Abstract

Objective: Transgenic expression of diacylglycerol acyltransferase-1 (DGAT1) in skeletal muscle leads to protection against fat-induced insulin resistance despite accumulation of intramuscular triglyceride (TG), a phenomenon similar to what is known as the “athlete paradox”. The primary objective of this study is to determine how DGAT1 affects muscle fatty acid (FA) oxidation in relation to whole-body energy metabolism and insulin sensitivity.

Research Design and Methods: We first quantified insulin-sensitivity and the relative tissue contributions to the improved whole-body insulin-sensitivity in muscle creatine kisase (MCK)-Dgat1 transgenic mice by hyperinsulinemic-euglycemic clamps. Metabolic consequences of Dgat1-overexpression in skeletal muscles were determined by quantifying TG synthesis/storage (anabolic) and FA oxidation (catabolic), in conjunction with gene expression levels of representative marker genes in FA metabolism. Whole-body energy metabolism including food consumption, body weights, oxygen consumption, locomotor activity, and respiration exchange ratios were determined at steady states.

Results: MCK-Dgat1 mice were protected against muscle lipoptoxicity, although they remain susceptible to hepatic lipotoxicity. While augmenting TG synthesis, Dgat1-overexpression also led to increased muscle mitochondrial FA-oxidation efficiency, as compared with wild-type muscles. On a high-fat diet (HFD), MCK-Dgat1 mice displayed higher basal metabolic rates and 5-10% lower body weights compared with wild-type littermates, while food consumption was not different.

Conclusions: DGAT1-overexpression in skeletal muscle led to parallel increases in TG synthesis and FA oxidation. Seemingly paradoxical, this phenomenon is characteristic of insulin sensitive myofibers and suggests that DGAT1 plays an active role in metabolic “remodeling” of skeletal muscle coupled with insulin sensitization.