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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.

Toward a Medical Gastric Bypass: Chronic Feeding Studies With Liraglutide + PYY3-36 Combination Therapy in Diet-Induced Obese Rats