956 IW-9179, a Potent Guanylate Cyclase-C (GC-C) Agonist, Improves Gastric Emptying In Vivo and Modulates Gastric Vagal Afferent Mechanosensitivity In Vitro

Ge, Pei; Shea, Courtney; Kentish, Stephen J.; Avitahl-Curtis, Nicole; Rivers, Sam; Kessler, Marco M.; Zimmer, Daniel P.; Richardson, Jannell; Sahibzada, Niaz; Gillis, Richard A.; Cali, Brian M.; Page, Amanda J.; Silos‐Santiago, Inmaculada; Currie, Mark G.

doi:10.1016/s0016-5085(15)30619-3

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“…Data gleaned in recent years have shown that vagal afferents play a role in many biological functions [30]. In fact, it is known that activation of Gucy2c modulates gastric vagal afferent mechanosensitivity [31] In this sense, gut peptides (e.g., ghrelin, CCK) are able to bind to receptors at the vagal afferent pathway terminal that extend into the mucosal layer of the digestive tract, and by doing so, send signals through the vagus nerve to different brain areas including the hypothalamus. Future studies using retrograde tracing are needed to further clarify this issue.…”

Section: Discussionmentioning

confidence: 99%

Oral Pharmacological Activation of Hypothalamic Guanylate Cyclase 2C Receptor Stimulates Brown Fat Thermogenesis to Reduce Body Weight

et al. 2020

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Linaclotide is a synthetic peptide approved by the FDA for the treatment of constipation-predominant irritable bowel syndrome and chronic constipation. Linaclotide binds and activates the transmembrane receptor guanylate cyclase 2C (Gucy2c). Uroguanylin (UGN) is a 16 amino acid peptide that is mainly secreted by enterochromaffin cells in the duodenum and proximal small intestine. UGN is the endogenous ligand of Gucy2c and decreases body weight in diet-induced obese (DIO) mice via the activation of the thermogenic program in brown adipose tissue. Therefore, we wanted to evaluate whether oral linaclotide could also improve DIO mice metabolic phenotype. In this study, we have demonstrated that DIO mice orally treated with linaclotide exhibited a significant reduction of body weight without modifying food intake. Linaclotide exerts its actions through the central nervous system, and more specifically, via Gucy2c receptors located in the mediobasal hypothalamus, leading to the activation of the sympathetic nervous system to trigger the thermogenic activity of brown fat stimulating energy expenditure. These findings indicate for first time that, in addition to its effects at intestinal level C.F. and F.L.T.-L. contributed equally to this work.

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Section: Discussionmentioning

confidence: 99%