Ciliary ARL13B prevents obesity in mice.

• Type of Material: Article
• Authors: Tiffany T. Terry, Emory University; Eduardo D. Gigante, Emory University; Coralie M. Alexandre, University of California San Francisco; Kathryn M. Brewer, Indiana University; Staci E. Engle, Indiana University; Xinyu Yue, University of California San Francisco; Nicolas F. Berbari, Indiana University; Christian Vaisse, University of California San Francisco; Tamara Caspary, Emory University
• Language: English
• Date: 2023-08-04
• Publisher: NIH
• Publication Version: Preprint (Prior to Peer Review)
• Copyright Statement: The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1101/2023.08.02.551695
• Title of Journal or Parent Work: bioRxiv
• Grant/Funding Information: This work was supported by the National Institutes of Health: diversity supplement to R35GM122549 (TTT); T32NS096050, diversity supplement to R01NS090029 and F31NS106755 (EDG); Larry L. Hillblom Foundation fellowship (CMA), University Fellowship (KMB); American Heart Association pre-doctoral fellowship (XY), R01DK114008 (NFB); R01DK124769, R01DK106404 and R01DK060540 (CV) and R01NS090029, R35GM122549 and R35GM148416 (TC).
• Keywords: energy homeostasis; cilia; obesity; ARL13B; hyperphagia
• Research Categories: Health Sciences, Public Health; Biology, Cell

Abstract

Cilia are near ubiquitous small, cellular appendages critical for cell-to-cell communication. As such, they are involved in diverse developmental and homeostatic processes, including energy homeostasis. ARL13B is a regulatory GTPase highly enriched in cilia. Mice expressing an engineered ARL13B variant, ARL13BV358A which retains normal biochemical activity, display no detectable ciliary ARL13B. Surprisingly, these mice become obese. Here, we measured body weight, food intake, and blood glucose levels to reveal these mice display hyperphagia and metabolic defects. We showed that ARL13B normally localizes to cilia of neurons in specific brain regions and pancreatic cells but is excluded from these cilia in the Arl13bV358A/V358A model. In addition to its GTPase function, ARL13B acts as a guanine nucleotide exchange factor (GEF) for ARL3. To test whether ARL13B's GEF activity is required to regulate body weight, we analyzed the body weight of mice expressing ARL13BR79Q, a variant that lacks ARL13B GEF activity for ARL3. We found no difference in body weight. Taken together, our results show that ARL13B functions within cilia to control body weight and that this function does not depend on its role as a GEF for ARL3. Controlling the subcellular localization of ARL13B in the engineered mouse model, ARL13BV358A, enables us to define the cilia-specific role of ARL13B in regulating energy homeostasis.