title: Peripheral exendin-4 and peptide YY(3-36) synergistically reduce food intake through different mechanisms in mice.
abstract: Glucagon-like peptide-1(7-36NH2) (GLP-1) and peptide YY(3-36NH2) (PYY(3-36NH2)) are cosecreted from the intestine in response to nutrient ingestion. Peripheral administration of GLP-1 or PYY(3-36NH2) decreases food intake (FI) in rodents and humans; however, the exact mechanisms by which these peptides regulate FI remain unclear. Male C57BL/6 mice were injected (ip) with exendin-4(1-39) (Ex4, a GLP-1 receptor agonist) and/or PYY(3-36NH2) (0.03-3 microg), and FI was determined for up to 24 h. Ex4 and PYY(3-36NH2) alone decreased FI by up to 83 and 26%, respectively (P < 0.05-0.001), whereas a combination of the two peptides (0.06 microg Ex4 plus 3 microg PYY(3-36NH2)) further reduced FI for up to 8 h in a synergistic manner (P < 0.05-0.001). Ex4 and/or PYY(3-36NH2) delayed gastric emptying by a maximum of 19% (P < 0.01-0.001); however, there was no significant effect on locomotor activity nor was there induction of taste aversion. Capsaicin pretreatment prevented the inhibitory effect of Ex4 on FI (P < 0.05), but had no effect on the anorexigenic actions of PYY(3-36NH2). Similarly, exendin-4(9-39) (a GLP-1 receptor antagonist) partially abolished Ex4-induced anorexia (P < 0.05), but did not affect the satiation produced by PYY(3-36NH2). Conversely, BIIE0246 (a Y2 receptor antagonist) completely blocked the anorexigenic effects of PYY(3-36NH2) (P < 0.001), but had no effect on Ex4-induced satiety. Thus, Ex4 and PYY(3-36NH2) suppress FI via independent mechanisms involving a GLP-1 receptor-dependent, sensory afferent pathway (Ex4) and a Y2-receptor mediated pathway (PYY(3-36NH2)). These findings suggest that administration of low doses of Ex4 together with PYY(3-36NH2) may increase the suppression of FI without inducing significant side effects.
authors.affiliation: Department of Physiology, Room 3366, Medical Sciences Building, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8.
authors.forename: Tanvi
authors.initials: T
authors.lastname: Talsania
authors.forename: Younes
authors.initials: Y
authors.lastname: Anini
authors.forename: Stephanie
authors.initials: S
authors.lastname: Siu
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Drucker
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Brubaker
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004435:Eating / Q000187:drug effects* / Q000502:physiology; D000077270:Exenatide; D005746:Gastric Emptying / Q000187:drug effects / Q000502:physiology; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000188:drug therapy / Q000503:physiopathology; D010446:Peptide Fragments; D019894:Peptide YY / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology*; D012528:Satiety Response / Q000187:drug effects / Q000502:physiology; D014688:Venoms / Q000494:pharmacology*
chemical_list: D010446:Peptide Fragments; D010455:Peptides; D014688:Venoms; D019894:Peptide YY; C061785:peptide YY (3-36); D000077270:Exenatide