University of California, San Francisco

New Molecular and Cellular Aspects of the Regulation of Energy Homeostasis by the Leptin-Melanocortin Pathway

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Obesity significantly increases the risk of mortality and metabolic comorbidities (type 2 diabetes, atherosclerosis, non-alcoholic fatty liver disease, etc.). This multifactorial disease results from a combination of environmental and genetic factors. Human genetics studies have identified a neural system crucial for the regulation of energy homeostasis, the leptin-melanocortin hypothalamic system. A key player in this system is the melanocortin 4 receptor (MC4R), essential for the regulation of food intake. MC4R is expressed in the neurons of the paraventricular nucleus of the hypothalamus (PVN), one of the regulatory centers of energy homeostasis.
In this project, we rely on recent discoveries to elucidate the molecular and cellular mechanisms through which MC4R neurons control energy homeostasis. Specifically, we will determine whether the localization of MC4R at its functional site, an organelle called the primary cilium, is dependent on: 1) the concentration of its ligands and 2) the concentration of potential effectors of its signaling pathway within the primary cilium in these PVN neurons.
This project will provide a better understanding of the cellular and molecular basis of body weight control by the leptin-melanocortin system, thereby opening new therapeutic avenues for obesity.