Disrupted glucose homeostasis and skeletal-muscle-specific glucose uptake in an exocyst knockout mouse model

• Published in: The Journal of biological chemistry Vol. 296; p. 100482
• Main Authors: Fujimoto, Brent A., Young, Madison, Nakamura, Nicole, Ha, Herena, Carter, Lamar, Pitts, Matthew W., Torres, Daniel, Noh, Hye-Lim, Suk, Sujin, Kim, Jason K., Polgar, Noemi
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2021; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Carbohydrate Metabolism; Cell Membrane - metabolism; Cytoplasm - metabolism; diabetes; exocyst complex; Exocytosis; Female; Glucose - metabolism; Glucose Intolerance - genetics; Glucose Transport Proteins, Facilitative - metabolism; glucose transporter; Glucose Transporter Type 4 - metabolism; Homeostasis; Insulin - analysis; Insulin - blood; Insulin - metabolism; insulin resistance; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Multiprotein Complexes; Muscle, Skeletal - metabolism; Muscle, Skeletal - physiology; Myoblasts, Skeletal - metabolism; Protein Transport; skeletal muscle; Vesicular Transport Proteins - metabolism; Vesicular Transport Proteins - physiology; EE; IRS-1; GTT; HFD; IP; T2D; ITT; GSV; exocyst complex; HSA-MCM; HGP; glucose transporter; skeletal muscle; GLUT4; diabetes; insulin resistance; RER; Pdk1
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1016/j.jbc.2021.100482

Skeletal muscle is responsible for the majority of glucose disposal following meals, and this is achieved by insulin-mediated trafficking of glucose transporter type 4 (GLUT4) to the cell membrane. The eight-protein exocyst trafficking complex facilitates targeted docking of membrane-bound vesicles, a process underlying the regulated delivery of fuel transporters. We previously demonstrated the role of exocyst subunit EXOC5 in insulin-stimulated GLUT4 exocytosis and glucose uptake in cultured rat skeletal myoblasts. However, the in vivo role of EXOC5 in skeletal muscle remains unclear. Using mice with inducible, skeletal-muscle-specific knockout of exocyst subunit EXOC5 (Exoc5-SMKO), we examined how muscle-specific disruption of the exocyst would affect glucose homeostasis in vivo. We found that both male and female Exoc5-SMKO mice displayed elevated fasting glucose levels. Additionally, male Exoc5-SMKO mice had impaired glucose tolerance and lower serum insulin levels. Using indirect calorimetry, we observed that male Exoc5-SMKO mice have a reduced respiratory exchange ratio during the light period and lower energy expenditure. Using the hyperinsulinemic–euglycemic clamp method, we further showed that insulin-stimulated skeletal muscle glucose uptake is reduced in Exoc5-SMKO males compared with wild-type controls. Overall, our findings indicate that EXOC5 and the exocyst are necessary for insulin-stimulated glucose uptake in skeletal muscle and regulate glucose homeostasis in vivo.