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

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), VO2 (p = 0.029), and VCO2 (p = 0.016); as well as during the light cycle with lower Total Energy Expenditure (p = 0.04), VO2 (p = 0.044), and VCO2 (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.

PACAP and VIP Neuropeptides’ and Receptors’ Effects on Appetite, Satiety and Metabolism

“…This mechanism could be mediated through the VPAC2 receptor, as feeding behavior observations in VPAC2 −/− mice showed a significantly reduced daily amount of food intake [77]. Our group recently demonstrated, by indirect calorimetric analysis, no significant differences in food consumption and the amount of time spent feeding in VPAC1 −/− mice, even though there was an increase in the number of feeding bouts during the dark cycle [78]. Previously, other researchers showed that a long-term treatment with a VPAC1 agonist inhibited food intake over a 28-day experimental period [79].…”

Gene deletion of the PACAP/VIP receptor, VPAC2R, alters glycemic responses during metabolic and psychogenic stress in adult female mice

“…Similarly, no significant relationship was detected between plasma GLP‐1 and insulin glycemia response, stress glycemia, or plasma epinephrine in Vipr2 −/− mice. Little is known about the role of VPAC2R in GLP‐1 hormone regulation, although VPAC1R and VIP‐deficient mouse phenotypes and PACAP receptor antagonism are associated with increased fasting and postprandial GLP‐1 levels 7,72,73 . PAC1R‐ and VIP‐deficient fed or fasted mice also exhibit hyperinsulinemia 14,74 .…”

“…Little is known about the role of VPAC2R in GLP-1 hormone regulation, although VPAC1R and VIP-deficient mouse phenotypes and PACAP receptor antagonism are associated with increased fasting and postprandial GLP-1 levels. 7,72,73 PAC1R-and T A B L E 3 PCR transcripts in adrenal gland.…”

Gene Deletion of the PACAP/VIP Receptor, VPAC2R, Alters Glycemic Responses During Metabolic and Psychogenic Stress in Adult Female Mice

“…Similarly, no significant relationship was detected between plasma GLP-1 and insulin glycemia response, stress glycemia or plasma epinephrine in Vipr2 -/- mice. Little is known about the role of VPAC2R in GLP-1 hormone regulation, although VPAC1R and VIP-deficient mouse phenotypes and PACAP receptor antagonism are characterized by increased fasting and postprandial GLP-1 levels [7,72,73]. PAC1R- and VIP-deficient fed or fasted mice also exhibit hyperinsulinemia [14,74].…”