Effects of PYY[3-36] in rodent models of diabetes and obesity

BACKGROUND: Peptide YY (PYY) is a 36 amino-acid peptide secreted from ileal L cells following meals. The cleaved subpeptide PYY[ 3 - 36] is biologically active and may constitute the majority of circulating PYY-like immunoreactivity. The peptide family that includes PYY, pancreatic peptide and neuropeptide Y is noted for its orexigenic effect following intracerebroventricular administration. OBJECTIVE: To investigate the effects of peripheral ( intraperitoneal and chronic subcutaneous) infusions of PYY[ 3 - 36] on food intake, body weight and glycemic indices. DESIGN/RESULTS: Food intake was measured in normal mice and in several rodent models of obesity and type II diabetes. In marked contrast to the reported central orexigenic effects, in the present study, PYY[ 3 - 36] acutely inhibited food intake by up to 45%, with an ED50 of 12.5 mug/kg in fasted female NIH/Swiss mice. A 4-week infusion reduced weight gain in female ob/ob mice, without affecting the cumulative food intake. In diet-induced obese male mice, PYY[ 3 - 36] infusion reduced cumulative food intake, weight gain and epididymal fat weight ( as a fraction of carcass) with similar ED50's ( 466, 297 and 201 mug/kg/day, respectively) and prevented a diet-induced increase in HbA1c. Infusion at 100 mug/kg/day for 8 weeks in male fa/ fa rats reduced the weight gain (288 +/- 11 vs 326 +/- 12 g in saline-infused controls; P<0.05), similar to effects in a pair-fed group. In female ob/ob and db/db mice, there was no acute effect of PYY[3-36] on plasma glucose concentrations. In male diabetic fatty Zucker rats, PYY[ 3 - 36] infused for 4 weeks reduced HbA1c and fructosamine (ED50's 30 and 44 mu g/kg/day). CONCLUSION: Peripheral PYY[ 3 - 36] administration reduced the food intake, body weight gain and glycemic indices in diverse rodent models of metabolic disease of both sexes. These findings justify further exploration of the potential physiologic and therapeutic roles of PYY[ 3 - 36].