Survodutide acts through circumventricular organs in the brain and activates neuronal regions associated with appetite regulation.
This preclinical study examined how survodutide — a dual glucagon receptor (GCGR) and GLP-1 receptor (GLP-1R) agonist in clinical development for obesity and MASH — acts in the brain to reduce body weight. Researchers first mapped GCGR and GLP-1R expression in human and mouse circumventricular organs (CVOs), finding that GCGR is barely detectable in the area postrema (AP) and arcuate nucleus of the hypothalamus (ARH), whereas GLP-1R is expressed in both regions. Using a fluorophore-labeled version of survodutide in mice, the study found that the compound accesses CVOs and nearby hypothalamic and hindbrain nuclei directly, without evidence of broadly crossing the blood-brain barrier. C-Fos activation mapping showed that survodutide activated multiple brain nuclei associated with food intake control. A long-acting GCGR-selective agonist, by contrast, did not activate satiety-related brain regions or reduce food intake, though it did reduce body weight, suggesting the appetite-suppressing effects of survodutide are primarily GLP-1R dependent. Limitations include the exclusively preclinical (mouse) design and the use of a labeled surrogate compound. The authors conclude the findings support a dual mechanism for survodutide's weight-lowering effects.
Why this grade: All mechanistic experiments were conducted in mice (with some receptor expression mapping in human tissue), with no direct human efficacy or safety outcomes measured in this study.
Survodutide is a novel GCG/GLP-1 receptor (GCGR/GLP-1R) dual agonist in clinical development for people with obesity and people with metabolic dysfunction-associated steatohepatitis (MASH). Preclinically, survodutide demonstrated body weight lowering efficacy through decreased energy intake and increased energy expenditure. Here, we investigated the central site of action of survodutide and provide further insights into its mechanism of action in reducing body weight. We assessed GCGR and GLP1R expression in human and mouse circumventricular organs (CVOS) and showed for the first time that GCGR is barely detectable in area postrema (AP) and arcuate nucleus of the hypothalamus (ARH) at the single cell level. In contrast, GLP1R is expressed in these tissues. Using a fluorophore labeled survodutide to visualize sites of action in the mouse brain, survodutide was observed to directly access the CVOs and adjacent hypothalamic and hindbrain nuclei, without evidence of uniformly crossing the blood-brain-barrier. In addition, c-Fos labeling showed that multiple nuclei associated with the control of food intake were activated by survodutide. Consistent with the hypothesis that the intake suppressive effects of survodutide are GLP-1R dependent, a long-acting GCGR agonist did not induce neuronal activation in satiety-mediating regions, nor reduced food intake but showed reduction in body weight. These data further support the dual mode of action of survodutide and its potential to provide clinical benefit for people with obesity and/or MASH.
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