Skeletal Muscle-Specific Deletion of Lipoprotein Lipase Enhances Insulin Signaling in Skeletal Muscle but Causes Insulin Resistance in Liver and Other Tissues

Abstract

Objective: Skeletal muscle-specific LPL knockout mouse (SMLPL-/-) were created to study the systemic impact of reduced lipoprotein lipid delivery in skeletal muscle on insulin sensitivity, body weight and composition.

Methods: Tissue-specific insulin sensitivity was assessed using a hyperinsulinemic-euglycemic clamp and 2-deoxyglucose uptake. Gene expression and insulin signaling molecules were compared in skeletal muscle and liver of SMLPL-/- and control mice.

Results: Nine week old SMLPL-/- mice showed no differences in body weight, fat mass, or whole body insulin sensitivity, but older SMLPL-/- mice had greater weight gain and whole body insulin resistance. High fat diet feeding accelerated the development of obesity. In young SMLPL-/- mice, insulin-stimulated glucose uptake was increased 58% in the skeletal muscle, but reduced in WAT and heart. Insulin action was also diminished in liver: 40% suppression of hepatic glucose production in SMLPL-/- vs. 90% in control mice. Skeletal muscle triglyceride (TG) was 38% lower and insulin-stimulated phosphorylated Akt (Ser473) was 2-fold greater in SMLPL-/- mice without changes in IRS-1 tyrosine phosphorylation and PI3 kinase activity. Hepatic TG and LXR, ChREBP and PEPCK mRNAs were unaffected in SMLPL-/- mice, but PGC-1 alpha and IL-1 beta mRNAs were higher and SCD-1 and PPAR gamma mRNAs were reduced.

Conclusions: LPL deletion in skeletal muscle reduces lipid storage and increases insulin signaling in skeletal muscle without changes in body composition. Moreover, lack of LPL in skeletal muscle results in insulin resistance in other key metabolic tissues and ultimately leads to obesity and systemic insulin resistance.