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1.
Cell Metab ; 34(12): 1932-1946.e7, 2022 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-36243005

RESUMO

Low-grade, sustained inflammation in white adipose tissue (WAT) characterizes obesity and coincides with type 2 diabetes mellitus (T2DM). However, pharmacological targeting of inflammation lacks durable therapeutic effects in insulin-resistant conditions. Through a computational screen, we discovered that the FDA-approved rheumatoid arthritis drug auranofin improved insulin sensitivity and normalized obesity-associated abnormalities, including hepatic steatosis and hyperinsulinemia in mouse models of T2DM. We also discovered that auranofin accumulation in WAT depleted inflammatory responses to a high-fat diet without altering body composition in obese wild-type mice. Surprisingly, elevated leptin levels and blunted beta-adrenergic receptor activity achieved by leptin receptor deletion abolished the antidiabetic effects of auranofin. These experiments also revealed that the metabolic benefits of leptin reduction were superior to immune impacts of auranofin in WAT. Our studies uncover important metabolic properties of anti-inflammatory treatments and contribute to the notion that leptin reduction in the periphery can be accomplished to treat obesity and T2DM.


Assuntos
Artrite Reumatoide , Diabetes Mellitus Tipo 2 , Animais , Camundongos , Camundongos Obesos , Hipoglicemiantes , Auranofina/farmacologia , Auranofina/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Obesidade/tratamento farmacológico
2.
Mol Metab ; 48: 101221, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33771728

RESUMO

OBJECTIVE: White adipose tissue (WAT) expansion regulates energy balance and overall metabolic homeostasis. The absence or loss of WAT occurring through lipodystrophy and lipoatrophy contributes to the development of hepatic steatosis and insulin resistance. We previously demonstrated that sole small ubiquitin-like modifier (SUMO) E2-conjugating enzyme Ube2i represses human adipocyte differentiation. The role of Ube2i during WAT development remains unknown. METHODS: To determine how Ube2i impacts body composition and energy balance, we generated adipocyte-specific Ube2i knockout mice (Ube2ia-KO). CRISPR/Cas9 gene editing inserted loxP sites flanking exons 3 and 4 at the Ube2i locus. Subsequent genetic crosses to Adipoq-Cre transgenic mice allowed deletion of Ube2i in white and brown adipocytes. We measured multiple metabolic endpoints that describe energy balance and carbohydrate metabolism in Ube2ia-KO and littermate controls during postnatal growth. RESULTS: Surprisingly, Ube2ia-KO mice developed hyperinsulinemia and hepatic steatosis. Global energy balance defects emerged from dysfunctional WAT marked by pronounced local inflammation, loss of serum adipokines, hepatomegaly, and near absence of major adipose tissue depots. We observed progressive lipoatrophy that commences in the early adolescent period. CONCLUSIONS: Our results demonstrate that Ube2i expression in mature adipocytes allows WAT expansion during postnatal growth. Deletion of Ube2i in fat cells compromises and diminishes adipocyte function that induces WAT inflammation and ectopic lipid accumulation in the liver. Our findings reveal an indispensable role for Ube2i during white adipocyte expansion and endocrine control of energy balance.


Assuntos
Adipócitos Marrons/metabolismo , Adipócitos Brancos/metabolismo , Deleção de Genes , Hiperinsulinismo/complicações , Hiperinsulinismo/metabolismo , Lipodistrofia/complicações , Lipodistrofia/metabolismo , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/metabolismo , Transdução de Sinais/genética , Enzimas de Conjugação de Ubiquitina/genética , Enzimas de Conjugação de Ubiquitina/metabolismo , Adipocinas/sangue , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Composição Corporal/genética , Metabolismo Energético/genética , Feminino , Hiperinsulinismo/genética , Resistência à Insulina/genética , Lipodistrofia/genética , Masculino , Camundongos , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/genética
3.
Diabetes ; 69(12): 2630-2641, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32994273

RESUMO

Obesity fosters low-grade inflammation in white adipose tissue (WAT) that may contribute to the insulin resistance that characterizes type 2 diabetes. However, the causal relationship of these events remains unclear. The established dominance of STAT1 function in the immune response suggests an obligate link between inflammation and the comorbidities of obesity. To this end, we sought to determine how STAT1 activity in white adipocytes affects insulin sensitivity. STAT1 expression in WAT inversely correlated with fasting plasma glucose in both obese mice and humans. Metabolomic and gene expression profiling established STAT1 deletion in adipocytes (STAT1 a-KO ) enhanced mitochondrial function and accelerated tricarboxylic acid cycle flux coupled with reduced fat cell size in subcutaneous WAT depots. STAT1 a-KO reduced WAT inflammation, but insulin resistance persisted in obese mice. Rather, elimination of type I cytokine interferon-γ activity enhanced insulin sensitivity in diet-induced obesity. Our findings reveal a permissive mechanism that bridges WAT inflammation to whole-body insulin sensitivity.


Assuntos
Tecido Adiposo/metabolismo , Regulação da Expressão Gênica/fisiologia , Inflamação/metabolismo , Resistência à Insulina/fisiologia , Fator de Transcrição STAT1/metabolismo , Adipócitos/metabolismo , Animais , Metabolismo Energético/genética , Metabolismo Energético/fisiologia , Feminino , Glucose/metabolismo , Homeostase/fisiologia , Humanos , Interferon gama/genética , Interferon gama/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/metabolismo , Interferência de RNA , Receptores de Interferon/genética , Receptores de Interferon/metabolismo , Fator de Transcrição STAT1/genética , Receptor de Interferon gama
4.
Am J Physiol Cell Physiol ; 318(1): C63-C72, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31596606

RESUMO

Endocrine-disrupting chemicals interact with transcription factors essential for adipocyte differentiation. Exposure to endocrine-disrupting chemicals corresponds with elevated risks of obesity, but the effects of these compounds on human cells remain largely undefined. Widespread use of bisphenol AF (BPAF) as a bisphenol A (BPA) alternative in the plastics industry presents unknown health risks. To this end, we discovered that BPAF interferes with the metabolic function of mature human adipocytes. Although 4-day exposures to BPAF accelerated adipocyte differentiation, we observed no effect on mature fat cell marker genes. Additional gene and protein expression analysis showed that BPAF treatment during human adipocyte differentiation failed to suppress the proinflammatory transcription factor STAT1. Microscopy and respirometry experiments demonstrated that BPAF impaired mitochondrial function and structure. To test the hypothesis that BPAF fosters vulnerabilities to STAT1 activation, we treated mature adipocytes previously exposed to BPAF with interferon-γ (IFNγ). BPAF increased IFNγ activation of STAT1 and exposed mitochondrial vulnerabilities that disrupt adipocyte lipid and carbohydrate metabolism. Collectively, our data establish that BPAF activates inflammatory signaling pathways that degrade metabolic activity in human adipocytes. These findings suggest how the BPA alternative BPAF contributes to metabolic changes that correspond with obesity.


Assuntos
Adipócitos Brancos/efeitos dos fármacos , Tecido Adiposo Branco/efeitos dos fármacos , Compostos Benzidrílicos/toxicidade , Disruptores Endócrinos/toxicidade , Metabolismo Energético/efeitos dos fármacos , Paniculite/induzido quimicamente , Fenóis/toxicidade , Adipócitos Brancos/metabolismo , Adipócitos Brancos/patologia , Adipogenia/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/patologia , Células Cultivadas , Regulação da Expressão Gênica , Humanos , Interferon gama/farmacologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , PPAR gama/genética , PPAR gama/metabolismo , Paniculite/metabolismo , Paniculite/patologia , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/metabolismo , Transdução de Sinais
5.
Endocrinology ; 160(7): 1645-1658, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31107528

RESUMO

The immune system plays a critical role in white adipose tissue (WAT) energy homeostasis and, by extension, whole-body metabolism. Substantial evidence from mouse and human studies firmly establishes that insulin sensitivity deteriorates as a result of subclinical inflammation in the adipose tissue of individuals with diabetes. However, the relationship between adipose tissue expandability and immune cell infiltration remains a complex problem important for understanding the pathogenesis of obesity. Notably, a large body of work challenges the idea that all immune responses are deleterious to WAT function. This review highlights recent advances that describe how immune cells and adipocytes coordinately enable WAT expansion and regulation of energy homeostasis.


Assuntos
Adipócitos Brancos/imunologia , Tecido Adiposo Branco/imunologia , Metabolismo Energético/imunologia , Sistema Imunitário/imunologia , Obesidade/imunologia , Animais , Inflamação/imunologia , Resistência à Insulina/fisiologia
6.
Front Physiol ; 10: 1638, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-32038305

RESUMO

Overnutrition and sedentary activity reinforce the growing trend of worldwide obesity, insulin resistance, and type 2 diabetes. However, we have limited insight into how food intake generates sophisticated metabolic perturbations associated with obesity. Accumulation of mitochondrial oxidative stress contributes to the metabolic changes in obesity, but the mechanisms and significance are unclear. In white adipose tissue (WAT), mitochondrial oxidative stress, and the generation of reactive oxygen species (ROS) impact the endocrine and metabolic function of fat cells. The central role of mitochondria in nutrient handling suggests pharmacological targeting of pathological oxidative stress likely improves the metabolic profile of obesity. This review will summarize the critical pathogenic mechanisms of obesity-driven oxidative stress in WAT.

7.
Diabetes ; 67(12): 2541-2553, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30002134

RESUMO

Chronic inflammation accompanies obesity and limits subcutaneous white adipose tissue (WAT) expandability, accelerating the development of insulin resistance and type 2 diabetes mellitus. MicroRNAs (miRNAs) influence expression of many metabolic genes in fat cells, but physiological roles in WAT remain poorly characterized. Here, we report that expression of the miRNA miR-30a in subcutaneous WAT corresponds with insulin sensitivity in obese mice and humans. To examine the hypothesis that restoration of miR-30a expression in WAT improves insulin sensitivity, we injected adenovirus (Adv) expressing miR-30a into the subcutaneous fat pad of diabetic mice. Exogenous miR-30a expression in the subcutaneous WAT depot of obese mice coupled improved insulin sensitivity and increased energy expenditure with decreased ectopic fat deposition in the liver and reduced WAT inflammation. High-throughput proteomic profiling and RNA-Seq suggested that miR-30a targets the transcription factor STAT1 to limit the actions of the proinflammatory cytokine interferon-γ (IFN-γ) that would otherwise restrict WAT expansion and decrease insulin sensitivity. We further demonstrated that miR-30a opposes the actions of IFN-γ, suggesting an important role for miR-30a in defending adipocytes against proinflammatory cytokines that reduce peripheral insulin sensitivity. Together, our data identify a critical molecular signaling axis, elements of which are involved in uncoupling obesity from metabolic dysfunction.


Assuntos
Resistência à Insulina/fisiologia , Fígado/metabolismo , MicroRNAs/metabolismo , Obesidade/metabolismo , Gordura Subcutânea/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Dieta Hiperlipídica/efeitos adversos , Metabolismo Energético/fisiologia , Camundongos , MicroRNAs/genética , Obesidade/etiologia , Obesidade/genética , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/metabolismo
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