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Role of ciliary dysfunction in a new model of obesity and non-alcoholic steatohepatitis: the foz/fozmice

Introduction

Foz/foz mice are deficient for Alms1, a ubiquitous protein essential for proper primary cilium function. They are prone to insulin resistance, obesity and diabetes, a phenotype accelerated by high-fat diet (HFD) feeding. Their unique metabolic phenotype has been linked to hyperphagia resulting from abnormal ciliary function in the central nervous system [1]. The aim of our study is to verify the dependence of the phenotype on over-feeding and to explore the role of Alms1 deficiency in intestinal energy absorption.

Materials and methods

Male foz/foz (Alms1-/-) and wild-type (WT) littermates were fed a HFD for 4 weeks to evaluate their food intake, metabolic parameters (glucose tolerance, steatosis, adiposity) and tissue inflammation. We next performed a pair-feeding experiment in which foz/foz mice had access to the exact same amount of HFD consumed by WT the day before. Lipid absorption was evaluated by oral fat tolerance test and total lipid content in the feces.

Results

As expected, foz/foz mice ate more (18.2 vs 14.1 kcal/d, p<0.001), became more obese (42.5 vs 26.8g, p=0.01) and glucose intolerant than WT mice fed a HFD (p=0.008). Unlike WT mice, they also developed steatosis, adipose tissue and liver inflammation. In the pair-feeding experiment, foz/foz mice and WT mice were fed iso-calorically. However, foz/foz mice gained more weight (+54.3% vs +29.7%, p<0.001), were more glucose intolerant and presented higher adipose inflammation than WT mice. To explain the metabolic alterations, we hypothesized that Alms1 deficiency in intestine could contribute to increased nutrient absorption. We found that fecal lipid content was lower in foz/foz than in WT mice matched for HFD intake (31.3 vs 45.9 mg/24h feces, p=0.01). Moreover, upon oral fat load, foz/foz mice had higher plasma triglyceride levels than WT mice (79.1 vs 15.7 mg/dL, p< 0.05).

Conclusion

These results suggest that, beside causing hyperphagia, Alms1 deficiency increased dietary energy extraction, that could participate to the metabolic phenotype leading to insulin resistance and obesity. The understanding of the mechanisms at play may uncover new potential therapeutic targets.

References

  1. 1.

    Heydet D, et al: A truncating mutation of Alms1 reduces the number of hypothalamic neuronal cilia in obese mice. Devl Neurobiol. 2012, 73: 1-13.

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Correspondence to Laurence Poekes.

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This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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Poekes, L., Legry, V., Farrell, G. et al. Role of ciliary dysfunction in a new model of obesity and non-alcoholic steatohepatitis: the foz/fozmice. Arch Public Health 72, O7 (2014). https://doi.org/10.1186/2049-3258-72-S1-O7

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Keywords

  • Primary Cilium
  • Metabolic Phenotype
  • Increase Nutrient Absorption
  • Fecal Lipid
  • Cilium Function