The role of peptide YY in appetite regulation and obesity

Abstract

The last decade has witnessed a marked increase in our understanding of the importance of gut hormones in the regulation of energy homeostasis. In particular, the discovery that the gut hormone peptide YY 3-36 (PYY3-36) reduced feeding in obese rodents and humans fuelled interest in the role of PYY3-36 in body weight regulation. Pharmacological and genetic approaches have revealed that the Y2-receptor mediates the anorectic effects of PYY3-36 whilst mechanistic studies in rodents identified the hypothalamus, vagus and brainstem regions as potential sites of action. More recently, using functional brain imaging techniques in humans, PYY3-36 was found to modulate neuronal activity within hypothalamic and brainstem, and brain regions involved in reward processing. Several lines of evidence suggest that low circulating PYY concentrations predispose towards the development and or maintenance of obesity. Subjects with reduced postprandial PYY release exhibit lower satiety and circulating PYY levels that correlate negatively with markers of adiposity. In addition, mice lacking PYY are hyperphagic and become obese. Conversely, chronic PYY3-36 administration to obese rodents reduces adiposity, and transgenic mice with increased circulating PYY are resistant to diet-induced obesity. Moreover, there is emerging evidence that PYY3-36 may partly mediate the reduced appetite and weight loss benefits observed post-gastric bypass surgery. Taken together these findings, coupled with the retained responsiveness of obese subjects to the effects of PYY3-36, suggest that targeting the PYY system may offer a therapeutic strategy to help treat obesity.

A single-cell survey of the small intestinal epithelium

“…SILA, expressing ghrelin ( Ghrl ), the hunger hormone 29 , and proglucagon ( Gcg , GLP-1), validated in situ (Fig. 3c,d) were enriched in the duodenum (FDR < 0.25, χ 2 test, Methods ), while SIL-P and SIK-P, both expressing the hormone peptide YY, which reduces appetite upon feeding 30 , were mainly found in the ileum (FDR < 0.1, χ 2 test) (Fig. 3e and Extended Data Fig.…”

Factors affecting circulating levels of peptide YY in humans: a comprehensive review

“…PYY 1 -36 binds and activates all five Y receptors (Y1-Y5). If the first two amino acids at the N-terminal are removed, the receptor selectivity changes because PYY 3 -36 only has a high affinity for the Y2 receptor (21) . While both forms are biologically active at all times, PYY 3 -36 is the main storage and circulating form of PYY (14) and is thought to more actively control food intake (22) .…”

“…Intravenous infusions of PYY reduce appetite and energy intake in healthy human subjects, suggesting that PYY plays a role in regulating satiety (21,24,25) . Circulating levels of PYY are low in the fasted state and both the 3 -36 and 1-36 forms increase rapidly upon nutrient ingestion (14) .…”

Microbiota in Obesity

“…Several lines of evidence suggest that low circulating PYY concentrations predisposes individuals to obesity and vice versa. Mice lacking PYY are hyperphagic and have obese phenotype, conversely, chronic PYY3-36 (one of the two major forms of PYY) administration to obese rodents reduces adiposity [19]. Reduced expression of PYY in FFAR3 deficient mice resulted in lower body fat mass and increased lean body mass [15].…”