The VIP/VPAC1R Pathway Regulates Energy and Glucose Homeostasis by Modulating GLP-1, Glucagon, Leptin and PYY Levels in Mice

SIMPLE SUMMARY: The current study is the first complete characterization of the phenotypic, metabolic, calorimetric, and homeostatic effects of VPAC1R in a null murine model. To evaluate the role of VPAC1R on body phenotype, feeding behavior, glucose/energy homeostasis, metabolic rate and plasma hormones, a long-term study was conducted in VPAC1R(−/−) and WT mice. The outcome data document that VPAC1R(−/−) mice have altered metabolism and insulin intolerance, with significant increase of feeding bouts, reduction of total energy expenditure and respiratory gases during both the dark and light cycle, together with elevated fasting levels of GLP-1 and PYY, and higher postprandial levels of GLP-1, glucagon leptin and PYY. These findings suggests that VPAC1R controls glucose homeostasis and energy balance by regulating plasma metabolic hormones. ABSTRACT: Vasoactive Intestinal Peptide binds with high affinity to VPAC1R and VPAC2R, thus regulating key physiologic functions. Previously, we documented in VIP(−/−) mice a leaner body phenotype and altered metabolic hormones. Past reports described in VPAC2(−/−) mice impaired circadian rhythm, reduced food intake, and altered metabolism. To better define the effects of VPAC1R on body phenotype, energy/glucose homeostasis, and metabolism, we conducted a 12-week study in a VPAC1R null model. Our results reveal that VPAC1(−/−) mice experienced significant metabolic alterations during the dark cycle with greater numbers of feeding bouts (p = 0.009), lower Total Energy Expenditure (p = 0.025), VO(2) (p = 0.029), and VCO(2) (p = 0.016); as well as during the light cycle with lower Total Energy Expenditure (p = 0.04), VO(2) (p = 0.044), and VCO(2) (p = 0.029). Furthermore, VPAC1(−/−) mice had significantly higher levels of GLP-1 and PYY during fasting, and higher levels of GLP-1, glucagon leptin and PYY during postprandial conditions. In addition, VPAC1(−/−) mice had lower levels of glucose at 60′ and 120′, as assessed by insulin tolerance test. In conclusion, this study supports a key role for VPAC1R in the regulation of body glucose/energy homeostasis and metabolism.