RESUMO
Dietary obesity is a major factor in the development of type 2 diabetes and is associated with intra-adipose tissue hypoxia and activation of hypoxia-inducible factor 1α (HIF1α). Here we report that, in mice, Hif1α activation in visceral white adipocytes is critical to maintain dietary obesity and associated pathologies, including glucose intolerance, insulin resistance, and cardiomyopathy. This function of Hif1α is linked to its capacity to suppress ß-oxidation, in part, through transcriptional repression of sirtuin 2 (Sirt2) NAD(+)-dependent deacetylase. Reduced Sirt2 function directly translates into diminished deacetylation of PPARγ coactivator 1α (Pgc1α) and expression of ß-oxidation and mitochondrial genes. Importantly, visceral adipose tissue from human obese subjects is characterized by high levels of HIF1α and low levels of SIRT2. Thus, by negatively regulating the Sirt2-Pgc1α regulatory axis, Hif1α negates adipocyte-intrinsic pathways of fatty acid catabolism, thereby creating a metabolic state supporting the development of obesity.
Assuntos
Adipócitos/metabolismo , Metabolismo Energético , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , NAD/metabolismo , Obesidade/patologia , Sirtuína 2/metabolismo , Acetilação , Adipócitos/citologia , Animais , Sequência de Bases , Diferenciação Celular , Células Cultivadas , Dieta , Ácidos Graxos/metabolismo , Regulação da Expressão Gênica , Humanos , Masculino , Camundongos , Mitocôndrias/metabolismo , Dados de Sequência Molecular , Oxirredução , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Alinhamento de Sequência , Sirtuína 2/genética , Transativadores/metabolismo , Fatores de TranscriçãoRESUMO
Adipose tissue is the largest compartment in the mammalian body for storing energy as fat, providing an important reservoir of fuel for maintaining whole body energy homeostasis. Herein, we identify the transcriptional cofactor hairless (HR) to be required for white adipogenesis. Moreover, forced expression of HR in non-adipogenic precursor cells induces adipogenic gene expression and enhances adipocyte formation under permissive conditions. HR exerts its proadipogenic effects by regulating the expression of PPARγ, one of the central adipogenic transcription factors. In conclusion, our data provide a new mechanism required for white adipogenesis.
Assuntos
Adipócitos Brancos/citologia , Adipogenia/genética , Regulação da Expressão Gênica no Desenvolvimento , PPAR gama/metabolismo , Fatores de Transcrição/metabolismo , Células 3T3 , Adipócitos Brancos/metabolismo , Animais , Diferenciação Celular , Camundongos , Camundongos Knockout , Mutação , PPAR gama/genética , Fatores de Transcrição/genética , Transcrição GênicaRESUMO
Mitogen-activated protein kinase (MAPK) signalling occurs in response to almost any change in the extracellular or intracellular milieu that affects the metabolism of the cell, organ or the entire organism. MAPK-dependent signal transduction is required for physiological metabolic adaptation, but inappropriate MAPK signalling contributes to the development of several interdependent pathological traits, collectively known as metabolic syndrome. Metabolic syndrome leads to life-threatening clinical consequences, such as type 2 diabetes. This Review provides an overview of the MAPK-signalling mechanisms that underly basic cellular metabolism, discussing their link to disease.