Novel metabolic disorders in skeletal muscle of Lipodystrophic Bscl2/Seipin deficient mice.

Bscl2^-/- mice recapitulate many of the major metabolic manifestations in Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2) individuals, including lipodystrophy, hepatosteatosis, muscular hypertrophy, and insulin resistance. Metabolic defects in Bscl2^-/- mice with regard to glucose and lipid metabolism in skeletal muscle have never been investigated. Here, we identified Bscl2^-/- mice displayed reduced intramyocellular triglyceride (IMTG) content but increased glycogen storage predominantly in oxidative type I soleus muscle (SM). These changes were associated with increased incomplete fatty acid oxidation and glycogen synthesis. Interestingly, SM in Bscl2^-/- mice demonstrated a fasting duration induced insulin sensitivity which was further confirmed by hyperinsulinemic-euglycemic clamp in SM of overnight fasted Bscl2^-/- mice but reversed by raising circulating NEFA levels through intralipid infusion. Furthermore, mice with skeletal muscle-specific inactivation of BSCL2 manifested no changes in muscle deposition of lipids and glycogen, suggesting BSCL2 does not play a cell-autonomous role in muscle lipid and glucose homeostasis. Our study uncovers a novel link between muscle metabolic defects and insulin resistance, and underscores an important role of circulating NEFA in regulating oxidative muscle insulin signaling in BSCL2 lipodystrophy.

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