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Endocrinology ; 159(1): 323-340, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29040448

RESUMO

It is unknown how the lack of insulin receptor (IR)/insulinlike growth factor I receptor (IGFIR) in a tissue-specific manner affects brown fat development and mitochondrial integrity and function, as well as its effect on the redistribution of the adipose organ and the metabolic status. To address this important issue, we developed IR/IGFIR double-knockout (DKO) in a brown adipose tissue-specific manner. Lack of those receptors caused severe brown fat atrophy, enhanced beige cell clusters in inguinal fat; loss of mitochondrial mass; mitochondrial damage related to cristae disruption; and the loss of proteins involved in autophagosome formation, mitophagy, mitochondrial quality control, and dynamics and thermogenesis. More important, DKO mice showed an impaired thermogenesis upon cold exposure, based on a failure in the mitochondrial fission mechanisms and a much lower uncoupling protein 1 transcription rate and content. As a result, DKO mice under normal conditions showed an obesity susceptibility, revealed by increased body fat mass and insulin resistance. Upon consumption of a high-fat diet, DKO mice displayed frank obesity, as shown by increased body weight, increased adiposity, insulin resistance, hyperinsulinemia, and hypertriglyceridemia, all consistent with a metabolic syndrome. Collectively, our data suggest a cause-and-effect relationship between failure in brown fat thermogenesis and increased adiposity and obesity.


Assuntos
Tecido Adiposo Marrom/metabolismo , Síndrome Metabólica/metabolismo , Dinâmica Mitocondrial , Obesidade/metabolismo , Receptor IGF Tipo 1/metabolismo , Receptor de Insulina/metabolismo , Termogênese , Tecido Adiposo Bege/metabolismo , Tecido Adiposo Bege/patologia , Tecido Adiposo Bege/ultraestrutura , Tecido Adiposo Marrom/patologia , Tecido Adiposo Marrom/ultraestrutura , Adiposidade , Animais , Atrofia , Dieta Hiperlipídica/efeitos adversos , Hiperinsulinismo/etiologia , Hipertrigliceridemia/etiologia , Resistência à Insulina , Masculino , Síndrome Metabólica/etiologia , Síndrome Metabólica/patologia , Síndrome Metabólica/fisiopatologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Eletrônica de Transmissão , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Mitocôndrias/ultraestrutura , Obesidade/etiologia , Obesidade/patologia , Obesidade/fisiopatologia , Especificidade de Órgãos , Receptor IGF Tipo 1/genética , Receptor de Insulina/genética , Aumento de Peso
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