The AMPK 2 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 2 subunit of AMPK in sys-temic energy metabolism, we characterized 2 subunit-deficient mice. Using these mutant mice, we demonstrated that the 2 subunit plays an important role in regulating glucose, glycogen, and lipid metabolism during metabolic stress. The 2 mutant animals failed to maintain euglycemia andmuscle ATP levels during fasting. In addition, 2-deficient animals showed classic symptoms of metabolic syndrome, including hyperglycemia, glucose intolerance, and insulin resistance whenmaintained 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 2 mutant animals on an HFD. In addition, they displayed poor exercise perfor-mance and impaired muscle glycogenmetabolism. These mutant mice had decreased activation of AMPK and deficits in PGC1-mediated transcription in skeletal muscle. Our results highlight specific roles of AMPK complexes containing the 2 subunit and suggest the potential utility of AMPK isoform-specific pharmacological modulators for treatment of metabolic, cardiac, and neurological disorders. AMP activated protein kinase (AMPK) plays a crucial role inmaintaining systemic energy homeostasis through its coordi-nated actions on the central nervous system and peripheral tissues (54). Loss of AMPK function causes metabolic abnormalities i