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

Author:

Dasgupta Biplab1,Ju Jeong Sun2,Sasaki Yo3,Liu Xiaona1,Jung Su-Ryun4,Higashida Kazuhiko4,Lindquist Diana5,Milbrandt Jeffrey3

Affiliation:

1. Department of Pediatrics, Division of Hematology and Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA

2. Departments of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA

3. Department of Genetics and HOPE Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri, USA

4. Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA

5. Imaging Research Center, Department of Radiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA

Abstract

ABSTRACT 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 β2 subunit of AMPK in systemic energy metabolism, we characterized β2 subunit-deficient mice. Using these mutant mice, we demonstrated that the β2 subunit plays an important role in regulating glucose, glycogen, and lipid metabolism during metabolic stress. The β2 mutant animals failed to maintain euglycemia and muscle ATP levels during fasting. In addition, β2-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 β2 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 PGC1α-mediated transcription in skeletal muscle. Our results highlight specific roles of AMPK complexes containing the β2 subunit and suggest the potential utility of AMPK isoform-specific pharmacological modulators for treatment of metabolic, cardiac, and neurological disorders.

Publisher

American Society for Microbiology

Subject

Cell Biology,Molecular Biology

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