Targeting GUCY2C for anti-obesity pharmacotherapy Uroguanylin Replacement Opposes Obesity by Restoring Anorexigenic GUCY2C Signaling Silenced by Overnutrition-Induced Uroguanylin Deficiency
The expression of guanylyl cyclase C (GUCY2C) has principally been ascribed to the intestine and gastrointestinal tumors, and studies have primarily investigated GUCY2C for its critical role in antitumorigenesis and as a target for colorectal cancer diagnostic staging and immunotherapy. Recent discoveries, however, identified a novel gut-brain endocrine axis regulating appetite, wherein hypothalamic GUCY2C mediates satiety when activated by the GUCY2C hormone, uroguanylin, which is postprandially released into the circulation from the intestine. The revelation of its noncanonical expression in the hypothalamus and endocrine activation in mechanisms of energy homeostasis expanded our knowledge of GUCY2C-centered biology and offered a new target in the development of anti-obesity drugs. Despite the welcome arrival of new medications recently approved for adjunctive therapy in chronic weight management, issues of safety and efficacy continue to plague current anti-obesity therapeutic modalities, and obesity remains a global pandemic. Here, we addressed this unmet clinical need and explored the anti-obesity potential of pharmacotherapeutically targeting hypothalamic GUCY2C. We determined that GUCY2C maps to the arcuate nucleus and that endocrine stimulation of GUCY2C induces expression of c-Fos and POMC in the hypothalamus, defining the topographic and mechanistic basis underlying GUCY2C-induced satiety behavior. However, diet-induced obesity severed this satiety circuit by inducing intestinal ER stress and driving the loss of uroguanylin, engendering a hormone deficiency. Notably, though, expression of hypothalamic GUCY2C was not only preserved but compensatorily elevated with chronic nutritional excess. Consequently, targeting this hypothalamic GUCY2C with exogenous uroguanylin administration suppressed food intake and weight gain on an obesogenic diet, and drove improvements in indices of obesity, including visceral adiposity, glycemic control, and hepatic steatosis. Thus, hormone replacement therapy reconstituted the GUCY2C endocrine axis pathophysiologically damaged by diet-induced obesity. These results provide the proof of concept for translational targeting of GUCY2C for anti-obesity pharmacotherapy. Furthermore, they suggest the intriguing possibility that overnutrition-driven hormone loss is a novel pathophysiological mechanism underlying the demonstrated association between obesity and colorectal cancer, and that therapeutic hormone replacement would suppress both obesity and tumorigenesis. Moreover, the GUCY2C agonist, linaclotide, received FDA approval in 2012 for the treatment of chronic idiopathic constipation and irritable bowel syndrome with constipation, validating GUCY2C-targeted pharmacotherapy as safe and effective in the clinical setting.
Kim, Gilbert W, "Targeting GUCY2C for anti-obesity pharmacotherapy Uroguanylin Replacement Opposes Obesity by Restoring Anorexigenic GUCY2C Signaling Silenced by Overnutrition-Induced Uroguanylin Deficiency" (2015). ETD Collection for Thomas Jefferson University. AAI10004233.