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Genetics and Epigenetics

Deficiency of Irx5 protects mice from obesity and associated metabolic abnormalities

Abstract

Objective

Obesity, a leading cause of several metabolic abnormalities, is mainly caused by imbalanced energy homeostasis. IRX3 and IRX5 have been suggested as genetic determinants of obesity in connection with the intronic variants of the FTO gene, the strongest genetic risk factor of polygenic obesity in humans. Although the causal effects of Irx3 and its cooperation with Irx5 in obesity and associated metabolic abnormalities have been demonstrated in vivo, the function of Irx5 in energy homeostasis remains unclear. Here we aim to decipher the actions of Irx5 in the regulation of obesity and metabolic abnormalities.

Methods

We employed a mouse model homozygous for an Irx5-knockout (Irx5KO) allele and determined its metabolic phenotype in the presence or absence of a high-fat diet challenge. To investigate the function of Irx5 in the regulation of energy homeostasis, adipose thermogenesis and hypothalamic leptin response were assessed, and single-cell RNA sequencing (scRNA-seq) in the hypothalamic arcuate-median eminence (ARC-ME) was conducted.

Results

Irx5KO mice were leaner and resistant to diet-induced obesity as well as associated metabolic abnormalities, primarily through loss of adiposity. Assessments of energy expenditure and long-term dietary intake revealed that an increase in basal metabolic rate with adipose thermogenesis and a reduction of food intake with improved hypothalamic leptin response in Irx5KO mice may contribute to the anti-obesity effects. Utilizing scRNA-seq and marker gene analyses, we demonstrated the number of ARC-ME neurons was elevated in Irx5KO mice, suggesting a direct role for Irx5 in hypothalamic feeding control.

Conclusions

Our study demonstrates that Irx5 is a genetic factor determining body mass/composition and obesity and regulates both energy expenditure and intake.

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Fig. 1: Lean and anti-obesity phenotype of Irx5 knockout mice.
Fig. 2: Improved metabolic health in Irx5KO mice.
Fig. 3: Increased energy expenditure with adipose thermogenesis in Irx5KO mice.
Fig. 4: Suppressed energy intake with enhanced hypothalamic leptin response in Irx5KO mice.
Fig. 5: Elevated number of neurons in the hypothalamic ARC-ME of Irx5KO mice.
Fig. 6: Schematic model depicting that Irx5 deficiency protects mice from obesity and associated metabolic abnormalities.

Data availability

The sequencing data have been deposited in the GEO under accession code GSE201736.

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Acknowledgements

The research was supported by the Canadian Institutes of Health Research (PJT-178147) and the Canada Research Chairs program to CCH. JES was supported by a post-doctoral fellowship award from Diabetes Canada. JES was awarded a Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2018R1A6A3A03012237). KHK was supported by the Canadian Institutes of Health Research (PJT-173281) and the National New Investigator Award from the Heart and Stroke Foundation of Canada.

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JES, KHK, and CCH conceived and designed the study. JES, ZD, and KHK performed the experiments. JES, KHK, and CCH wrote the manuscript.

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Correspondence to Kyoung-Han Kim or Chi-Chung Hui.

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Son, J.E., Dou, Z., Kim, KH. et al. Deficiency of Irx5 protects mice from obesity and associated metabolic abnormalities. Int J Obes 46, 2029–2039 (2022). https://doi.org/10.1038/s41366-022-01221-0

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