adipose Tissue, Brown, Adipose Tissue, White, Animals, Body Composition, Carrier Proteins, Diet, High-Fat, Gene Knockdown Techniques, Lipid Droplets, Mice, Mice, Transgenic, Weight Gain
Show Abstract · Added March 3, 2020
Previous studies in our laboratory have established the presence of MTP in both white and brown adipose tissue in mice as well as in 3T3-L1 cells. Additional studies demonstrated an increase in MTP levels as 3T3-L1 cells differentiate into adipocytes concurrent with the movement of MTP from the juxtanuclear region of the cell to the surface of lipid droplets. This suggested a role for MTP in lipid droplet biogenesis and/or maturation. To probe the role of MTP in adipocytes, we used a Cre-Lox approach with aP2-Cre and Adipoq-Cre recombinase transgenic mice to knock down MTP expression in brown and white fat of mice. MTP expression was reduced approximately 55% in white fat and 65-80% in brown fat. Reducing MTP expression in adipose tissue had no effect on weight gain or body composition, whether the mice were fed a regular rodent or high fat diet. In addition, serum lipids and unesterified fatty acid levels were not altered in the knockdown mice. Importantly, decreased MTP expression in adipose tissue was associated with smaller lipid droplets in brown fat and smaller adipocytes in white fat. These results combined with our previous studies showing MTP lipid transfer activity is not necessary for lipid droplet initiation or growth in the early stages of differentiation, suggest that a structural feature of the MTP protein is important in lipid droplet maturation. We conclude that MTP protein plays a critical role in lipid droplet maturation, but does not regulate total body fat accumulation.
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HDAC3 is a molecular brake of the metabolic switch supporting white adipose tissue browning.
Ferrari A, Longo R, Fiorino E, Silva R, Mitro N, Cermenati G, Gilardi F, Desvergne B, Andolfo A, Magagnotti C, Caruso D, Fabiani E, Hiebert SW, Crestani M
(2017) Nat Commun 8: 93
MeSH Terms: Adipocytes, Adipose Tissue, Brown, Adipose Tissue, White, Animals, Cell Line, Diet, High-Fat, Gene Expression Regulation, Gene Silencing, Histone Deacetylases, Lipid Metabolism, Male, Mice, Mice, Knockout
Show Abstract · Added February 7, 2019
White adipose tissue (WAT) can undergo a phenotypic switch, known as browning, in response to environmental stimuli such as cold. Post-translational modifications of histones have been shown to regulate cellular energy metabolism, but their role in white adipose tissue physiology remains incompletely understood. Here we show that histone deacetylase 3 (HDAC3) regulates WAT metabolism and function. Selective ablation of Hdac3 in fat switches the metabolic signature of WAT by activating a futile cycle of de novo fatty acid synthesis and β-oxidation that potentiates WAT oxidative capacity and ultimately supports browning. Specific ablation of Hdac3 in adipose tissue increases acetylation of enhancers in Pparg and Ucp1 genes, and of putative regulatory regions of the Ppara gene. Our results unveil HDAC3 as a regulator of WAT physiology, which acts as a molecular brake that inhibits fatty acid metabolism and WAT browning.Histone deacetylases, such as HDAC3, have been shown to alter cellular metabolism in various tissues. Here the authors show that HDAC3 regulates WAT metabolism by activating a futile cycle of fatty acid synthesis and oxidation, which supports WAT browning.
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Prostaglandin E2 receptor EP3 regulates both adipogenesis and lipolysis in mouse white adipose tissue.
Xu H, Fu JL, Miao YF, Wang CJ, Han QF, Li S, Huang SZ, Du SN, Qiu YX, Yang JC, Gustafsson JÅ, Breyer RM, Zheng F, Wang NP, Zhang XY, Guan YF
(2016) J Mol Cell Biol 8: 518-529
MeSH Terms: Adipocytes, Adipogenesis, Adipose Tissue, White, Animals, Cell Differentiation, Gene Deletion, Inflammation, Insulin Resistance, Lipolysis, Lipoproteins, VLDL, Mice, Mice, Obese, Obesity, Phenotype, Protein Isoforms, Rats, Sprague-Dawley, Receptors, Prostaglandin E, EP3 Subtype, Signal Transduction, Triglycerides
Show Abstract · Added February 7, 2019
Among the four prostaglandin E2 receptors, EP3 receptor is the one most abundantly expressed in white adipose tissue (WAT). The mouse EP3 gene gives rise to three isoforms, namely EP3α, EP3β, and EP3γ, which differ only at their C-terminal tails. To date, functions of EP3 receptor and its isoforms in WAT remain incompletely characterized. In this study, we found that the expression of all EP3 isoforms were downregulated in WAT of both db/db and high-fat diet-induced obese mice. Genetic ablation of three EP3 receptor isoforms (EP3 mice) or EP3α and EP3γ isoforms with EP3β intact (EP3β mice) led to an obese phenotype with increased food intake, decreased motor activity, reduced insulin sensitivity, and elevated serum triglycerides. Since the differentiation of preadipocytes and mouse embryonic fibroblasts to adipocytes was markedly facilitated by either pharmacological blockade or genetic deletion/inhibition of EP3 receptor via the cAMP/PKA/PPARγ pathway, increased adipogenesis may contribute to obesity in EP3 and EP3β mice. Moreover, both EP3 and EP3β mice had increased lipolysis in WAT mainly due to the activated cAMP/PKA/hormone-sensitive lipase pathway. Taken together, our findings suggest that EP3 receptor and its α and γ isoforms are involved in both adipogenesis and lipolysis and influence food intake, serum lipid levels, and insulin sensitivity.
© The Author (2016). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS. All rights reserved.
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Decreased Consumption of Branched-Chain Amino Acids Improves Metabolic Health.
Fontana L, Cummings NE, Arriola Apelo SI, Neuman JC, Kasza I, Schmidt BA, Cava E, Spelta F, Tosti V, Syed FA, Baar EL, Veronese N, Cottrell SE, Fenske RJ, Bertozzi B, Brar HK, Pietka T, Bullock AD, Figenshau RS, Andriole GL, Merrins MJ, Alexander CM, Kimple ME, Lamming DW
(2016) Cell Rep 16: 520-530
MeSH Terms: Adipose Tissue, White, Amino Acids, Branched-Chain, Animals, Blood Glucose, Dietary Proteins, Fibroblast Growth Factors, Gluconeogenesis, Glucose Intolerance, Humans, Insulin-Secreting Cells, Male, Mice, Inbred C57BL, Middle Aged, Obesity, Organ Size, Stress, Physiological
Show Abstract · Added August 2, 2016
Protein-restricted (PR), high-carbohydrate diets improve metabolic health in rodents, yet the precise dietary components that are responsible for these effects have not been identified. Furthermore, the applicability of these studies to humans is unclear. Here, we demonstrate in a randomized controlled trial that a moderate PR diet also improves markers of metabolic health in humans. Intriguingly, we find that feeding mice a diet specifically reduced in branched-chain amino acids (BCAAs) is sufficient to improve glucose tolerance and body composition equivalently to a PR diet via metabolically distinct pathways. Our results highlight a critical role for dietary quality at the level of amino acids in the maintenance of metabolic health and suggest that diets specifically reduced in BCAAs, or pharmacological interventions in this pathway, may offer a translatable way to achieve many of the metabolic benefits of a PR diet.
Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.
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16 MeSH Terms
Activation of mTORC1 is essential for β-adrenergic stimulation of adipose browning.
Liu D, Bordicchia M, Zhang C, Fang H, Wei W, Li JL, Guilherme A, Guntur K, Czech MP, Collins S
(2016) J Clin Invest 126: 1704-16
MeSH Terms: 3T3-L1 Cells, Adaptor Proteins, Signal Transducing, Adipose Tissue, Brown, Adipose Tissue, White, Animals, Cyclic AMP-Dependent Protein Kinases, HEK293 Cells, Humans, Insulin, Mechanistic Target of Rapamycin Complex 1, Mice, Mice, Knockout, Multiprotein Complexes, Receptors, Adrenergic, beta, Regulatory-Associated Protein of mTOR, Ribosomal Protein S6 Kinases, 70-kDa, Ribosomal Protein S6 Kinases, 90-kDa, Signal Transduction, TOR Serine-Threonine Kinases, Uncoupling Protein 1
Show Abstract · Added July 22, 2020
A classic metabolic concept posits that insulin promotes energy storage and adipose expansion, while catecholamines stimulate release of adipose energy stores by hydrolysis of triglycerides through β-adrenergic receptor (βARs) and protein kinase A (PKA) signaling. Here, we have shown that a key hub in the insulin signaling pathway, activation of p70 ribosomal S6 kinase (S6K1) through mTORC1, is also triggered by PKA activation in both mouse and human adipocytes. Mice with mTORC1 impairment, either through adipocyte-specific deletion of Raptor or pharmacologic rapamycin treatment, were refractory to the well-known βAR-dependent increase of uncoupling protein UCP1 expression and expansion of beige/brite adipocytes (so-called browning) in white adipose tissue (WAT). Mechanistically, PKA directly phosphorylated mTOR and RAPTOR on unique serine residues, an effect that was independent of insulin/AKT signaling. Abrogation of the PKA site within RAPTOR disrupted βAR/mTORC1 activation of S6K1 without affecting mTORC1 activation by insulin. Conversely, a phosphomimetic RAPTOR augmented S6K1 activity. Together, these studies reveal a signaling pathway from βARs and PKA through mTORC1 that is required for adipose browning by catecholamines and provides potential therapeutic strategies to enhance energy expenditure and combat metabolic disease.
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The PGE2 EP3 Receptor Regulates Diet-Induced Adiposity in Male Mice.
Ceddia RP, Lee D, Maulis MF, Carboneau BA, Threadgill DW, Poffenberger G, Milne G, Boyd KL, Powers AC, McGuinness OP, Gannon M, Breyer RM
(2016) Endocrinology 157: 220-32
MeSH Terms: Adipose Tissue, White, Adiposity, Animals, Cell Size, Crosses, Genetic, Diabetes Mellitus, Type 2, Diet, High-Fat, Insulin Resistance, Lipid Metabolism, Liver, Macrophage Activation, Male, Mice, Inbred C57BL, Mice, Knockout, Muscle, Skeletal, Necrosis, Non-alcoholic Fatty Liver Disease, Obesity, Panniculitis, Receptors, Prostaglandin E, EP3 Subtype, Weight Gain
Show Abstract · Added January 12, 2016
Mice carrying a targeted disruption of the prostaglandin E2 (PGE2) E-prostanoid receptor 3 (EP3) gene, Ptger3, were fed a high-fat diet (HFD), or a micronutrient matched control diet, to investigate the effects of disrupted PGE2-EP3 signaling on diabetes in a setting of diet-induced obesity. Although no differences in body weight were seen in mice fed the control diet, when fed a HFD, EP3(-/-) mice gained more weight relative to EP3(+/+) mice. Overall, EP3(-/-) mice had increased epididymal fat mass and adipocyte size; paradoxically, a relative decrease in both epididymal fat pad mass and adipocyte size was observed in the heaviest EP3(-/-) mice. The EP3(-/-) mice had increased macrophage infiltration, TNF-α, monocyte chemoattractant protein-1, IL-6 expression, and necrosis in their epididymal fat pads as compared with EP3(+/+) animals. Adipocytes isolated from EP3(+/+) or EP3(-/-) mice were assayed for the effect of PGE2-evoked inhibition of lipolysis. Adipocytes isolated from EP3(-/-) mice lacked PGE2-evoked inhibition of isoproterenol stimulated lipolysis compared with EP3(+/+). EP3(-/-) mice fed HFD had exaggerated ectopic lipid accumulation in skeletal muscle and liver, with evidence of hepatic steatosis. Both blood glucose and plasma insulin levels were similar between genotypes on a control diet, but when fed HFD, EP3(-/-) mice became hyperglycemic and hyperinsulinemic when compared with EP3(+/+) fed HFD, demonstrating a more severe insulin resistance phenotype in EP3(-/-). These results demonstrate that when fed a HFD, EP3(-/-) mice have abnormal lipid distribution, developing excessive ectopic lipid accumulation and associated insulin resistance.
3 Communities
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21 MeSH Terms
Spleen supports a pool of innate-like B cells in white adipose tissue that protects against obesity-associated insulin resistance.
Wu L, Parekh VV, Hsiao J, Kitamura D, Van Kaer L
(2014) Proc Natl Acad Sci U S A 111: E4638-47
MeSH Terms: Adipose Tissue, White, Animals, B-Lymphocytes, CD5 Antigens, Diet, High-Fat, Immunity, Innate, Insulin Resistance, Interleukin-10, Lymphocyte Count, Male, Mice, Inbred C57BL, Obesity, Peritoneal Cavity, Phenotype, Spleen, Splenectomy
Show Abstract · Added January 20, 2015
Lipid accumulation in obesity triggers a low-grade inflammation that results from an imbalance between pro- and anti-inflammatory components of the immune system and acts as the major underlying mechanism for the development of obesity-associated diseases, notably insulin resistance and type 2 diabetes. Innate-like B cells are a subgroup of B cells that respond to innate signals and modulate inflammatory responses through production of immunomodulatory mediators such as the anti-inflammatory cytokine IL-10. In this study, we examined innate-like B cells in visceral white adipose tissue (VAT) and the relationship of these cells with their counterparts in the peritoneal cavity and spleen during diet-induced obesity (DIO) in mice. We show that a considerable number of innate-like B cells bearing a surface phenotype distinct from the recently identified "adipose natural regulatory B cells" populate VAT of lean animals, and that spleen represents a source for the recruitment of these cells in VAT during DIO. However, demand for these cells in the expanding VAT outpaces their recruitment during DIO, and the obese environment in VAT further impairs their function. We further show that removal of splenic precursors of innate-like B cells through splenectomy exacerbates, whereas supplementation of these cells via adoptive transfer ameliorates, DIO-associated insulin resistance. Additional adoptive transfer experiments pointed toward a dominant role of IL-10 in mediating the protective effects of innate-like B cells against DIO-induced insulin resistance. These findings identify spleen-supplied innate-like B cells in VAT as previously unrecognized players and therapeutic targets for obesity-associated diseases.
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16 MeSH Terms
β-Aminoisobutyric acid induces browning of white fat and hepatic β-oxidation and is inversely correlated with cardiometabolic risk factors.
Roberts LD, Boström P, O'Sullivan JF, Schinzel RT, Lewis GD, Dejam A, Lee YK, Palma MJ, Calhoun S, Georgiadi A, Chen MH, Ramachandran VS, Larson MG, Bouchard C, Rankinen T, Souza AL, Clish CB, Wang TJ, Estall JL, Soukas AA, Cowan CA, Spiegelman BM, Gerszten RE
(2014) Cell Metab 19: 96-108
MeSH Terms: Adipocytes, Brown, Adipocytes, White, Adipose Tissue, Brown, Adipose Tissue, White, Aminoisobutyric Acids, Animals, Cardiovascular Diseases, Cell Differentiation, Exercise, Gene Expression Regulation, Glucose Tolerance Test, Humans, Induced Pluripotent Stem Cells, Liver, Metabolic Diseases, Mice, Organ Specificity, Oxidation-Reduction, PPAR alpha, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Phenotype, Physical Conditioning, Animal, Risk Factors, Transcription Factors, Transcription, Genetic, Weight Gain
Show Abstract · Added February 28, 2014
The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) regulates metabolic genes in skeletal muscle and contributes to the response of muscle to exercise. Muscle PGC-1α transgenic expression and exercise both increase the expression of thermogenic genes within white adipose. How the PGC-1α-mediated response to exercise in muscle conveys signals to other tissues remains incompletely defined. We employed a metabolomic approach to examine metabolites secreted from myocytes with forced expression of PGC-1α, and identified β-aminoisobutyric acid (BAIBA) as a small molecule myokine. BAIBA increases the expression of brown adipocyte-specific genes in white adipocytes and β-oxidation in hepatocytes both in vitro and in vivo through a PPARα-mediated mechanism, induces a brown adipose-like phenotype in human pluripotent stem cells, and improves glucose homeostasis in mice. In humans, plasma BAIBA concentrations are increased with exercise and inversely associated with metabolic risk factors. BAIBA may thus contribute to exercise-induced protection from metabolic diseases.
Copyright © 2014 Elsevier Inc. All rights reserved.
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26 MeSH Terms