Effects of AMPK Activation on Insulin Sensitivity and Metabolism in Leptin-Deficient ob/ob Mice

• DOI: 10.2337/db13-0670
• Publication Date: 2014-02-01T05:08:14Z
• Authors: Robby Zachariah Tom; Pablo M. Garcia-R...; Rasmus J.O. Sjögren; Lake Q. Jiang; Maria H. Holmström; Atul S. Deshmukh; Elaine Vieira; Alexander V. Chib...; Marie Björnholm; Juleen R. Zierath
• Keywords: Leptin; Male; 0301 basic medicine; Insulin/metabolism; Ratolins (Animals de laboratori); Physiology; Adenylate Kinase/metabolism; Leptin/genetics; Acetyl-CoA Carboxylase/metabolism; Fisiologia; Mice, Obese; Obese; Mice; 03 medical and health sciences; Leptina; Esquelet; Obesity/metabolism; Genetics; Animals; Insulin; Obesity; Glucagon/metabolism; Phosphorylation; Muscle, Skeletal; Skeletal/drug effects; Skeleton; 2. Zero hunger; Muscles; Músculs; Adenylate Kinase; Phosphorylation/drug effects; Insulin resistance; Glucagon; Lipid Metabolism; Metabolisme; Metabolism; Mice (Laboratory animals); Muscle; Obesitat; Female; Resistència a la insulina; Insulin Resistance; Insulin Resistance/physiology; Genètica; Acetyl-CoA Carboxylase

AMP-activated protein kinase (AMPK) is a heterotrimeric complex, composed of a catalytic subunit (α) and two regulatory subunits (β and γ), which act as a metabolic sensor to regulate glucose and lipid metabolism. A mutation in the γ3 subunit (AMPKγ3R225Q) increases basal AMPK phosphorylation, while concomitantly reducing sensitivity to AMP. AMPKγ3R225Q (γ3R225Q) transgenic mice are protected against dietary-induced triglyceride accumulation and insulin resistance. We determined whether skeletal muscle–specific expression of AMPKγ3R225Q prevents metabolic abnormalities in leptin-deficient ob/ob (ob/ob-γ3R225Q) mice. Glycogen content was increased, triglyceride content was decreased, and diacylglycerol and ceramide content were unaltered in gastrocnemius muscle from ob/ob-γ3R225Q mice, whereas glucose tolerance was unaltered. Insulin-stimulated glucose uptake in extensor digitorum longus muscle during the euglycemic-hyperinsulinemic clamp was increased in lean γ3R225Q mice, but not in ob/ob-γ3R225Q mice. Acetyl-CoA carboxylase phosphorylation was increased in gastrocnemius muscle from γ3R225Q mutant mice independent of adiposity. Glycogen and triglyceride content were decreased after leptin treatment (5 days) in ob/ob mice, but not in ob/ob-γ3R225Q mice. In conclusion, metabolic improvements arising from muscle-specific expression of AMPKγ3R225Q are insufficient to ameliorate insulin resistance and obesity in leptin-deficient mice. Central defects due to leptin deficiency may override any metabolic benefit conferred by peripheral overexpression of the AMPKγ3R225Q mutation.