Toward a Medical Gastric Bypass: Chronic Feeding Studies With Liraglutide + PYY(3-36) Combination Therapy in Diet-Induced Obese Rats

BACKGROUND: Combination therapies of anorectic gut hormones partially mimic the beneficial effects of bariatric surgery. Thus far, the effects of a combined chronic systemic administration of Glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine 3-36 (PYY(3-36)) have not been directly compared to Roux-en-Y gastric bypass (RYGB) in a standardized experimental setting. METHODS: High-fat diet (HFD)-induced obese male Wistar rats were randomized into six treatment groups: (1) RYGB, (2) sham-operation (shams), (3) liraglutide, (4) PYY(3-36), (5) PYY(3-36)+liraglutide (6), saline. Animals were kept on a free choice high- and low-fat diet. Food intake, preference, and body weight were measured daily for 4 weeks. Open field (OP) and elevated plus maze (EPM) tests were performed. RESULTS: RYGB reduced food intake and achieved sustained weight loss. Combined PYY(3-36)+liraglutide treatment led to similar and plateaued weight loss compared to RYGB. Combined PYY(3-36)+liraglutide treatment was superior to PYY(3-36) (p ≤ 0.0001) and liraglutide (p ≤ 0.05 or p ≤ 0.01) mono-therapy. PYY(3-36)+liraglutide treatment and RYGB also reduced overall food intake and (less pronounced) high-fat preference compared to controls. The animals showed no signs of abnormal behavior in OF or EPM. CONCLUSIONS: Liraglutide and PYY(3-36) combination therapy vastly mimics reduced food intake, food choice and weight reducing benefits of RYGB.