Enhanced energy expenditure, glucose utilization, and insulin sensitivity in VAMP8 null mice.
OBJECTIVE
Previous studies have demonstrated that the VAMP8 protein plays a complex role in the control of granule secretion, transport vesicle trafficking, phagocytosis, and endocytosis. The present study was aimed to investigate the role of VAMP8 in mediating GLUT4 trafficking and therefore insulin action in mice.


METHODS
Physiological parameters were measured using Oxymax indirect calorimetry system in 12-week-old VAMP8 null mice. Dynamic analysis of glucose homeostasis was assessed using euglycemic-hyperinsulinemic clamp coupled with tracer radioactively labeled 2-deoxyglucose. Insulin stimulated GLUT4 protein expressions on muscle cell surface were examined by immunofluorescence microscopy.


RESULTS
VAMP8 null mice display reduced adiposity with increased energy expenditure despite normal food intake and reduced spontaneous locomotor activity. In parallel, the VAMP8 null mice also had fasting hypoglycemia (84 ± 11 vs. 115 ± 4) and enhanced glucose tolerance with increased insulin sensitivity due to increases in both basal and insulin-stimulated glucose uptake in skeletal muscle (0.19 ± 0.04 vs. 0.09 ± 0.01 mmol/kg/min during basal, 0.6 ± 0.04 vs. 0.31 ± 0.06 mmol/kg/min during clamp in red-gastrocnemius muscle, P < 0.05). Consistent with a role for VAMP8 in the endocytosis of the insulin-responsive GLUT4, sarcolemma GLUT4 protein levels were increased in both the basal and insulin-stimulated states without any significant change in the total amount of GLUT4 protein or related facilitative glucose transporters present in skeletal muscle, GLUT1, GLUT3, and GLUT11.


CONCLUSIONS
These data demonstrate that, in the absence of VAMP8, the relative subcellular distribution of GLUT4 is altered, resulting in increased sarcolemma levels that can account for increased glucose clearance and insulin sensitivity.
Zong
Haihong
H
Department of Medicine and Molecular Pharmacology, The Albert Einstein College of Medicine, Bronx, New York, USA.
Wang
Cheng-Chun
CC
Vaitheesvaran
Bhavapriya
B
Kurland
Irwin J
IJ
Hong
Wanjin
W
Pessin
Jeffrey E
JE
D000273:Adipose Tissue / Q000033:anatomy & histology; D000818:Animals; D001835:Body Weight; D002153:Calorimetry, Indirect; D004734:Energy Metabolism; D005947:Glucose / Q000378:metabolism*; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D051275:Glucose Transporter Type 4 / Q000378:metabolism*; D006801:Humans; D006946:Hyperinsulinism; D007328:Insulin / Q000494:pharmacology / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010587:Phagocytosis; D011086:Polycythemia; D050683:R-SNARE Proteins / Q000172:deficiency / Q000502:physiology*; D015431:Weight Loss / Q000235:genetics
D051275:Glucose Transporter Type 4; D007328:Insulin; D050683:R-SNARE Proteins; C491831:Vamp8 protein, mouse; D005947:Glucose