Endocrine Abstracts

Background: Circulating levels of the appetite-suppressing and glucoregulatory gut hormones glucagon-like peptide 1 (GLP-1) and peptide tyrosine tyrosine 3–36 (PYY_3–36) are markedly increased after Roux-en-Y gastric bypass surgery (RYGB), which may contribute to some of its profound metabolic benefits in morbidly obese individuals.

Objectives: To directly compare the metabolic effects of chronic systemic administration of the clinically approved GLP-1 analogue liraglutide in combination with PYY_3–36 to RYGB in a standardized and controlled setting.

Methods: High-fat diet-induced obese male Wistar rats (n = 58) were randomized into 6 treatment groups: RYGB (n = 15), sham-operation (n = 13), liraglutide subcutaneous (s.c.; 0.4 mg/kg/day) + saline mini-pump (n = 5), PYY_3–36 mini-pump (1 mg/kg/day) + saline s.c. (n = 5), liraglutide + PYY_3–36 (n = 11), saline s.c. + mini-pump (n = 9). At the start of interventions, animals were given simultaneous free access to high-fat and low-fat diets ad libitum, high-fat food preference and body weight were measured at regular intervals. Open field (OF) and elevated plus maze (EPM) tests were performed about 4 weeks after intervention. Terminal blood samples were collected for biochemical analysis.

Results: Post intervention, the RYGB group lost maximally 8.6 ± 2.9% body weight, while the sham treated animals gained weight continuously. Compared to sham, the bodyweight of RYGB treated animals was about 20% less in the end of the observation period. The PYY+liraglutide and liraglutide only group lost maximally 7.7 ± 3.2% and 5.5 ± 2.4%, whereas the saline and PYY only group gained weight continuously. PYY + liraglutide treated animals were maximally about 17%, liraglutide only treated animals about 13.5% lighter than saline treated animals. Food intake largely followed the same pattern with the RYGB group consuming the least food followed by the liraglutide + PYY_3–36 group and then by the liraglutide group. Only RYGB treated animals showed a significantly reduced preference for 60% fat diet compared to sham treated animals in the observation period. PYY + liraglutide or RYGB led to no clear differences regarding the behavior in OF or EPM compared to saline or sham.

Conclusions: Liraglutide and PYY_3–36 combination therapy partially achieves the metabolic benefits of RYGB. Other double or triple gut hormone combination therapies may therefore be required to achieve the full metabolic benefits of RYGB.