PYY[3-36]ADMINISTRATION DECREASES THE RESPIRATORY QUOTIENT AND REDUCES ADIPOSITY IN DIET-INDUCED OBESE MICE 1,2

Authors: Adams, Sean; LEI, CHUNLI - AMYLIN PHARMACEUTICALS, I; JODKA, CAROLYN - AMYLIN PHARMACEUTICALS; NIKOULINA, SVETLANA - AMYLIN PHARMACEUTICALS; HOYT, JULIE - AMYLIN PHARMACEUTICALS; GEDULIN, BRONISLAVA - AMYLIN PHARMACEUTICALS; MACK, CHRISTINE - AMYLIN PHARMACEUTICALS; KENDALL, ERIC - AMLYLIN PHARMACEUTICALS

Submitted to: Journal of Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/18/2005
Publication Date: 1/1/2006
Citation: Adams, S.H., Lei, C., Jodka, C.M., Nikoulina, S.E., Hoyt, J.A., Gedulin, B., Mack, C.M., Kendall, E.S. Pyy[3-36]administration decreases the respiratory quotient and reduces adiposity in diet-induced obese mice 1,2. Journal of Nutrition. Vol.136:195-201, 2006.

Interpretive Summary: Gut-derived hormones such as the peptide YY (PYY) cleavage product PYY may play a role in modulating energy balance and adiposity through actions that regulate food intake, the efficiency of energy uptake, and tissue metabolism of nutrients. Interestingly, circulating total PYY concentration increases following food ingestion (especially fat-rich meals), and has been reported to be low in obese humans. PYY has recently been implicated in the regulation of food intake, since its peripheral infusion resulted in reduced hunger in human subjects. In rodent models, peripheral administration of PYY[3-36] was shown to reduce food intake and/or body weight gain. At least one study suggested that the peptide’s anorexigenic properties in rodents are influenced by factors such as daily handling and acclimation to injection. However, food intake reduction has also been observed following PYY administration in naïve mouse models and data herein. It remains to be established whether PYY influences other processes impacting energy balance such as gut nutrient uptake, metabolic rate, and fuel partitioning. Several lines of evidence indicate that PYY regulates gut function, and it has been proposed that the hormone participates in the ileal brake mechanism in which unabsorbed nutrients reaching the distal intestine trigger signals that slow gastrointestinal motility and reduce gastric/pancreatic secretion. Peripheral administration of full-length PYY has been reported to decrease the cephalic phase of gallbladder emptying in humans. This effect may be species-specific, since it was not observed in dogs, and activation of gallbladder contraction was reported for anesthetized guinea pigs given PYY. Full-length PYY decreased gastric acid secretion, gastric emptying, and exocrine pancreas function, and increased orocecal transit time. Further, PYY was recently reported to inhibit gastric emptying in primates. In addition to potential gastrointestinal tract motility and secretory effects, PYY [3-36] administration reduced feed efficiency (body weight gain relative to energy intake) and adiposity in high fat diet-induced obese (DIO) mice, suggesting that PYY regulates intestinal caloric uptake and/or tissue-level metabolism. We used DIO mice to test the hypothesis that increased metabolic rate and higher fat combustion contribute to the reductions in body weight and adiposity following pharmacologic administration of PYY[3-36]. Furthermore, we examined whether the peptide reduces net energy uptake in the gastrointestinal tract as part of its mechanism-of-action. Summary of the data: the current results extend previous reports of the effects of PYY[3-36] on ingestive behavior by characterizing other components of the energy balance equation. It appears that reduced food intake coupled to maintenance of body mass-specific metabolic rate were the primary processes leading to energy deficit and hence rapid weight loss and marked fat loss in DIO mice. Interestingly, body weight differences between control and PYY[3-36]-treated DIO mice persisted through at least 56 d, illustrating that the hormone retains activity for long periods of time when given pharmacologically. Should the effects of PYY[3-36] observed in DIO mice--persistently reduced body weight, fat loss and maintenance of lean mass--translate to a clinical setting, activation of PYY[3-36]-related pathways may prove to be a new approach to treating metabolic disorders."

Technical Abstract: In rodents, weight reduction following peptide YY[3-36] (PYY[3-36]) administration may be largely due to decreased food consumption. Effects on other processes impacting energy balance (energy expenditure, fuel partitioning, gut nutrient uptake) remain poorly understood. We examined whether subcutaneous infusion of 1 mg/(kg'd) PYY[3-36] (up to 7 d) increases metabolic rate, fat combustion, and/or fecal energy loss in obese, high-fat diet fed mice. PYY[3-36] transiently reduced food intake (e.g., 25-43% lower at d 2 relative to pre-treatment baseline) and decreased body wt (e.g., 9-10% reduced at d 2 vs. baseline) in three separate studies. Mass-specific metabolic rate in kJ/(kg'h) in PYY[3-36]-treated mice did not differ from controls. The dark cycle respiratory quotient (RQ) was transiently decreased (e.g., d 2, 0.747 ± 0.008 vs. 0.786 ± 0.004 in controls; P<0.001), and light cycle RQ was reduced throughout the study in PYY[3-36]-treated mice (0.730 ± 0.006 vs. 0.750 ± 0.009 in controls; P<0.001). Epididymal fat pad wt in PYY[3-36]-treated mice was ~50% decreased (P < 0.01 vs. controls). Fat pad lipolysis ex vivo was not stimulated by PYY[3-36]. PYY[3-36] decreased basal gallbladder emptying in non-obese mice. Fecal energy loss was negligible (~2% of ingested energy) and not significantly different in PYY[3-36]-treated mice vs. controls. Thus, negative energy balance following PYY[3-36] administration in diet-induced obese mice results from reduced food intake with a relative maintenance of mass-specific energy expenditure. Fat loss and reduced RQ highlight the potential for PYY[3-36] to drive increased mobilization of fat stores to help meet caloric requirements in this model.