Ciliary ARL13B prevents obesity in mice

Abstract

Cilia are near ubiquitous small, cellular appendages critical for cell-to-cell communication. As such, they are involved in diverse developmental and homeostatic processes, including energy homeostasis. ARL13B is a regulatory GTPase highly enriched in cilia. Mice expressing an engineered ARL13B variant, ARL13B ^V358A which retains normal biochemical activity, display no detectable ciliary ARL13B. Surprisingly, these mice become obese. Here, we measured body weight, food intake, and blood glucose levels to reveal these mice display hyperphagia and metabolic defects. We showed that ARL13B normally localizes to cilia of neurons in specific brain regions and pancreatic cells but is excluded from these cilia in the Arl13b ^V358A/V358A model. 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 ARL13B ^R79Q , a variant that lacks ARL13B GEF activity for ARL3. We found no difference in body weight. Taken together, our results show that ARL13B functions within cilia to control body weight and that this function does not depend on its role as a GEF for ARL3. Controlling the subcellular localization of ARL13B in the engineered mouse model, ARL13B ^V358A , enables us to define the cilia-specific role of ARL13B in regulating energy homeostasis.

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.

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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.

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Ciliary ARL13B prevents obesity in mice

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