Paradoxical regulation of IGF2 in promoting lipid metabolism in adipose tissues
Background and aims: Metabolic diseases, including diabetes, obesity, and dyslipidemia, are significant public health concerns worldwide. The insulin-like growth factor 2 (IGF2) gene have been implicated in various physiological processes, but its specific role in lipid metabolism remains unclear. We aim to elucidate the role of IGF2 in regulating lipid metabolism in adipose tissues and its association with metabolic syndrome (MetS).  Methods: The research employed a multidisciplinary approach to investigate the role of IGF2 in lipid metabolism. We investigated the correlation between genetic variations within the IGF2 gene and metabolic parameters. We conduct a cross-sectional human study to evaluate relationships between varying IGF2 serum concentrations and the incidence of MetS. Additionally, manipulation of IGF2 expression levels in mouse and cell models via overexpression and knockdown to assess impacts on lipid metabolism in adipose tissue, specifically lipid accumulation, insulin resistance, and the balance between lipogenesis and lipolysis. Furthermore, the study employs metabolomics techniques to scrutinize the broader metabolic profiles in adipose tissues in response to IGF2 modulation.  Results: 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. We observed that IGF2 was mainly concentrated in adipose tissues and adipocytes. Enhanced IGF2 expression stimulated adipogenesis and lipid accumulation, whereas IGF2 knockdown hindered lipolysis, exacerbating ectopic lipid accumulation and insulin resistance. There is a substantial enlargement of pancreatic tissue and heightened insulin generation in mice deficient in IGF2. 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.  Conclusions: Our study demonstrated that upregulation of IGF2 enhanced adipogenesis and lipogenesis, while knockdown of IGF2 inhibited lipolysis, which resulting in accelerating lipid accumulation through PI3K/Akt-AMPK pathway. Overall design: Global transcriptome profiling was performed by RNA-Seq using epididymal white adipose tissue of Ad-IGF2 (n=2, 2 replicate sequencing)  or Ad-GFP mice (n=3, 2 replicate sequencing) and IGF2-RNAi  (n=2, 2 replicate sequencing) or NC-RNAi mice (n=3, 2 replicate sequencing). RNA was extracted, sequenced, and analyzed by a custom service provided by Novogene using an Illumina NovaSeq 6000. The bioinformatics analysis was conducted utilizing the OmicStudio tools available at the following website: https://www.omicstudio.cn/tool. The differential expression cut-off threshold was determined relied on |log2fold change (log2FC) | > 1 and p-value < 0.05.