RESUMO
Resistin is an adipokine that contributes to insulin resistance in mice. In humans, however, studies investigating the link between resistin and metabolic disease are conflicting. Further complicating the matter, human resistin is produced mainly by macrophages rather than adipocytes. To address this important issue, we generated mice that lack adipocyte-derived mouse resistin but produce human resistin in a pattern similar to that found in humans, i.e., in macrophages (humanized resistin mice). When placed on a high-fat diet, the humanized resistin mice rapidly developed accelerated white adipose tissue (WAT) inflammation, leading to increased lipolysis and increased serum free fatty acids. Over time, these mice accumulated lipids, including diacylglycerols, in muscle. We found that this resulted in increased Pkcq pathway activity, leading to increased serine phosphorylation of Irs-1 and insulin resistance. Thus, although the site of resistin production differs between species, human resistin exacerbates WAT inflammation and contributes to insulin resistance.
Assuntos
Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/patologia , Inflamação/metabolismo , Resistência à Insulina , Macrófagos/metabolismo , Resistina/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Estruturas Animais/metabolismo , Animais , Antígenos CD/genética , Antígenos de Diferenciação Mielomonocítica/genética , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Citocinas/genética , Gorduras na Dieta/farmacologia , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , Técnica Clamp de Glucose , Teste de Tolerância a Glucose , Humanos , Inflamação/patologia , Insulina/sangue , Proteínas Substratos do Receptor de Insulina/metabolismo , Isoenzimas/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/fisiologia , Lipídeos/sangue , Lipólise/efeitos dos fármacos , Lipólise/fisiologia , Lipase Lipoproteica/genética , Lipase Lipoproteica/metabolismo , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Proteína Quinase C/metabolismo , Proteína Quinase C-theta , Resistina/sangue , Resistina/genética , Síndrome das Pernas Inquietas , Transdução de Sinais/fisiologiaRESUMO
The circadian clock temporally coordinates metabolic homeostasis in mammals. Central to this is heme, an iron-containing porphyrin that serves as prosthetic group for enzymes involved in oxidative metabolism as well as transcription factors that regulate circadian rhythmicity. The circadian factor that integrates this dual function of heme is not known. We show that heme binds reversibly to the orphan nuclear receptor Rev-erbalpha, a critical negative component of the circadian core clock, and regulates its interaction with a nuclear receptor corepressor complex. Furthermore, heme suppresses hepatic gluconeogenic gene expression and glucose output through Rev-erbalpha-mediated gene repression. Thus, Rev-erbalpha serves as a heme sensor that coordinates the cellular clock, glucose homeostasis, and energy metabolism.