Two Distinct GUCY2C Neuronal Pathways in the Hypothalamus and Midbrain

Obesity is a global pandemic with accelerating trends in morbidity, mortality, and medical expenditures. Treatments have been limited in efficacy, or burdened with safety concerns. In the context of this unmet clinical need for more effective and safe anti-obesity therapies, the recent discovery of a new gut-brain endocrine axis regulating appetite and metabolism offers a unique opportunity to advance treatment and prevention for this disease. The transmembrane receptor guanylate cyclase C (GUCY2C) recently was characterized in dopaminergic neurons of the ventral midbrain, and identified in the hypothalamus. The GUCY2C ligand uroguanylin, made in the intestine, induces satiety, and impaired GUCY2C signaling is associated with hyperphagia and obesity. Moreover, obesity is associated with reduced uroguanylin expression, suggesting a pathophysiological positive feedback loop whereby chronic overnutrition disrupts satiety signaling, leading to further increases in food intake. The following work describes advances in the understanding of the uroguanylin-GUCY2C gut-brain neuroendocrine axis, both in normal physiology as well as in the context of obesity. In chapter 2, we reveal that chronic overnutrition is associated with endoplasmic reticulum (ER) stress in the intestine, and that this ER stress underlies the loss of intestinal uroguanylin expression in obesity. Moreover, we reveal that intestinal uroguanylin loss is reversible if ER stress is alleviated, either pharmacologically or via caloric restriction. Finally, we demonstrate that GUCY2C is present in multiple hypothalamic nuclei, is upregulated and hyper-responsive in obesity, and can be targeted by GUCY2C ligand to reduce weight gain in mice exposed to high fat diet. Together, these findings demonstrate that GUCY2C may serve as a valuable therapeutic target in the treatment of obesity, particularly in patients with reduced circulating uroguanylin. Chapter 3 further investigates the normal physiology of GUCY2C in the central nervous system, mapping GUCY2C expression throughout the brain. This work demonstrates that two discrete pools of neurons in the brain are responsible for widespread GUCY2C protein expression throughout the brain, including the striatum, amygdala, and septal nuclei, as well as numerous hypothalamic nuclei. These two neuronal populations are comprised of GUCY2C+, TH+ dopaminergic neurons of the ventral midbrain, and GUCY2C+, TH–, neurons in the ventral premammillary nucleus (PMV) of the hypothalamus, some of which are also LepR+. Moreover, GUCY2C protein is expressed in distal neuronal projections and presynaptic terminals, suggesting a potential role for GUCY2C in modulation of neurotransmission. Finally, this work reveals that GUCY2C is also expressed in the human hypothalamus and midbrain, with patterns of expression similar to mice, suggesting that GUCY2C neurobiology is conserved across species. Together, these studies provide insight into the uroguanylin-GUCY2C gut-brain neuroendocrine axis, and suggest a potential role for GUCY2C in integrating acute intestinal signaling in both homeostatic and hedonic feeding regulation