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

• Published in: Molecular and cellular endocrinology Vol. 482; pp. 1 - 10
• Main Authors: Xu, Wenqiong, Zhou, Hongyi, Xuan, Hongzhuan, Saha, Pradip, Wang, Gongxian, Chen, Weiqin
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 15.02.2019
• Subjects: Animals; BSCL2; Disease Models, Animal; Female; Gene Knockout Techniques; Glucose - metabolism; Glycogen - metabolism; GTP-Binding Protein gamma Subunits; Heterotrimeric GTP-Binding Proteins - genetics; Hyperinsulinemic-euglycemic clamp; Insulin Resistance; Lipid Metabolism; Lipodystrophy; Lipodystrophy, Congenital Generalized - genetics; Lipodystrophy, Congenital Generalized - metabolism; Male; Mice; Muscle, Skeletal - metabolism; Organ Specificity; Oxidation-Reduction; Skeletal muscle; Triglycerides - metabolism; BSCL2; Insulin resistance; Lipodystrophy; Hyperinsulinemic-euglycemic clamp; Skeletal muscle
• ISSN: 0303-7207; 1872-8057
• DOI: 10.1016/j.mce.2018.12.001

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. •Bscl2−/− mice display reduced triglyceride but increased glycogen storage in skeletal muscle.•Fatty acid oxidation in oxidative soleus muscle of fed Bscl2−/− mice is enhanced.•Prolonged fasting sensitizes insulin sensitivity in oxidative soleus muscle of Bscl2−/− mice.•Intralipid infusion mitigates muscle insulin sensitivity in Bscl2−/− mice after a prolonged fasting.•BSCL2 does not play a cell-autonomous role in skeletal muscle triglyceride and glycogen metabolism.