Hypothalamic anorexigenic signaling pathways (leptin, amylin, and proopiomelanocortin) are semaglutide (GLP-1 analog) targets in obesity control in mice

We aimed to examine the effects of semaglutide on the neuropeptide signaling implicated in the hypothalamic energy metabolism of the diet-induced obese (DIO) mice. Mice (C57BL/6J) were fed a control diet (C) or a high-fat diet (HF) (n = 45/group) for 16 weeks, and then they were divided into six groups (n = 15/group) for an additional study of four weeks: control (C), control+semaglutide (CS, 40 μg/kg), control pair-feeding (CPF), high-fat (HF), high-fat+semaglutide (HFS, 40 μg/kg) and high-fat pair-feeding (HPF). Body weight (BW) and food and energy intake were determined. In addition, plasmatic determinations and hypothalamus were prepared for biochemical and molecular analysis (immunofluorescence and RT-qPCR). The hypothalamus was stereotaxically sectioned in a cryostat in a coronal plane, evaluating the hypothalamus and the arcuate nucleus. DIO mice showed increased energy intake and BW linked to leptin and amylin resistance. Semaglutide improved leptin sensitivity and anorexigenic signaling but lessened orexigenic signaling. In addition, an anorexigenic activity downregulation was indicated by decreased POMC/MC4R expression and increased NPY/AgRP signaling. Biometric data were modified by diet and semaglutide. Also, hypothalamic gene expressions were affected by diet and semaglutide, and diet and semaglutide interacted on all expressions. Semaglutide activated anorexigenic signaling in DIO mice by restoring leptin, amylin, and POMC pathways. Furthermore, the beneficial anorectic effects of semaglutide extended to weight loss and decreased energy intake. However, the findings reinforce previous mentions that semaglutide beneficial effects are not always weight loss dependent.