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The discovery of incretin mimetics represents a major turning point in obesity and diabetes medicine. These small molecules are agonists of one or more receptors of glucagon, GLP-1, and GIP. Despite their efficacy and widespread use, the mechanism for the reduction in bodyweight has not been elucidated. Energy homeostasis is regulated in the hypothalamus and hindbrain, where incretin receptors are also expressed, leading to the hypothesis that incretin mimetics act in these brain regions to exert their appetite suppressing effects. The aim of this study is to identify mechanisms of action in the hypothalamus and hindbrain of GLP-1 and GIP agonists.Adult, diet-induced obese male CL57BL/6-J mice were injected IP with vehicle, GLP-1R agonist, GIPR agonist, GIPR antagonist, and MAR709, a mouse and human GLP-1R/GIPR dual-agonist, n=6. 8h after injection, the hypothalamus and hindbrain were collected and single-nuclei RNA and ATAC (assay for transposase-accessible chromatin) sequencing was performed, yielding 211537 hypothalamic and 57844 hindbrain nuclei after pre-processing (removal of low-quality nuclei Boeher Inglehim. T.D. Müller: Stock/Shareholder; Novo Nordisk, Eli Lilly and Company. Research Support; Novo Nordisk. Speaker's Bureau; Novo Nordisk, Merck & Co., Inc., Eli Lilly and Company, Novo Nordisk.
Gutgesell et al. (Fri,) studied this question.
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