Ciliary ARL13B is essential for body weight regulation in mice

<jats:p>&lt;p dir="ltr"&gt;Primary cilia are sensory cellular appendages that regulate diverse developmental and homeostatic processes, including energy homeostasis. In animal models and humans, their dysfunction can lead to hyperphagia and obesity. ARL13B is a regulatory GTPase enriched in cilia. We engineered an &lt;i&gt;Arl13b&lt;/i&gt; mouse allele, &lt;i&gt;Arl13b&lt;/i&gt;&lt;sup&gt;&lt;em&gt;V358A&lt;/em&gt;&lt;/sup&gt;, that disrupts ARL13B from localizing to primary cilia. Homozygous &lt;i&gt;Arl13b&lt;/i&gt;&lt;sup&gt;&lt;em&gt;V358A/V358A&lt;/em&gt;&lt;/sup&gt; mice become hyperphagic, obese, and insulin resistant. Restoring wildtype ARL13B to cilia in 4-week-old &lt;i&gt;Arl13b&lt;/i&gt;&lt;sup&gt;&lt;em&gt;V358A/V358A&lt;/em&gt;&lt;/sup&gt;&lt;sup&gt; &lt;/sup&gt;mice fully rescued the obesity and metabolic dysfunction. Additionally, the selective exclusion of ARL13B from cilia in the nervous system caused obesity. Together, these findings establish that ciliary ARL13B function within the nervous system is necessary for body weight regulation. Our ability to genetically uncouple the ciliary and non-ciliary functions of ARL13B in a cell-type-specific manner enables us to define its cilia-specific role and offers new insights into the molecular mechanisms underlying primary cilia control of energy homeostasis.&lt;/p&gt;</jats:p>