The AMPK β2 Subunit Is Required for Energy Homeostasis during Metabolic Stress

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 beta 2 subunit of AMPK in systemic energy metabolism, we characterized beta 2 subunit-deficient mice. Using these mutant mice, we demonstrated that the beta 2 subunit plays an important role in regulating glucose, glycogen, and lipid metabolism during metabolic stress. The beta 2 mutant animals failed to maintain euglycemia and muscle ATP levels during fasting. In addition, beta 2-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 beta 2 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 PGC1 alpha-mediated transcription in skeletal muscle. Our results highlight specific roles of AMPK complexes containing the beta 2 subunit and suggest the potential utility of AMPK isoform-specific pharmacological modulators for treatment of metabolic, cardiac, and neurological disorders.