NFIA in adipocytes reciprocally regulates mitochondrial and inflammatory gene program to improve glucose homeostasis

• DOI: 10.1073/pnas.2308750120
• Publication Date: 2023-07-24T19:08:10Z
• Authors: Yuta Hiraike; Kaede Saito; Misato Oguchi; Takahito Wada; Gotaro Toda; Shuichi Tsutsumi; Kana Bando; Junji Sagawa; Gaku Nagano; Haruya Ohno; Naoto Kubota; Tetsuya Kubota; Hiroyuki Aburatani; Takashi Kadowaki; Hironori Waki; Shintaro Yanagimoto; Toshimasa Yamauchi
• Keywords: Inflammation; Mice; NFI Transcription Factors; Diabetes Mellitus, Type 2; Adipose Tissue, Brown; Adipocytes; Humans; Animals; Homeostasis; Cytokines; Biological Sciences

Adipose tissue is central to regulation of energy homeostasis. Adaptive thermogenesis, which relies on mitochondrial oxidative phosphorylation (Ox-Phos), dissipates energy to counteract obesity. On the other hand, chronic inflammation in adipose tissue is linked to type 2 diabetes and obesity. Here, we show that nuclear factor I-A (NFIA), a transcriptional regulator of brown and beige adipocytes, improves glucose homeostasis by upregulation of Ox-Phos and reciprocal downregulation of inflammation. Mice with transgenic expression of NFIA in adipocytes exhibited improved glucose tolerance and limited weight gain. NFIA up-regulates Ox-Phos and brown-fat-specific genes by enhancer activation that involves facilitated genomic binding of PPARγ. In contrast, NFIA in adipocytes, but not in macrophages, down-regulates proinflammatory cytokine genes to ameliorate adipose tissue inflammation. NFIA binds to regulatory region of the Ccl2 gene, which encodes proinflammatory cytokine MCP-1 (monocyte chemoattractant protein-1), to down-regulate its transcription. CCL2 expression was negatively correlated with NFIA expression in human adipose tissue. These results reveal the beneficial effect of NFIA on glucose and body weight homeostasis and also highlight previously unappreciated role of NFIA in suppressing adipose tissue inflammation.