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

AMP-activated protein kinase (AMPK) is an essential sensor of cellular energy status. Defects in the alpha 2 catalytic subunit of AMPK (AMPK alpha 1) are associated with metabolic syndrome. The current study investigated the role AMPK alpha 1 in the pathogenesis of obesity and inflammation using male AMPK alpha 1-deficent (AMPK alpha 1(-/-)) mice and their wild-type (WT) littermates. After being fed a high-fat diet (HFD), global AMPK alpha 1(-/-) 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 AMPK alpha 1(-/-) mice showed increased insulin resistance but not obesity, whereas irradiated AMPK alpha 1(-/-) mice with WT bone marrow had a phenotype of metabolic dysregulation that was similar to that of global AMPK alpha 1(-/-) mice. AMPK alpha 1 deficiency in macrophages markedly increased the macrophage proinflammatory status. In addition, AMPK alpha 1 knockdown enhanced adipocyte lipid accumulation and exacerbated the inflammatory response and insulin resistance. Together, these data show that AMPK alpha 1 protects mice from diet-induced obesity and insulin resistance, demonstrating that AMPK alpha 1 is a promising therapeutic target in the treatment of the metabolic syndrome. Diabetes 61:3114-3125, 2012