Zhou Caiping, Gui Weiwei, Zhu Weifen, Zhao Hanxin, Wu Dingting, Wu Fang, Wang Gangliang, Lin Xihua
Department of Endocrinology and Metabolism, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
Department of Clinical Nutrition, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
Commun Biol. 2025 Jul 9;8(1):1026. doi: 10.1038/s42003-025-08458-1.
Metabolic diseases such as diabetes, obesity, and dyslipidemia pose major public health challenges globally. While the insulin-like growth factor 2 (IGF2) gene is known to be involved in various physiological processes, its precise role in lipid metabolism is still not well understood. Here we show that IGF2 plays a crucial role in regulating lipid metabolism in adipose tissues and is linked to metabolic syndrome (MetS). Multiple SNP loci in the IGF2 gene were significantly associated with BMI, HbA1c, and diabetes. Insufficient or excessive expression of IGF2 was identified as a risk factor for hyperlipidemia, low HDL-c, and central obesity in MetS. Enhanced IGF2 expression stimulated adipogenesis and lipid accumulation, whereas IGF2 knockdown hindered lipolysis, exacerbating ectopic lipid accumulation and insulin resistance. Activation of the PI3K/Akt pathway through IGF1R in IGF2 excess or INSR in conditions of IGF2 scarcity, along with inhibition of AMPK, implies a common downstream process that favors lipid accumulation and metabolic reprogramming in adipocytes. This research provides valuable insights into the mechanisms underlying IGF2's impact on lipid metabolism and has the potential to guide future therapeutic strategies for metabolic diseases.
糖尿病、肥胖症和血脂异常等代谢性疾病在全球范围内构成了重大的公共卫生挑战。虽然已知胰岛素样生长因子2（IGF2）基因参与多种生理过程，但其在脂质代谢中的精确作用仍未得到充分了解。在此，我们表明IGF2在调节脂肪组织中的脂质代谢方面起着关键作用，并与代谢综合征（MetS）相关。IGF2基因中的多个单核苷酸多态性位点与体重指数（BMI）、糖化血红蛋白（HbA1c）和糖尿病显著相关。IGF2表达不足或过度被确定为代谢综合征中高脂血症、低高密度脂蛋白胆固醇（HDL-c）和中心性肥胖的危险因素。增强的IGF2表达刺激脂肪生成和脂质积累，而敲低IGF2则阻碍脂肪分解，加剧异位脂质积累和胰岛素抵抗。在IGF2过量时通过IGF1R激活磷脂酰肌醇-3-激酶（PI3K）/蛋白激酶B（Akt）途径，或在IGF2缺乏时通过胰岛素受体（INSR）激活该途径，同时抑制腺苷酸活化蛋白激酶（AMPK），这意味着存在一个共同的下游过程，有利于脂肪细胞中的脂质积累和代谢重编程。这项研究为IGF2对脂质代谢影响的潜在机制提供了有价值的见解，并有可能指导未来代谢性疾病的治疗策略。
