Ciliary ARL13B is essential for body weight regulation in adult 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

Reviewed by

Read the full article See related articles

Listed in

Log in to save this article

Abstract

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, Arl13b V358A , 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 ARL13B’s GEF activity is required to regulate body weight, we analyzed the body weight of mice expressing an ARL13B variant lacking ARL3 GEF activity ( Arl13b R79Q ). 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 Arl13b V358A/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.

Article activity feed

  1. Version published to 10.1101/2023.08.02.551695v2 on bioRxiv
  2. 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.

  3. Version published to 10.1101/2023.08.02.551695v1 on bioRxiv