This project focuses on understanding a fundamental cellular mechanism underlying the control of feeding and
obesity in humans. The mechanism uses an ancient cellular signaling organelle, the primary cilium, to control
responses to satiety signals generated following feeding. Bardet-Biedl syndrome (BBS) is a rare human syndrome
called a ciliopathy because of mutations in genes encoding components of the primary cilium. Patients with
mutations in BBS genes have inherited mutations in genes linked to a complex called the BBSome, discovered in
our laboratory, that fail to present G-protein coupled receptors critical to controlling feeding after a meal. An
additional pathway organized by the Tubby/TULP3-IFT-A complex is essential for entry of GPCRs and other
signaling molecules into cilia. These trafficking pathways control essential GPCRs that regulate feeding and satiety
in the hypothalamus and defects in cilia cause a loss of feeding control. Our work has found that cilia also control
the generation of fat tissue and the secretion of insulin via the pancreas, adding peripheral control to CNS
regulation. We have found in ciliopathies, monogenic obesity syndromes and now GWAS studies that mutations in
structural or signaling components, or in the receptors themselves can cause strong defects in ciliary signaling. Our
current hypothesis is that the sum of these diverse mutations in ciliary genes underlie some of the complex,
polygenic nature of obesity and metabolic disease. We have previously searched GPCRs known to be linked to
metabolism and found many localized to cilia including three new receptors described here GPR45, GPR63 and
GPR135. These receptors have specific links to obesity and metabolic disease including preliminary mouse data
and human Genome Wide Associations Studies. Finding one or more these receptors linked to metabolic
disease may offer new understanding and new targets for much needed therapeutics for obesity or diabetes.
Creating these first models will also facilitate intercrossing of these mice and other ciliary drivers of obesity to
build a better picture of the complex polygenic drivers of obesity and diabetes. The preliminary studies
proposed here would thus serve as a bridge to later funding focused on the best candidates discovered in
these screening studies here. The specific aims are: Aim 1 Construct mouse KOs of GPR45, GPR63 and
GPR135 and test for obesity phenotypes; Aim 2 Use newly produced antibodies to determine the target tissues for
these orphan GPCRs; and Aim 3 Use tissue proteomics of KO mice to understand the molecular phenotypes of
signaling. By identifying signaling pathways defective in obesity and diabetes, we can identify targets to protect or
restore these tissues and molecular profiles of patients to facilitate patient selection.