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The GLP-1 receptor agonist liraglutide is marketed for obesity treatment where it induces body weight reduction possibly via the hypothalamus, which regulates energy homeostasis. In animal studies, acute liraglutide treatment triggers satiety, weight loss and activates thermogenesis in adipose tissue. However, the precise mechanisms how liraglutide affects in particular chronic weight loss are still under investigation.We aimed to evaluate whether chronic hypothalamic or chronic subcutaneous administration of liraglutide induces sustained weight loss through altered adipose tissue function and to what extent hypothalamic neuronal appetite regulators are involved in the liraglutide-induced weight loss in healthy lean rats on a normal diet.We continuously administered liraglutide either intrahypothalamically (10 μg per day) or subcutaneously (200 μg kg-1 per day) for 28 days to lean Sprague Dawley rats (n = 8 each). We assessed changes in body weight, adipose tissue mass, adipocyte size and adipose tissue volume in the abdominal region by using micro-CT. We analyzed genetic expression patterns of browning, thermogenic and adipocyte differentiation regulators in adipose tissues as well as particular neuronal appetite regulators in the hypothalamus.Intrahypothalamic liraglutide administration induced an 8% body weight reduction at day 9 compared with the control group (P < 0.01) and a 7% body weight loss at day 9 compared with subcutaneous liraglutide treatment (P < 0.01), supported by a significant reduction in adipose tissue mass and volume with intrahypothalamic liraglutide administration (P < 0.05). Our data show that chronic intrahypothalamic liraglutide treatment triggered an 18-fold induction of the hypothalamic mc4r gene (P < 0.01) accompanied by a significant increase in circulating thyroxine (T4) levels (P < 0.05).Chronic intrahypothalamic liraglutide administration resulted in a profound reduction in body weight and fat mass loss most likely mediated by the hypothalamic melanocortin system rather than by adipose tissue browning or improved thermogenesis.