Faculty of Medicine, Lomonosov Moscow State University, Russia; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Russia.
Faculty of Medicine, Lomonosov Moscow State University, Russia.
Biochimie. 2021 Jun;185:68-77. doi: 10.1016/j.biochi.2021.02.011. Epub 2021 Mar 4.
Obesity is a key health problem and is associated with a high risk of type 2 diabetes and other metabolic diseases. Increased weight as well as dysregulation of adipocyte homeostasis are the main drivers of obesity. Pathological adipogenesis plays a central role in obesity-related complications such as type 2 diabetes, hypertension and others. Thus, an understanding of the molecular mechanisms involved in physiological and pathogenic adipogenesis can help to develop new strategies to prevent or cure obesity and related diseases. Previously, genetic polymorphisms in the HHEX gene that encodes the homeobox transcription factor HEX (PRH) were found to be associated with type 2 diabetes and high body mass index at birth by GWAS in distinct human populations. To understand whether HHEX has a regulatory function in adipogenesis, we performed RNAi-mediated knockdown of Hhex in preadipocyte cell line 3T3-L1 in vitro, and studied changes in the efficacy of adipogenesis. We found that Hhex knockdown blocks adipogenesis in preadipocytes in a dose-dependent manner and leads to a significant decrease of PPAR-gamma protein - the main regulator of adipogenesis. We also propose that Hhex can play an important role in adipocyte differentiation by affecting the level of the PPAR-gamma protein. Our study supports the claim that Hhex plays an important role in adipocyte differentiation program and can contribute to fat tissue homeostasis.
肥胖是一个主要的健康问题，与 2 型糖尿病和其他代谢性疾病的高风险相关。体重增加以及脂肪细胞稳态失调是肥胖的主要驱动因素。病理性脂肪生成在与肥胖相关的并发症（如 2 型糖尿病、高血压等）中起着核心作用。因此，了解生理和病理性脂肪生成中涉及的分子机制有助于开发预防或治疗肥胖和相关疾病的新策略。先前，通过在不同人群中的全基因组关联研究（GWAS）发现，编码同源盒转录因子 HEX（PRH）的 HHEX 基因中的遗传多态性与 2 型糖尿病和出生时的高体重指数有关。为了了解 HHEX 是否在脂肪生成中具有调节功能，我们在体外对前脂肪细胞系 3T3-L1 中的 Hhex 进行了 RNAi 介导的敲低，并研究了脂肪生成效率的变化。我们发现 Hhex 敲低以剂量依赖性方式阻断前脂肪细胞中的脂肪生成，并导致 PPAR-γ 蛋白的显著减少 - 脂肪生成的主要调节剂。我们还提出 Hhex 可以通过影响 PPAR-γ 蛋白的水平在脂肪细胞分化中发挥重要作用。我们的研究支持 Hhex 在脂肪细胞分化程序中发挥重要作用并有助于脂肪组织稳态的观点。
