Deficiency of Irx5 protects mice from obesity and associated metabolic abnormalities

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 (Irx5^KO) 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: Irx5^KO 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 Irx5^KO 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 Irx5^KO 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.