Peptide YY_3–36Inhibits Food Intake in Mice through a Melanocortin-4 Receptor-Independent Mechanism

Abstract

Peptide YY(3-36) (PYY(3-36)), a peptide released postprandially by the gut, has been demonstrated to inhibit food intake. Little is known about the mechanism by which PYY(3-36) inhibits food intake, although the peptide has been shown to increase hypothalamic proopiomelanocortin (POMC) mRNA in vivo and to activate POMC neurons in an electrophysiological slice preparation. Understanding the physiology of PYY(3-36) is further complicated by the fact that some laboratories have had difficulty demonstrating inhibition of feeding by the peptide in rodents. We demonstrate here that, like cholecystokinin, PYY(3-36) dose-dependently inhibits food intake by approximately 20-45% over a 3- to 4-h period post ip administration, with no effect on 12-h food intake. This short-lived satiety effect is not seen in animals that are not thoroughly acclimated to handling and ip injection, thus potentially explaining the difficulty in reproducing the effect. Surprisingly, PYY(3-36) was equally efficacious in inducing satiety in wild-type and melanocortin-4 receptor (MC4-R)-deficient mice and thus does not appear to be dependent on MC4-R signaling. The expression of c-Fos, an indirect marker of neuronal activation, was also examined in forebrain and brainstem neurons after ip treatment with a dose of PYY(3-36) shown to induce satiety. The peptide induced no significant neuronal activation in the brainstem by this assay, and only modest activation of hypothalamic POMC neurons. Thus, unlike cholecystokinin, PYY(3-36)-induced satiety is atypical, because it does not produce detectable activation of brainstem satiety centers and is not dependent on MC4-R signaling.

Peptide YY ablation in mice leads to the development of hyperinsulinaemia and obesity

“…Both PYY1-36 [8,9] and PYY3-36 suppress appetite and food intake in rodents [10][11][12][13][14]. However, one report was unable to confirm this finding [15].…”

Effects of oral ingestion of sucralose on gut hormone response and appetite in healthy normal-weight subjects

“…The gut hormones peptide YY (PYY) and glucagon-like peptide (GLP)-1 are co-secreted from intestinal enteroendocrine L-cells and released post-prandially in proportion to the amount of energy ingested (Ghatei et al, 1983;Adrian et al, 1985;Le Roux et al, 2006). PYY and GLP-1 have both been shown to be satiety factors, reducing food intake when administered to rodents (Batterham et al, 2002;Challis et al, 2003;Halatchev et al, 2004;Chelikani et al, 2005aChelikani et al, , b, 2006Talsania et al, 2005) and to humans (Flint et al, 1998;Gutzwiller et al, 1999;Batterham et al, 2002;Degen et al, 2005;Le Roux et al, 2006). The incretin effect of GLP-1, augmentation of insulin secretion in response to an oral glucose load, has been well characterised (Elrick et al, 1964).…”

PYY transgenic mice are protected against diet-induced and genetic obesity

“…Recent studies have demonstrated acute affects of PYY1-36 and PYY3-36 in inhibiting food intake in animals and in man (Adams et al, 2004, Batterham et al, 2002, Challis et al, 2003, Chelikani et al, 2004, Chelikani et al, 2005, Halatchev et al, 2004and Riediger et al, 2004. It is thought that after a meal, PYY3-36, the main form of PYY circulating postprandially, acts on the arcuate nucleus of the hypothalamus.…”