Ciliary ARL13B prevents obesity in mice

Cilia are near ubiquitous cellular appendages critical for cell-to-cell communication and involved in diverse developmental and homeostatic processes. ARL13B is a regulatory GTPase enriched in cilia. We engineered an Arl13b mouse allele, Arl13bV358A, which retains ARL13B biochemical activities but renders ARL13B undetectable in cilia. Surprisingly, these mice are hyperphagic and become obese and insulin resistant. In addition to its GTPase function, ARL13B acts as a guanine nucleotide exchange factor (GEF) for ARL3. To test whether ARL13Bs GEF activity is required to regulate body weight, we analyzed the body weight of mice expressing an ARL13B variant lacking ARL3 GEF activity (Arl13bR79Q). We found no difference in body weight, indicating ARL13B is unlikely to regulate weight via its ARL3 GEF activity. Ciliary ARL13B could control energy homeostasis through a role in development or in adult mice. We induced wildtype ARL13B expression, which localizes to cilia, in 4-week-old Arl13bV358A/V358A mice and found the obesity phenotype and associated metabolic impairments were rescued, consistent with ARL13B regulating homeostatic signaling within cilia in adult mice. These results show that ciliary ARL13B functions to control body weight. Our ability to genetically control the subcellular localization of ARL13B by removing and introducing it into cilia enables us to define the cilia-specific role of ARL13B and provides key information for understanding how cilia act as a signaling hub critical for energy homeostasis. Author SummaryPrimary cilia are essential for energy homeostasis, and their disruption leads to syndromic obesity. However, the mechanisms by which ciliary components regulate energy balance remain unclear. Here, we identify a key role for the ciliary GTPase ARL13B in energy homeostasis. Using a mouse model expressing the ARL13BV358A variant, which is excluded from cilia but retains biochemical activity, we show that ciliary ARL13B regulates body weight, as Arl13bV358A/V358A mice become obese and hyperphagic. Remarkably, restoring ciliary ARL13B in these mice rescues obesity, demonstrating its crucial role in acute ciliary signaling for energy balance. This study directly links ciliary ARL13B with energy balance in adult animals.