AMP-Activated Protein Kinase α1 Protects Against Diet-Induced Insulin Resistance and Obesity

摘要

AMP-activated protein kinase (AMPK) is an essential sensor of cellular energy status. Defects in the a2 catalytic subunit of AMPK (AMPKal) are associated with metabolic syndrome. The current study investigated the role AMPKal in the pathogenesis of obesity and inflammation using male AMPKal-deficent (AMPKα1~(-/-)) mice and their wild-type (WT) littermates. After being fed a high-fat diet (HFD), global AMPKα1~(-/-) mice gained more body weight and greater adiposity and exhibited systemic insulin resistance and metabolic dysfunction with increased severity in their adipose tissues compared with their WT littermates. Interestingly, upon HFD feeding, irradiated WT mice that received the bone marrow of AMPKα1~(-/-) mice showed increased insulin resistance but not obesity, whereas irradiated AMPKα1~(-/-) mice with WT bone marrow had a phenotype of metabolic dysregulation that was similar to that of global AMPKα1~(-/-) mice. AMPKal deficiency in macrophages markedly increased the macrophage proinflamrnatory status. In addition, AMPKal knockdown enhanced adipocyte lipid accumulation and exacerbated the inflammatory response and insulin resistance. Together, these data show that AMPKal protects mice from diet-induced obesity and insulin resistance, demonstrating that AMPKα1 is a promising therapeutic target in the treatment of the metabolic syndrome.