Ciliary ARL13B is essential for body weight regulation in mice

  1. Tiffany T. Terry
  2. Eduardo D. Gigante
  3. Coralie M. Alexandre
  4. Kathryn M. Brewer
  5. Xinyu Yue
  6. Nicolas F. Berbari
  7. Christian Vaisse
  8. Tamara Caspary

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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.

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  1. PREreview

    This Zenodo record is a permanently preserved version of a PREreview. You can view the complete PREreview at https://prereview.org/reviews/8308506.

    This review reflects comments and contributions from Femi Arogundade, Elena Sena, Luciana Gallo & Olakunle Jaiyesimi. Review synthesized by Jonny Coates.

    This study delves into the function of the ARL13B protein (a regulatory GTPase found in cilia) in maintaining energy balance. By examining mice expressing an altered ARL13B variant lacking ciliary localization, the study uncovers that these mice become obese due to issues with metabolism and overeating. It's suggested that ARL13B has a distinct role within cilia that influences body weight and food consumption, separate from its GEF activity for ARL3.Additionally, the study proposes that ARL13B's interaction with INPP5E in cilia plays a role in energy balance, offering insights into cilia-mediated signaling pathways related to energy regulation.

    Major comments:

    • We do not have any major comments for this article

    Minor comments:

    • Write out in full for first use of POMC and MC4R

    • Discuss the differences between male and female body weight (fig 1)

    • Arl13bhnn allele would flow better if written as "Arl13bhnn allele bearing mice". Moreover, when discussing in-text, the term "cilia-excluded ARL13B" would help readers follow better.

    • Repeating the information that the mutation V358A in ARL13B excludes ARL13B from the cilia when mentioned first in the results would aid in readability. 

    • When discussing fig 1 in-text, the descriptions are shifted (i.e. Fig 1B is described as Fig 1C)

    • "The feeding behavior in Arl13bV358A/V358A mice implicates the hypothalamus is involved" should read as "The feeding behavior in Arl13bV358A/V358A mice implies that the hypothalamus is involved".

    • Abbreviations used in the legend of Fig 2 are not used in the figure itself. 

    • Figure 2 would benefit from the addition of appropriate blanks to serve as controls for the antibodies used

    • Additionally, figure 4 would also benefit from a negative control

    Suggestions for future studies

    • Integration of metabolomics analysis for the assessment of metabolic fate will provide molecular mechanisms underlying the phenotypes of interest

    Competing interests

    The author declares that they have no competing interests.

  2. Version published to 10.1101/2023.08.02.551695 on bioRxiv