Glucose-dependent insulinotropic
polypeptide (GIP) and
peptide YY (PYY) are secreted from the intestinal K- and L-cells, respectively, following a meal. Both
peptides are believed to play a key role in
glucose homeostasis and energy expenditure. This study investigated the effects of daily administration of the stable and specific GIP-R antagonist, (
Pro(3))GIP (25 nmol/kg) and the endogenous truncated form of PYY, PYY(3-36) (50 nmol/kg), in mice fed with a high fat diet. Daily i.p. injection of (
Pro(3))GIP, PYY(3-36) or combined
peptide administration over 24 days significantly (P<0.05-0.01) decreased
body weight compared with saline-treated controls without change in food intake. Plasma
glucose levels and
glucose tolerance were significantly (P<0.05) lowered by (
Pro(3))GIP treatment alone, and in combination with PYY(3-36). These changes were accompanied by a slight improvement of
insulin sensitivity in all of the treatment groups. (
Pro(3))GIP treatment significantly reduced plasma
corticosterone (P<0.05), while combined administration with PYY(3-36) significantly lowered serum
glucagon (P<0.05). No appreciable changes were observed in either circulating or
glucose-stimulated insulin secretion in all treatment groups. (Pro(3))GIP-treated mice had significantly (P<0.01) lowered fasting
glucose levels and an improved (P<0.05) glycemic response to feeding. These comparative data indicate that chemical ablation of
GIP receptor action using (
Pro(3))GIP provides an especially effective means of countering
obesity and related abnormalities induced by consumption of high fat energy rich diet.