Year: 2023
Type: preprint
Abstract: 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 Arl13b mouse allele, Arl13b V358A , that disrupts ARL13B from localizing to primary cilia. Homozygous Arl13b V358A/V358A mice become hyperphagic, obese, and insulin resistant. Restoring wildtype ARL13B to cilia in 4-week-old Arl13b V358A/V358A 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.
Authors: Tiffany T. Terry, Eduardo D. Gigante, Coralie M. Alexandre, Kathryn M. Brewer, Xinyu Yue, Nicolas F. Berbari, Christian Vaisse, Tamara Caspary
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Awards: Genetic Dissection of Signaling and Cilia, G2109639526, G2450276990, G266737383, G3396464780, G5165986770, G548001603, UCSF Nutrition Obesity Research Center, G75694742, The Melanocortin-4 Receptor in Human Obesity, G9000044415, G9000101947, G9000150952, G9000188170, Genetic Dissection of Signaling and Cilia, Obesity in ciliopathies: How neuronal primary cilia control appetite, The Critical Role of Ciliary ARL13B in Controlling Energy Homeostasis
OpenAlex ID: W4385797977