Knockout of STAT3 in skeletal muscle does not prevent high-fat diet-induced insulin resistance

• Published in: Molecular metabolism (Germany) Vol. 4; no. 8; pp. 569 - 575
• Main Authors: White, Amanda T, LaBarge, Samuel A, McCurdy, Carrie E, Schenk, Simon
• Format: Journal Article
• Language: English
• Published: Germany Elsevier GmbH 01.08.2015; Elsevier
• Subjects: Brief Communication; Clamp; Cre-LoxP; Endocrinology & Metabolism; Glucose homeostasis; In vivo; Obesity; STAT3; adhesion G protein-coupled receptor E1; Glucose homeostasis; In vivo; Adgre1; HFD; IS-GDR; EDL; hyperinsulinemic-euglycemic; muscle creatine kinase; mKO; insulin-stimulated glucose disposal rate; muscle-specific knockout of STAT3; GA; normal chow, control diet; interleukin; WT; Cre-LoxP; knockout; Obesity; CON; IL; KO; 2-deoxyglucose; STAT3; T2D; adipose tissue; glucose infusion rate; signal transducer and activator of transcription 3; HGP; GIR; hepatic glucose production; AT; type 2 diabetes; MCK; HYP-EUG; high-fat diet; extensor digitorum longus; Clamp; gastrocnemius; wild-type; 2DOG; WT, wild-type; mKO, muscle-specific knockout of STAT3; 2DOG, 2-deoxyglucose; STAT3, signal transducer and activator of transcription 3; HGP, hepatic glucose production; EDL, extensor digitorum longus; T2D, type 2 diabetes; GA, gastrocnemius; Adgre1, adhesion G protein-coupled receptor E1; IS-GDR, insulin-stimulated glucose disposal rate; KO, knockout; MCK, muscle creatine kinase; HFD, high-fat diet; IL, interleukin; CON, normal chow, control diet; AT, adipose tissue; GIR, glucose infusion rate; HYP-EUG, hyperinsulinemic-euglycemic
• ISSN: 2212-8778; 2212-8778
• DOI: 10.1016/j.molmet.2015.05.001

Abstract Objective Increased signal transducer and activator of transcription 3 (STAT3) signaling has been implicated in the development of skeletal muscle insulin resistance, though its contribution, in vivo , remains to be fully defined. Therefore, the aim of this study was to determine whether knockout of skeletal muscle STAT3 would prevent high-fat diet (HFD)-induced insulin resistance. Methods We used Cre-LoxP methodology to generate mice with muscle-specific knockout (KO) of STAT3 (mKO). Beginning at 10 weeks of age, mKO mice and their wildtype/floxed (WT) littermates either continued consuming a low fat, control diet (CON; 10% of calories from fat) or were switched to a HFD (60% of calories from fat) for 20 days. We measured body composition, energy expenditure, oral glucose tolerance and in vivo insulin action using hyperinsulinemic-euglycemic clamps. We also measured insulin sensitivity in isolated soleus and extensor digitorum longus muscles using the 2-deoxy-glucose (2DOG) uptake technique. Results STAT3 protein expression was reduced ∼75–100% in muscle from mKO vs. WT mice. Fat mass and body fat percentage did not differ between WT and mKO mice on CON and were increased equally by HFD. There were also no genotype differences in energy expenditure or whole-body fat oxidation. As determined, in vivo (hyperinsulinemic-euglycemic clamps) and ex vivo (2DOG uptake), skeletal muscle insulin sensitivity did not differ between CON-fed mice, and was impaired similarly by HFD. Conclusions These results demonstrate that STAT3 activation does not underlie the development of HFD-induced skeletal muscle insulin resistance.