Glycemic Control, Skeletal Muscle Glucose Uptake And Lipid Metabolism In Mice With Skeletal Muscle Foxo1 Overexpression

Abstract

Previous research has indicated a possible role for Forkhead Box protein O1 (FoxO1) in the pathogenesis of type 2 diabetes through its purported role in affecting whole body glycemic control and lipid metabolism. However, the literature indicating such a relationship is limited and has primarily relied on in vitro models. PURPOSE: The purpose of the present study was to use in vivo and ex vivo methodology to examine the role of FoxO1 on whole body glycemic control, skeletal muscle glucose metabolism and lipid metabolism. METHODS: Transgenic mice with skeletal muscle-specific overexpression of FoxO1 were subjected to intraperitoneal glucose tolerance testing (IPGTT) with concomitant plasma insulin analysis followed by ex vivo examination of skeletal muscle insulin stimulated glucose uptake, intramyocellular triglyceride (IMTG) storage and fatty acid oxidation. RESULTS: IPGTT and plasma insulin analysis revealed no differences between FoxO1 transgenic and wildtype (WT) mice. Likewise, basal level skeletal muscle protein expression levels of phosphoinositide kinase-3 (PI3K) and serine473 phosphorylated Akt (pAkt473) were not different between mouse strains. Additionally, FoxO1 did not exhibit any impairment in insulin stimulated glucose uptake. However, IMTG and fatty acid oxidation capacity was significantly (p<0.05) reduced in FoxO1 transgenic mice. CONCLUSION: These findings indicate that in vivo skeletal muscle FoxO1 overexpression does not impede whole body glycemic control or skeletal muscle insulin action. However, it does appear to reduce IMTG while impairing skeletal muscle lipid oxidation capacity.