Obesity has become a major public health concern as it increases the risk for type 2 diabetes, heart disease and certain forms of cancer. Obesity, particularly in its most severe form, has an extremely strong genetic basis, but most of the genes in which mutations predispose to this condition, as well as the molecular and cellular pathway they outline, are unknown. This proposal bridges the expertise of two investigators to illuminate how dysfunction of a specific sub-cellular compartment of neurons predisposes humans to obesity
Our studies address how neuronal primary cilia control obesity. The primary cilium is a cell surface projection that receives and transduces select extracellular signals. In humans, mutations that disrupt the function of primary cilia cause ciliopathies, pleiotropic diseases of which obesity is a cardinal manifestation. How ciliary dysfunction leads to obesity is unclear, but is thought to involve disruption of neuronal signaling pathways that regulate energy homeostasis. The Melanocortin-4 receptor (MC4R) is a central mediator of the regulation of long-term energy homeostasis and mutations in MC4R are the most common monogenic cause of severe human obesity. We have found that MC4R and the recently described MC4R associated protein MRAP2 localize to the primary cilia and that disruption of primary cilia abolishes the anorexigenic function of MC4R in mice. These results suggest three important hypotheses: 1) MC4R functions at the cilium. 2) The endogenous MC4R ligands, αMSH and AGRP, are sensed by the second order MC4R-expressing neurons through their primary cilia, making this non- synaptic mechanism of modulating neuronal activity an important component of long-term energy homeostasis. 3) Disruption of MC4R signaling is the cause of obesity in ciliopathies. We will test these hypotheses by identifying how MC4R and MRAP2 are targeted to cilia, how ciliopathy-associated proteins participate in MC4R function, and how these proteins signal through cilia to indicate satiety. This work will define molecular and cellular steps of neuronal regulation of energy homeostasis and answer the long-standing question of how ciliary dysfunction causes obesity in humans.