| First Author | Rhein P | Year | 2021 |
| Journal | Mol Metab | Volume | 51 |
| Pages | 101228 | PubMed ID | 33798773 |
| Mgi Jnum | J:317473 | Mgi Id | MGI:6714672 |
| Doi | 10.1016/j.molmet.2021.101228 | Citation | Rhein P, et al. (2021) Compound- and fiber type-selective requirement of AMPKgamma3 for insulin-independent glucose uptake in skeletal muscle. Mol Metab :101228 |
| abstractText | OBJECTIVE: The metabolic master-switch AMP-activated protein kinase (AMPK) mediates insulin-independent glucose uptake in muscle and regulates the metabolic activity of brown and beige adipose tissue (BAT). The regulatory AMPKgamma3 isoform is uniquely expressed in skeletal muscle and potentially in BAT. Herein, we investigated the role that AMPKgamma3 plays in mediating skeletal muscle glucose uptake and whole-body glucose clearance in response to small-molecule activators that act on AMPK via distinct mechanisms. We also assessed whether gamma3 plays a role in adipose thermogenesis and browning. METHODS: Global AMPKgamma3 knockout (KO) mice were generated. A systematic whole-body, tissue, and molecular phenotyping linked to glucose homeostasis was performed in gamma3 KO and wild-type (WT) mice. Glucose uptake in glycolytic and oxidative skeletal muscle ex vivo as well as blood glucose clearance in response to small molecule AMPK activators that target the nucleotide-binding domain of the gamma subunit (AICAR) and allosteric drug and metabolite (ADaM) site located at the interface of the alpha and beta subunit (991, MK-8722) were assessed. Oxygen consumption, thermography, and molecular phenotyping with a beta3-adrenergic receptor agonist (CL-316,243) treatment were performed to assess BAT thermogenesis, characteristics, and function. RESULTS: Genetic ablation of gamma3 did not affect body weight, body composition, physical activity, and parameters associated with glucose homeostasis under chow or high-fat diet. gamma3 deficiency had no effect on fiber-type composition, mitochondrial content and components, or insulin-stimulated glucose uptake in skeletal muscle. Glycolytic muscles in gamma3 KO mice showed a partial loss of AMPKalpha2 activity, which was associated with reduced levels of AMPKalpha2 and beta2 subunit isoforms. Notably, gamma3 deficiency resulted in a selective loss of AICAR-, but not MK-8722-induced blood glucose-lowering in vivo and glucose uptake specifically in glycolytic muscle ex vivo. We detected gamma3 in BAT and found that it preferentially interacts with alpha2 and beta2. We observed no differences in oxygen consumption, thermogenesis, morphology of BAT and inguinal white adipose tissue (iWAT), or markers of BAT activity between WT and gamma3 KO mice. CONCLUSIONS: These results demonstrate that gamma3 plays a key role in mediating AICAR- but not ADaM site binding drug-stimulated blood glucose clearance and glucose uptake specifically in glycolytic skeletal muscle. We also showed that gamma3 is dispensable for beta3-adrenergic receptor agonist-induced thermogenesis and browning of iWAT. |
