GLP-1 and PYY3-36 reduce high-fat food preference additively after Roux-en-Y gastric bypass in diet-induced obese rats

Abstract Background Roux-en-Y gastric bypass (RYGB) modifies various aspects of feeding behavior in morbidly obese individuals to cause marked and lasting weight loss and improvements in metabolic health but the underlying mechanisms remain poorly understood. Objectives To assess the relative contributions of the gut hormones glucagon-like peptide 1 (GLP-1) and peptide tyrosine tyrosine 3-36 (PYY 3-36 ), whose circulating levels are enhanced by RYGB, in the reduced high-fat (HF) food preference that develops postoperatively. Setting University hospital, Wuerzburg, Germany. Methods HF diet-induced obese male Wistar rats underwent RYGB ( n=11 ) or sham ( n=7 ) surgeries and were subsequently maintained on a choice of low-fat (LF) (10% calories from fat) and HF (60% calories from fat) diets. From postoperative weeks 4-6, acute feeding studies were performed in which the selective GLP-1 receptor antagonist exendin-9 (30 μg/kg), the second-generation selective Y2 receptor antagonist JNJ-31020028 (10 mg/kg), or a combination of both drugs was administered intraperitoneally. Results During the observational period body weight, adiposity and total food intake were lower while postprandial plasma GLP-1 and PYY levels were higher for RYGB-operated compared to sham-operated rats. There was a gradual shift in preference from HF to LF food in RYGB-operated rats by postoperative week 3. Single antagonist treatments had a relatively modest impact on HF food preference in rats from both surgical groups. However, dual antagonist treatment caused a striking increase in HF food preference specifically in RYGB-operated rats. Conclusions GLP-1 and PYY 3-36 reduce HF food preference additively after RYGB supporting the use of gut hormone combination strategies for healthier feeding behavior.