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. ? ? ?
| Tower-Gilchrist, Cristy; Styers, Melanie L; Yoder, Bradley K et al. (2014) Monitoring endosomal trafficking of the g protein-coupled receptor somatostatin receptor 3. Methods Enzymol 534:261-80 |
| Berbari, Nicolas F; Malarkey, Erik B; Yazdi, S M Zaki R et al. (2014) Hippocampal and cortical primary cilia are required for aversive memory in mice. PLoS One 9:e106576 |
| Berbari, Nicolas F; Pasek, Raymond C; Malarkey, Erik B et al. (2013) Leptin resistance is a secondary consequence of the obesity in ciliopathy mutant mice. Proc Natl Acad Sci U S A 110:7796-801 |
| Berezniuk, Iryna; Sironi, Juan J; Wardman, Jonathan et al. (2013) Quantitative peptidomics of Purkinje cell degeneration mice. PLoS One 8:e60981 |
| Sharma, Neeraj; Malarkey, Erik B; Berbari, Nicolas F et al. (2013) Proximal tubule proliferation is insufficient to induce rapid cyst formation after cilia disruption. J Am Soc Nephrol 24:456-64 |
| Berbari, Nicolas F; Sharma, Neeraj; Malarkey, Erik B et al. (2013) Microtubule modifications and stability are altered by cilia perturbation and in cystic kidney disease. Cytoskeleton (Hoboken) 70:24-31 |
| McIntyre, Jeremy C; Davis, Erica E; Joiner, Ariell et al. (2012) Gene therapy rescues cilia defects and restores olfactory function in a mammalian ciliopathy model. Nat Med 18:1423-8 |
| Sharma, Neeraj; Kosan, Zachary A; Stallworth, Jannese E et al. (2011) Soluble levels of cytosolic tubulin regulate ciliary length control. Mol Biol Cell 22:806-16 |
| Berbari, Nicolas F; O'Connor, Amber K; Haycraft, Courtney J et al. (2009) The primary cilium as a complex signaling center. Curr Biol 19:R526-35 |
| Kesterson, Robert A; Berbari, Nicolas F; Pasek, Raymond C et al. (2009) Utilization of conditional alleles to study the role of the primary cilium in obesity. Methods Cell Biol 94:163-79 |
Showing the most recent 10 out of 11 publications
