Skeletal muscle-specific deletion of lipoprotein lipase enhances insulin signaling in skeletal muscle but causes insulin resistance in liver and other tissues.

Description

This study examined the impact of decreased lipoprotein-lipid delivery to the skeletal muscle on insulin sensitivity, body weight and body composition. To achieve this objective, skeletal muscle-specific lipoprotein lipase (LPL) knockout mice (SMLPL-/-) were created. The reduction in LPL activity in skeletal muscle did not alter body composition and whole-body insulin sensitivity in young SMLPL-/- mice (9-11-week-old mice). However, older SMLPL-/- mice (8-10-month-old mice) had greater weight gain and whole-body insulin resistance than control mice. A 6-week high-fat diet (45% fat) in 6-week-old SMLPL-/- mice was associated with a significant weight gain as compared to control mice. In young mice, glucose uptake increased in the skeletal muscle compared to controls but decreased in white adipose tissue and the heart. Hepatic glucose production was also reduced in SMLPL-/- vs. control mice. SMLPL-/- mice showed a significant reduction in skeletal muscle triglyceride concentrations but no difference in the liver and heart. Results of this study suggest that skeletal muscle LPL deletion reduces lipid storage and increases insulin sensitivity in skeletal muscle but also increases insulin resistance in other tissues, which may ultimately lead to weight gain and systemic insulin resistance. In the editorial accompanying the paper, Watt and Kraegen recognized the novelty of the investigation by Wang et al., who showed that the downregulation of LPL activity in skeletal muscle (skeletal muscle-specific LPL knockout mice: SMLPL-/-) had beneficial effects on skeletal muscle but harmful effects in other tissues. Watt and Kraegen raised several major unresolved questions in their commentary, and they concluded with the following statement: “In the end, is such a therapeutic approach just a classic case of robbing Peter to pay Paul?”