NFIA in adipocytes reciprocally regulates mitochondrial and inflammatory gene program to improve glucose homeostasis [ChIP-seq]

Adipose tissue is central to regulation of systemic energy homeostasis. Adaptive thermogenesis in brown and beige adipocytes, which relies on mitochondrial oxidative phosphorylation, dissipates energy to counteract obesity. On the other hand, chronic inflammation in adipose tissue is linked to insulin resistance, type 2 diabetes and obesity. Here we show that nuclear factor I-A (NFIA), a transcriptional regulator of brown and beige adipocytes, improves systemic glucose homeostasis via up-regulation of oxidative phosphorylation and reciprocal down-regulation of inflammation. Mice with transgenic expression of NFIA in adipocytes exhibited improved glucose tolerance, increased energy expenditure and limited weight gain on high fat diet. NFIA coordinately up-regulate genes involved in oxidative phosphorylation as well as a battery of brown-fat-specific genes through enhancer activation that involves facilitated genomic binding of PPAR?. In contrast, NFIA in adipocytes, but not in macrophages, down-regulate pro-inflammatory cytokine genes to ameliorate adipose tissue inflammation in vivo. NFIA binds to enhancer/promoter region of Ccl2 gene that encodes pro-inflammatory cytokine MCP-1, to down-regulate its transcription. NFIA expression and CCL2 expression was negatively correlated in human adipose tissue. These results indicate that NFIA in adipocytes reciprocally regulate mitochondrial and inflammatory gene program to improve systemic glucose homeostasis. Overall design: ChIP-seq analysis of WT and NFIA-Tg adipocytes

脂肪组织是全身能量稳态调控的核心节点。棕色与米色脂肪细胞的适应性产热依赖线粒体氧化磷酸化过程，通过消耗能量以对抗肥胖发生。与之相对，脂肪组织的慢性炎症与胰岛素抵抗、2型糖尿病及肥胖的发病密切相关。本研究证实，作为棕色与米色脂肪细胞的转录调控因子，核因子I-A（NFIA）可通过上调氧化磷酸化通路、反向抑制炎症反应，改善全身葡萄糖稳态。在高脂饮食喂养条件下，脂肪细胞特异性过表达NFIA的转基因小鼠，表现出葡萄糖耐量提升、能量消耗增加及体重增长受限的表型。NFIA可通过增强子激活机制，协同上调氧化磷酸化相关基因及一系列棕色脂肪特异性基因，该调控过程依赖过氧化物酶体增殖物激活受体γ（PPARγ）的基因组结合效率增强。与之相反，仅在脂肪细胞（而非巨噬细胞）中表达的NFIA，可下调促炎细胞因子基因的表达，在活体动物中缓解脂肪组织炎症。NFIA可结合至编码促炎细胞因子单核细胞趋化蛋白1（MCP-1）的小鼠Ccl2基因的增强子/启动子区域，抑制其转录。在人类脂肪组织中，NFIA的表达水平与CCL2的表达呈显著负相关。上述研究结果表明，脂肪细胞中的NFIA可双向调控线粒体与炎症相关基因程序，进而改善全身葡萄糖稳态。本研究的整体实验设计：对野生型（WT）与NFIA转基因（NFIA-Tg）脂肪细胞开展染色质免疫共沉淀测序（ChIP-seq）分析。