AMP activated protein kinase (AMPK) plays a key role in the regulatory network responsible for maintaining systemic energy homeostasis during exercise or nutrient deprivation. To understand the function of the regulatory â2 subunit of AMPK in systemic energy metabolism, we characterized â2 subunit-deficient mice. Using these mutant mice, we demonstrated that the â2 subunit plays an important role in regulating glucose, glycogen, and lipid metabolism during metabolic stress. The â2 mutant animals failed to maintain euglycemia and muscle ATP levels during fasting. In addition, â2-deficient animals showed classic symptoms of metabolic syndrome, including hyperglycemia, glucose intolerance, and insulin resistance when maintained on a high-fat diet (HFD), and were unable to maintain muscle ATP levels during exercise. Cell surface-associated glucose transporter levels were reduced in skeletal muscle from â2 mutant animals on an HFD. In addition, they displayed poor exercise performance and impaired muscle glycogen metabolism. These mutant mice had decreased activation of AMPK and deficits in PGC1á-mediated transcription in skeletal muscle. Our results highlight specific roles of AMPK complexes containing the â2 subunit and suggest the potential utility of AMPK isoform-specific pharmacological modulators for treatment of metabolic, cardiac, and neurological disorders.
AMP-Activated Protein Kinases Aminoimidazole Carboxamide