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In the current 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 stereotactically injected adeno-associated virus 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\u2013induced obesity and metabolic disturbances. Collectively, our data suggest that Foxi2 plays an important role in controlling energy metabolism by regulating AgRP expression.<\/jats:p>","DOI":"10.2337\/db22-0002","type":"journal-article","created":{"date-parts":[[2022,7,20]],"date-time":"2022-07-20T07:48:18Z","timestamp":1658303298000},"page":"2106-2122","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":0,"title":["Forkhead Box i2 Transcription Factor Regulates Systemic Energy Metabolism Via Neuropeptide AgRP"],"prefix":"10.2337","volume":"71","author":[{"given":"Yatong","family":"Fan","sequence":"first","affiliation":[{"name":"1Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Key Laboratory of Cellular Homeostasis and Disease, Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, 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