Cilial dysfunction and pathogenesis of obesity

University Of Alabama At Birmingham, Birmingham AL

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): The primary cilium has recently undergone a renaissance, coming from obscurity as a vestigial organelle to that of central importance in a number of developmental processes and diseases. It is now known that primary cilia have essential sensory and signaling roles during development that are needed for specification of the left-right body axis and for neural tube and limb patterning, and that cilia dysfunction is a causative factor in numerous diseases such as retinitis pigmentosa, polycystic kidney disease, and severe pancreatic and liver abnormalities. In contrast to the analysis of embryonic cilia, elucidating cilial functions in the adult or in specific tissues has been complicated by the fact that all germline null mutations that totally abolish ciliogenesis result in early embryonic lethality. To address this issue, we utilized conditional alleles of two genes required for cilia formation and induced cilia loss in the adult mouse after completion of development. Using this approach we have uncovered another important role for the primary cilium in maintaining normal energy homeostasis. The preliminary data show that loss of cilia in the adult mouse and more specifically in the hypothalamus results in rapid onset obesity due to hyperphagia. The phenotype is additionally associated with the development of hyperleptinemia and hyperinsulinemia. Thus, we propose a role for the primary cilium as a sensory organelle involved in reception, transmission, or regulation of satiety signaling in the CMS. The major objective of this application is to elucidate the connection between the primary cilium and a pathway(s) regulating energy homeostasis. As such, the goals of the proposed research are: (1) to characterize this obesity model with regards to effects on body composition, neuroendocrine expression profiles, circulating humoral factors, and on food intake and activity levels;(2) to determine where in the body cilia function is needed to maintain normal energy balance;(3) to analyze whether cilia are required for reception and/or transmission of specific anorexigenic signals;and (4) to determine where the primary cilium may function in essential pathways regulating energy balance. Overall, completion of the research goals described in the application will provide important and novel insights into how energy balance is maintained. Furthermore, the characterization of this novel obese mouse model will provide new opportunities to identify therapeutic targets directed at attenuating one of the most pervasive and costly health issue that the United States will need to address in the very near future.