Adipocyte ILF3 Deficiency Improves Diet-induced Obesity and Metabolic Disorders through PUFA Synthesis

A moderate long-chain polyunsaturated fatty acids (LC-PUFAs) intake may improve obesity and metabolic disorders. However, regulating endogenous LC-PUFAs and their function is unclear. Here, adipocyte ILF3 expression promotes high-fat diet (HFD)–induced obesity and metabolic disorders by inhibiting endogenous omega-3 LC-PUFAs (n-3-LC-PUFA) biosynthesis. In patients with obesity, serum ILF3 levels are elevated and positively correlate with high triglyceride levels. The expression of ILF3 in adipose tissue from patients with obesity and HFD-induced obese mouse models is positively correlated with adipocyte size. Adipose tissue ILF3 expression in patients with obesity and HFD–induced obese mice positively correlates with adipocyte size. Adipocyte ILF3 deficiency significantly increases white adipose tissue browning, promotes brown adipose tissue thermogenesis, and improves HFD–induced obesity and metabolic disorders. ILF3 recruits DNMT1, which reduces FADS2 transcription and inhibits n-3-LC-PUFA biosynthesis. Similarly, sc26196, a FADS2-specific inhibitor, exacerbates obesity and metabolic disorders. Fenofibrate, an anti-triglyceride drug, improves obesity and metabolic disorders by inhibiting ILF3 expression and increasing endogenous n-3-LC-PUFA biosynthesis. Collectively, inhibiting adipocyte ILF3 expression may be an effective alternative treatment for these conditions.