Peptide YY3-36 and glucagon-like peptide-17-36 inhibit food intake additively

Peptide YY (PYY) and glucagon like peptide (GLP)-1 are cosecreted from intestinal L cells, and plasma levels of both hormones rise after a meal. Peripheral administration of PYY3-36 and GLP-1(7-36) inhibit food intake when administered alone. However, their combined effects on appetite are unknown. We studied the effects of peripheral coadministration of PYY3-36 with GLP-1(7-36) in rodents and man. Whereas high-dose PYY3-36 (100 nmol/kg) and high-dose GLP-1(7-36) (100 nmol/ kg) inhibited feeding individually, their combination led to significantly greater feeding inhibition. Additive inhibition of feeding was also observed in the genetic obese models, ob/ob and db/db mice. At low doses of PYY3-36 (1 nmol/ kg) and GLP1(7-36) (10 nmol/ kg), which alone had no effect on food intake, coadministration led to significant reduction in food intake. To investigate potential mechanisms, c-fos immunoreactivity was quantified in the hypothalamus and brain stem. In the hypothalamic arcuate nucleus, no changes were observed after low-dose PYY3-36 or GLP-1(7-36) individually, but there were significantly more fos-positive neurons after coadministration. In contrast, there was no evidence of additive fos-stimulation in the brain stem. Finally, we coadministered PYY3-36 and GLP-1(7-36) in man. Ten lean fasted volunteers received 120-min infusions of saline, GLP-1(7-36) (0.4 pmol/kg(.)min), PYY3-36 (0.4 pmol/kg(.)min), and PYY3-36 (0.4 pmol/kg(.)min), GLP-1(7-36) (0.4 pmol/kg(.)min) on four separate days. Energy intake from a buffet meal after combined PYY3-36 + GLP-1(7-36) treatment was reduced by 27% and was significantly lower than that after either treatment alone. Thus, PYY3-36 and GLP1(7-36), cosecreted after a meal, may inhibit food intake additively.