Ciliary Mchr 1 Signaling in Feeding Behavior and Obesity

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PROJECT SUMMARY Obesity is a major cause of premature mortality due to its associated co-morbidities such as diabetes, heart disease and stroke. Two-thirds of adults in the United States are overweight, adding immense costs to the healthcare system. Although once considered to be a social issue of overindulgence, modern science has revealed a profound effect of genetics on body weight. Rare monogenetic forms of obesity in humans and animal models have revealed that the regulation of energy balance is complex, involving numerous intertwined signaling pathways. Both Bardet-Biedl syndrome (BBS) and Alström syndrome (ALMS) are genetic disorders that present with increases in eating and obesity. These rare syndromes are examples of ciliopathies, a class of genetic disorders that have cilia dysfunction as their etiological basis. Primary cilia are small, solitary, microtubule based cellular appendages that were long thought to be vestigial organelles. Thus, it was surprising that their dysfunction was associated with obesity in both humans and animal models. Disruption of cilia specifically within the brain of mice results in hyperphagia associated obesity. Recent work has implicated cilia or their associated proteins in coordinating leptin signaling, although this remains controversial and unclear. It has also recently been shown that several G-protein coupled receptors preferentially localize to the cilia of neurons. How these ciliary receptors and signaling pathways may impact feeding behavior and obesity also remains unclear. The goal of this project is to determine if altered signaling through a specific ciliary receptor that is known to have a role in feeding behavior, melanin concentrating hormone receptor 1, contributes to the obesity phenotype. A strong understanding of the connection between cilia and obesity could open new therapeutic approaches to address one of the most clinically important issues impacting the health of the American populace.