Peptide YY3–36 and Glucagon-Like Peptide-17–36 Inhibit Food Intake Additively

• Published in: Endocrinology (Philadelphia) 2005-12, Vol.146 (12), p.5120-5127
• Main Authors: Neary, Nicola M, Small, Caroline J, Druce, Maralyn R, Park, Adrian J, Ellis, Sandra M, Semjonous, Nina M, Dakin, Catherine L, Filipsson, Karin, Wang, Fang, Kent, Aysha S, Frost, Gary S, Ghatei, Mohammad A, Bloom, Stephen R
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Arcuate nucleus; Behavior, Animal - drug effects; Biological and medical sciences; Brain stem; c-Fos protein; Diabetes Mellitus - genetics; Diabetes Mellitus - physiopathology; Dose-Response Relationship, Drug; Double-Blind Method; Drug Combinations; Drug Synergism; Eating - drug effects; Energy intake; Energy Intake - drug effects; Feeding Behavior - drug effects; Female; Food; Food additives; Food intake; Fundamental and applied biological sciences. Psychology; Glucagon; Glucagon - administration & dosage; Glucagon - pharmacology; Glucagon-Like Peptide 1; Glucagon-Like Peptides - administration & dosage; Glucagon-Like Peptides - pharmacology; Hormones; Humans; Hypothalamus; Immunohistochemistry; Immunoreactivity; Injections, Intraperitoneal; L cells; Male; Mice; Mice, Inbred C57BL; Motor Activity - drug effects; Obesity - genetics; Obesity - physiopathology; Peptide Fragments - administration & dosage; Peptide Fragments - pharmacology; Peptide YY - administration & dosage; Peptide YY - pharmacology; Peptides; Plasma levels; Rats; Vertebrates: endocrinology
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2005-0237

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-17–36 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-17–36 in rodents and man. Whereas high-dose PYY3–36 (100 nmol/kg) and high-dose GLP-17–36 (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 GLP-17–36 (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-17–36 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-17–36 in man. Ten lean fasted volunteers received 120-min infusions of saline, GLP-17–36 (0.4 pmol/kg·min), PYY3–36 (0.4 pmol/kg·min), and PYY3–36 (0.4 pmol/kg·min) + GLP-17–36 (0.4 pmol/kg·min) on four separate days. Energy intake from a buffet meal after combined PYY3–36 + GLP-17–36 treatment was reduced by 27% and was significantly lower than that after either treatment alone. Thus, PYY3–36 and GLP-17–36, cosecreted after a meal, may inhibit food intake additively.