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Reciprocity Between Skeletal Muscle AMPK Deletion and Insulin Action in
Diet-Induced Obese Mice.
Authors Lantier L, Williams AS, Williams IM, Guerin A, Bracy DP, Goelzer M, Foretz M,
Viollet B, Hughey CC, Wasserman DH
Submitted By Submitted Externally on 9/28/2020
Status Published
Journal Diabetes
Year 2020
Date Published 8/1/2020
Volume : Pages 69 : 1636 - 1649
PubMed Reference 32439824
Abstract Insulin resistance due to overnutrition places a burden on energy-producing
pathways in skeletal muscle (SkM). Nevertheless, energy state is not
compromised. The hypothesis that the energy sensor AMPK is necessary to offset
the metabolic burden of overnutrition was tested using chow-fed and high-fat
(HF)-fed SkM-specific AMPKa1a2 knockout (mdKO) mice and AMPKa1a2lox/lox
littermates (wild-type [WT]). Lean mdKO and WT mice were phenotypically similar.
HF-fed mice were equally obese and maintained lean mass regardless of genotype.
Results did not support the hypothesis that AMPK is protective during
overnutrition. Paradoxically, mdKO mice were more insulin sensitive.
Insulin-stimulated SkM glucose uptake was approximately twofold greater in mdKO
mice in vivo. Furthermore, insulin signaling, SkM GLUT4 translocation,
hexokinase activity, and glycolysis were increased. AMPK and insulin signaling
intersect at mammalian target of rapamycin (mTOR), a critical node for cell
proliferation and survival. Basal mTOR activation was reduced by 50% in HF-fed
mdKO mice, but was normalized by insulin stimulation. Mitochondrial function was
impaired in mdKO mice, but energy charge was preserved by AMP deamination.
Results show a surprising reciprocity between SkM AMPK signaling and insulin
action that manifests with diet-induced obesity, as insulin action is preserved
to protect fundamental energetic processes in the muscle.


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