State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmacy, Guangxi Normal University, Guilin, 541004, Guangxi, P. R. China.
School of Environment and Resources, Guangxi Normal University, Guilin, 541004, Guangxi, P. R. China.
Cell Death Dis. 2022 Feb 24;13(2):175. doi: 10.1038/s41419-022-04636-9.
Obesity is a risk factor for many chronic diseases, and is associated with increased incidence rate of type 2 diabetes, hypertension, dyslipidemia and cardiovascular diseases. Adipocyte differentiation play critical role during development of obesity. Latexin (LXN), a mammalian carboxypeptidase inhibitor, plays important role in the proliferation and differentiation of stem cells, and highlights as a differentiation-associated gene that was significantly downregulated in prostate stem cells and whose expression increases through differentiation. However, it is unclear whether LXN is involved in adipocyte differentiation. The aim of this study was to evaluate the role of LXN on adipocyte differentiation, as well as its effects on high fat-induced obesity and metabolic disorders. In this study, we determine the expression of LXN in adipose tissue of lean and fat mice by Western blot, qPCR and immunohistochemistry. We found that LXN in fat tissues was continuous increased during the development of diet-induced obesity. We fed wild-type (WT) and LXNmice with high-fat diet (HFD) to study the effects of LXN on obesity and related metabolic functions. We found that mice deficient in LXN showed resistance against high-fat diet (HFD)-induced obesity, glucose tolerance, insulin tolerance and hepatic steatosis. In vitro studies indicated that LXN was highly induced during adipocyte differentiation, and positively regulated adipocyte differentiation and adipogenesis in 3T3-L1 cells and primary preadipocytes. Functional analysis revealed that the expression of LXN was positively regulated by mTOR/RXR/PPARɤ signaling pathway during the differentiation of adipocytes, while LXN deletion decreased the protein level of PPARɤ in adipocyte through enhancing FABP4 mediated ubiquitination, which led to impaired adipocyte differentiation and lipogenesis. Collectively, our data provide evidence that LXN is a key positive regulator of adipocyte differentiation, and therapeutics targeting LXN could be effective in preventing obesity and its associated disorders in clinical settings.
肥胖是许多慢性疾病的危险因素，与 2 型糖尿病、高血压、血脂异常和心血管疾病的发病率增加有关。脂肪细胞分化在肥胖的发展中起着关键作用。Latexin (LXN) 是一种哺乳动物羧肽酶抑制剂，在干细胞的增殖和分化中发挥重要作用，并作为一个分化相关基因突出显示，该基因在前列腺干细胞中显著下调，其表达在分化过程中增加。然而，尚不清楚 LXN 是否参与脂肪细胞分化。本研究旨在评估 LXN 在脂肪细胞分化中的作用，以及其对高脂肪诱导肥胖和代谢紊乱的影响。在这项研究中，我们通过 Western blot、qPCR 和免疫组织化学法确定了瘦鼠和胖鼠脂肪组织中 LXN 的表达。我们发现，在饮食诱导肥胖的发展过程中，脂肪组织中的 LXN 持续增加。我们用高脂肪饮食（HFD）喂养野生型（WT）和 LXN 小鼠，以研究 LXN 对肥胖和相关代谢功能的影响。我们发现，缺乏 LXN 的小鼠对高脂肪饮食（HFD）诱导的肥胖、葡萄糖耐量、胰岛素耐量和肝脂肪变性具有抗性。体外研究表明，LXN 在脂肪细胞分化过程中被高度诱导，并在 3T3-L1 细胞和原代前脂肪细胞中正向调节脂肪细胞分化和脂肪生成。功能分析表明，在脂肪细胞分化过程中，LXN 的表达受 mTOR/RXR/PPARγ信号通路的正向调节，而 LXN 缺失通过增强 FABP4 介导的泛素化降低脂肪细胞中 PPARγ的蛋白水平，导致脂肪细胞分化和脂生成受损。总之，我们的数据提供了证据表明，LXN 是脂肪细胞分化的关键正调节剂，针对 LXN 的治疗方法在临床环境中可能有效预防肥胖及其相关疾病。
