Elevated expression/activity of adipose
triglyceride lipase (ATGL) and/or reduced activity of
hormone-sensitive lipase (HSL) in skeletal muscle are causally linked to
insulin resistance in vitro. We investigated here the effect of high-fat feeding on skeletal muscle lipolytic
proteins, lipotoxicity, and
insulin signaling in vivo. Five-week-old C3H mice were fed normal chow diet (NCD) or 45% kcal high-fat diet (HFD) for 4 weeks. Wild-type and HSL knockout mice fed NCD were also studied. Whole-body and muscle
insulin sensitivity, as well as lipolytic
protein expression,
lipid levels, and
insulin signaling in skeletal muscle, were measured. HFD induced whole-body
insulin resistance and
glucose intolerance and reduced skeletal muscle
glucose uptake compared with NCD. HFD increased skeletal muscle total
diacylglycerol (DAG) content,
protein kinase Cθ and
protein kinase Cε membrane translocation, and impaired
insulin signaling as reflected by a robust increase of basal Ser1101
insulin receptor substrate 1 phosphorylation (2.8-fold, P < .05) and a decrease of
insulin-stimulated v-Akt murine
thymoma viral oncogene homolog Ser473 (-37%, P < .05) and AS160 Thr642 (-47%, P <.01) phosphorylation. We next showed that HFD strongly reduced HSL phosphorylation at Ser660. HFD significantly up-regulated the
muscle protein content of the ATGL coactivator comparative gene identification 58 and
triacylglycerol hydrolase activity, despite a lower ATGL
protein content. We further show a defective skeletal muscle
insulin signaling and DAG accumulation in HSL knockout compared with wild-type mice. Together, these data suggest a pathophysiological link between altered skeletal muscle
lipase expression and DAG-mediated
insulin resistance in mice.