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Objective: Combination therapies with gut hormone analogs represent promising treatment strategies for obesity. This pilot study investigates the therapeutic potential of modulators of the glucagon-like peptide 1 (GLP-1) and neuropeptide Y (NPY) system using GLP-1 receptor agonists (semaglutide) and antagonists (exendin 9-39), as well as non-selective and NPY-Y2-receptor selective peptide tyrosine tyrosine (PYY) analogs (PYY3-36/NNC0165-0020 and NNC0165-1273) and an NPY-Y2 receptor antagonist (JNJ31020028). Methods: High-fat diet (HFD)-induced obese rats were randomized into following treatment groups: group 1, nonselective PYY analog + semaglutide (n = 4); group 2, non-selective and NPY-Y2 receptor selective PYY analog + semaglutide (n = 2); group 3, GLP-1 receptor antagonist + NPY-Y2 receptor antagonist (n = 3); group 4, semaglutide (n = 5); and group 5, control (n = 5). Animals had free access to HFD and low-fat diet. Food intake, HFD preference and body weight were measured daily. Results: A combinatory treatment with a non-selective PYY analog and semaglutide led to a maximum body weight loss of 14.0 ± 4.9% vs 9.9 ± 1.5% with semaglutide alone. Group 2 showed a maximum weight loss of 20.5 ± 2.4%. While HFD preference was decreased in group 2, a strong increase in HFD preference was detected in group 3. Conclusions: PYY analogs (especially NPY-Y2 selective receptor agonists) could represent a promising therapeutic approach for obesity in combination with GLP-1 receptor agonists. Additionally, combined GLP-1 and PYY3-36 receptor agonists might have beneficial effects on food preference.

Obesity is a rapidly emerging health problem and an established risk factor for cardiovascular diseases. Bariatric surgery profoundly reduces body weight and mitigates sequelae of obesity. The open, randomized controlled Würzburg Adipositas Studie (WAS) trial compares the effects of Roux-en-Y gastric bypass (RYGB) vs psychotherapy-supported lifestyle modification in morbidly obese patients. The co-primar y endpoint addresses 1-year changes in cardiovascular function (peak VO2 during cardiopulmonary exercise testing) and the quality of life (QoL) (Short-Form-36 physical functioning scale). Prior to randomization, all included patients underwent a multimodal ant i-obesity treatment for 6–12 months. Thereafter, the patients were randomized and followed through month 12 to collect the primary endpoints. Afterwards, patients in the lifestyle group could opt for surgery, and final visit was scheduled for all patients 24 m onths after randomization. Sample size calculation suggested to enroll 90 patients in order to arrive at minimally 22 patients per group evaluable for the primary endpoint. Secondary objectives were to quantify changes in body weight, left ventricular hypertrophy, systolic and diastolic function (by echocardiography and cardiac MRI), functional brain MRI, psychometric scales, and endothelial and metabolic function. WAS enrolled 93 patients (72 women, median age 38 years, BMI 47.5 kg/m2) exhibiting a relevantly compromised exercise capacity (median peakVO2 18.3 mL/min/kg) and the QoL (median physical functioning scale 50). WAS is the first randomized controlled trial focusing on the effects of RYGB on cardiovascular function beyond hypertension. In addition, it will provide a wealth of h igh-quality data on the cerebral, psychiatric, hepatic, and metabolic function in obese patients after RYGB.