Abstract
Obesity is a global pandemic, with ominous trends in related morbidities, mortalities, and medical expenditures. Current therapies have proven limited in efficacy or burdened with safety concerns. The discovery of a new gut‐brain endocrine axis regulating appetite through the transmembrane receptor guanylyl cyclase C (GUCY2C) is a welcome opportunity for advancing clinical care. We aimed to define the hypothalamic organization and signaling of neuronal GUCY2C. Moreover, we assessed the integrity of the GUCY2C axis in the setting of obesity. Microdissection studies mapped GUCY2C expression and activity to key centers of central appetite control. Furthermore, mouse models of diet‐induced obesity suggest that obesity leads to intestinal GUCY2C hormone loss, which may contribute to appetite dysregulation. Thus, GUCY2C hormone supplementation to reconstitute GUCY2C signaling is promising, particularly given the recent regulatory approval for the GUCY2C ligand linaclotide in clinical use.
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