Obesity has emerged as a principal cause of mortality worldwide, reflecting comorbidities including
cancer risk, particularly in colorectum. Although this relationship is established epidemiologically, molecular mechanisms linking
colorectal cancer and
obesity continue to be refined.
Guanylyl cyclase C (GUCY2C), a membrane-bound
guanylyl cyclase expressed in intestinal epithelial cells, binds the paracrine
hormones guanylin and
uroguanylin, inducing cGMP signaling in colorectum and small intestine, respectively.
Guanylin is the most commonly lost gene product in sporadic
colorectal cancer, and its universal loss early in transformation silences GUCY2C, a
tumor suppressor, disrupting epithelial homeostasis underlying
tumorigenesis. In small intestine, eating induces endocrine secretion of
uroguanylin, the afferent limb of a novel gut-brain axis that activates hypothalamic GUCY2C-cGMP signaling mediating satiety opposing
obesity. Recent studies revealed that diet-induced
obesity suppressed
guanylin and
uroguanylin expression in mice and humans.
Hormone loss reflects reversible calorie-induced endoplasmic reticulum stress and the associated unfolded protein response, rather than the endocrine,
adipokine, or inflammatory milieu of
obesity. Loss of intestinal
uroguanylin secretion silences the hypothalamic GUCY2C endocrine axis, creating a feed-forward loop contributing to
hyperphagia in
obesity. Importantly, calorie-induced
guanylin loss silences the GUCY2C-cGMP paracrine axis underlying
obesity-induced epithelial dysfunction and colorectal
tumorigenesis. Indeed, genetically enforced
guanylin replacement eliminated diet-induced intestinal
tumorigenesis in mice. Taken together, these observations suggest that GUCY2C
hormone axes are at the intersection of
obesity and
colorectal cancer. Moreover, they suggest that
hormone replacement that restores GUCY2C signaling may be a novel therapeutic paradigm to prevent both
hyperphagia and intestinal
tumorigenesis in
obesity.