3054-LB: Limiting Mitochondrial Lipid Entry in Skeletal Muscle Improves Insulin Sensitivity and Protects against Adiposity in Females

Introduction and Objective: Excess intramuscular lipid pressure induces insulin resistance. We reported that limiting mitochondrial lipid burden in skeletal muscle enhanced glucose homeostasis and reduced fat mass in male mice; however, effects in females are unknown. This study tested the hypothesis that limiting mitochondrial lipid pressure in skeletal muscle would produce a similar protective metabolic phenotype in females. Methods: Mice with skeletal muscle-specific deletion of carnitine palmitoyltransferase 1b (Cpt1bM-/-; n=12) were generated to limit mitochondrial lipid entry and results were compared to floxed littermate controls (Cpt1bfl/fl; n=12). Mice were housed at room temperature with ad libitum access to a moderate-fat diet (LabDiet 5015; 26% fat, 54% carbohydrate, 20% protein). Mice underwent weekly body composition testing, glucose tolerance tests (GTT), and insulin tolerance tests (ITT) prior to necropsy at 24 weeks of age. Gastrocnemius muscle was used to test mitochondrial ([1-14C]-palmitate) and peroxisomal ([1-14C]-lignocerate) fatty acid oxidation through 14CO2 production. Results: Both male and female Cpt1bM-/- mice were protected from diet-induced adiposity; however, females were protected from the lean mass loss observed in males. GTT and ITT results indicate Cpt1bM-/- females have improved insulin sensitivity compared to controls; however, effects on glucose homeostasis are generally less robust than in males. Cpt1b deletion reduced [1-14C]-palmitate oxidation in females to a similar degree as in males. However, unlike males which increase peroxisomal lipid metabolism to compensate for defects in mitochondrial lipid entry, female Cpt1bM-/- mice showed lower [1-14C]-lignocerate oxidation, suggesting sex-specific peroxisomal decompensation. Conclusion: Limiting mitochondrial lipid entry in skeletal muscle generally induces a similar protective phenotype in females as those found in males; however, the molecular underpinnings may be unique. Disclosure A.E. Verret: None. R.C. Noland: None.