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

Abstract

AMP-activated protein kinase (AMPK) is a heterotrimeric complex, composed of a catalytic subunit (a) and two regulatory subunits (b and g), which act as a metabolic sensor to regulate glucose and lipid metabolism. A mutation in the g 3 subunit (AMPKg 3 R225Q) increases basal AMPK phosphorylation, while concomitantly reducing sensitivity to AMP. AMPKg 3 R225Q (g 3 R225Q ) transgenic mice are protected against dietary-induced triglyceride accumulation and insulin resistance. We determined whether skeletal muscle-specific expression of AMPKg 3 R225Q prevents metabolic abnormalities in leptin-deficient ob/ob (ob/ob-g 3 R225Q ) mice. Glycogen content was increased, triglyceride content was decreased, and diacylglycerol and ceramide content were unaltered in gastrocnemius muscle from ob/ob-g 3 R225Q mice, whereas glucose tolerance was unaltered. Insulinstimulated glucose uptake in extensor digitorum longus muscle during the euglycemic-hyperinsulinemic clamp was increased in lean g 3 R225Q mice, but not in ob/ob-g 3 R225Q mice. Acetyl-CoA carboxylase phosphorylation was increased in gastrocnemius muscle from g 3 R225Q 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-g 3 R225Q mice. In conclusion, metabolic improvements arising from muscle-specific expression of AMPKg 3 R225Q 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 AMPKg 3 R225Q mutation.

Tumor Necrosis Factor-α Promotes Phosphoinositide 3-Kinase Enhancer A and AMP-Activated Protein Kinase Interaction to Suppress Lipid Oxidation in Skeletal Muscle

“…Activation of AMPK pharmacologically or genetically improves the insulin sensitivity and glucose handling in a variety of animal models (33,34). Because we observed an upregulation of AMPK in the skeletal muscle of HFD-fed MPKO mice, we thus tested if the MPKO mice have better insulin sensitivity.…”

The GLP-1 receptor agonists exenatide and liraglutide activate Glucose transport by an AMPK-dependent mechanism

“…AMPK is a heterotrimeric protein which mediates several cellular processes, including stimulation of glucose uptake, mitochondrial biogenesis and inhibition of fatty acid synthesis via phosphorylation of ACC [ 19 – 22 ]. AMPK is known to regulate adipocyte metabolism, inflammation, and vascular function and defective AMPK activation is associated with insulin resistance and T2D [ 46 – 48 ]. Glucose transport relies on insulin stimulated AKT phosphorylation and PI3K activation, as well as an alternative pathway involving AMPK/Cbl-CAP signaling [ 49 ].…”

AMPK-Mediated Regulation of Lipid Metabolism by Phosphorylation

“…37) Moreover, AMPKα Ser485/491, which was confirmed by using recombinant protein, 35) was also autophosphorylated to limit AMPK activation in response to energy depletion or other regulators. 21) The functional roles of additional AMPK autophosphorylation sites, such as α1Thr477, α1Ser349, β1Thr158, and β1Thr80, 38) requires further investigation.…”