Obesity and its major co-morbidity, type 2 diabetes, have been an alarming epidemic prevalence without an effective treatment available. Sterol regulatory element-binding proteins (SREBPs) are major transcription factors regulating the expression of genes involved in biosynthesis of cholesterol, fatty acid and triglyceride. Therefore, inhibition of SREBP pathway may be a useful strategy to treat obesity with type 2 diabetes. Here, we identify a small molecule, Ganoderic Acid A (GAA), inhibits the SREBP expression and decreases the cellular levels of cholesterol and fatty acid in vitro. GAA also ameliorates body weight gain and fat accumulation in liver or adipose tissues, and improves serum lipid levels and insulin sensitivity in high fat diet (HFD)-induced obese mice. Consistently, GAA regulates SREBPs target genes and metabolism associated genes in liver or adipose tissues, which may directly contribute to the lower lipid level and improvement of insulin resistance. Taken together, GAA could be a potential leading compound for development of drugs for the prevention of obesity and insulin resistance.

肥胖及其主要的合并症，即2型糖尿病，在没有有效的治疗方法的情况下，已成为令人震惊的流​​行病。甾醇调节元件结合蛋白（SREBPs）是主要的转录因子，可调节参与胆固醇，脂肪酸和甘油三酸酯生物合成的基因的表达。因此，抑制SREBP途径可能是治疗2型糖尿病肥胖的有用策略。在这里，我们确定了一个小分子灵芝酸A（GAA），它可以抑制SREBP表达并降低体外胆固醇和脂肪酸的细胞水平。GAA还可以改善体重增加和肝脏或脂肪组织中的脂肪积累，并改善高脂饮食（HFD）诱导的肥胖小鼠的血清脂质水平和胰岛素敏感性。一致地，GAA调节肝脏或脂肪组织中的SREBPs目标基因和代谢相关基因，这可能直接有助于降低脂质水平和改善胰岛素抵抗。两者合计，GAA可能是开发用于预防肥胖和胰岛素抵抗的药物的潜在领先化合物。