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Forkhead box i2 (Foxi2) transcription factor regulates systemic energy metabolism via neuropeptide AgRP

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posted on 20.07.2022, 11:43 authored by Yatong Fan, Sufang Sheng, Cunle Guo, Wei Qiao, Yue Jin, Lu Tan, Yong Gao, Lei Zhang, Xi Dong, Jun Zhang, Xiaorong Li, Hui Shen, Yunfei Liao, Yongsheng Chang

The neuropeptide AgRP is essential for maintaining systemic energy homeostasis. In the present study, we show that hypothalamic Foxi2, as a novel regulator of nutrient sensing, controls systemic energy metabolism by specifically stimulating AgRP expression. Foxi2 was highly expressed in the hypothalamus, and its expression was induced by fasting. Immunofluorescence assays demonstrated that Foxi2 was localized in AgRP neurons. We stereotaxically injected AAV to selectively overexpress Foxi2 in AgRP-IRES-Cre mice and found that Foxi2 overexpression in AgRP neurons specifically increased AgRP expression, thereby increasing food intake and reducing energy expenditure, subsequently leading to obesity and insulin resistance. Mechanistically, Foxi2 stimulated AgRP expression by directly binding to it and activating its transcription. Furthermore, Foxi2 overexpression activated AgRP neuron activity, as revealed by whole-cell patch-clamp experiments. Conversely, global Foxi2 mutant mice became leaner with age and were resistant to high-fat diet (HFD)–induced obesity and metabolic disturbances. Collectively, our data suggest that Foxi2 plays an important role in controlling energy metabolism by regulating AgRP expression.

Funding

This work was supported by the National Natural Science Foundation of China (grants 81825004 and 81730024), the National Key Research and Development Program of China (2018YFA0800601), and the Scientific and Technological Research Project of Xinjiang Production and Construction Corps (grants 2018AB018 and 2021AB028).

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