Investigation of the preadipocyte primary cilia signalosome

Utah State Higher Education System--University Of Utah, Salt Lake City UT

Investigators

Abstract

Consequences associated with obesity can be miƟgated by shiŌing adipose Ɵssue expansion from hypertrophic to hyperplasƟc expansion; the former increases overall size of exisƟng adipocytes and correlates with increased inflammaƟon, insulin insensiƟvity, and fibrosis, while the laƩer differenƟates new adipocytes from resident preadipocytes through adipogenesis. Remedying the expansion of our adipose Ɵssue to favor healthier hyperplasƟc expansion is of the upmost importance to combat the obesity epidemic, as western diets high in fat and carbohydrates have shown to shiŌ the balance of fat expansion to the more consequenƟal hypertrophic expansion. All preadipocytes have primary cilia, which are criƟcal for their differenƟaƟon into mature adipocytes. These organelles are typically rich in signaling components, specifically G protein‐coupled receptors (GPCRs), though liƩle is known about ciliary protein composiƟon in preadipocytes. Thus far only one receptor has been discovered in the cilium of preadipocytes, and its acƟvaƟon increases ciliary cAMP and subsequent adipogenesis. Increases in cellular cAMP are necessary for ex vivo adipogenesis, but it is unknown what role compartmentalized ciliary cAMP has in adipogenesis, though ciliary cAMP in other cell types has been shown to have differenƟal funcƟons than whole cell cAMP. I hypothesize that cAMP in the cilium is necessary and sufficient to induce adipogenesis in preadipocytes, and that a suite of ciliary GPCRs acts to influence this process in a cilia‐dependent manner. My first aim will define the role of ciliary cAMP in adipogenesis, using chemogeneƟc and optogeneƟc tools to control the generaƟon or depleƟon of ciliary cAMP during adipogenesis to define its sufficiency and necessity in preadipocyte differenƟaƟon. My second aim will idenƟfy GPCRs that localize to preadipocyte cilia and invesƟgate their physiological roles in adipose expansion and prevalence in healthy versus unhealthy adipose Ɵssues. This work will be conducted at the University of Utah under the guidance of my sponsor, Dr. Keren Hilgendorf, and co‐ sponsor, Dr. Jeremy Reiter, both of whom specialize in ciliary signaling. My thesis commiƩee is composed of interdisciplinary researchers with a range of specialƟes all pertaining to different porƟons of this proposal, such adipose Ɵssue, signaling metabolites, GPCRs, and primary cilia signaling. Together, these mentors will provide expert guidance in all facets of this project. In addiƟon, this project will be supported by the work of mulƟple university core faciliƟes, including those that offer services in cellular microscopy, flow cytometry, mass spectrometry, and metabolomics. These faciliƟes offer excellent support and training services to facilitate my growth as a researcher. The training plan presented was developed to ulƟmately prepare me for a future in academia as an independent researcher in the field of ciliary signaling and cell fate determinaƟon. In addiƟon to the technical skills this project will provide, it will also further my development as a mentor and teacher through university‐supported training programs and laboratory opportuniƟes. Dr. Hilgendorf has fostered a supporƟve research environment that encourages scienƟfic exploraƟon and my development as a researcher. She has demonstrated dedicaƟon to my training and catered her mentorship to reflect my career goals.