Sex-Dependent Expression of Caveolin 1 in Response to Sex Steroid Hormones Is Closely Associated with Development of Obesity in Rats

Caveolin-1 (CAV1) is a conserved group of structural membrane proteins that form special cholesterol and sphingolipid-rich compartments, especially in adipocytes. Recently, it has been reported that CAV1 is an important target protein in sex hormone-dependent regulation of various metabolic pathways, particularly in cancer and diabetes. To clarify distinct roles of CAV1 in sex-dependent obesity development, we investigated the effects of high fat diet (HFD) and sex steroid hormones on CAV1 expression in adipose tissues of male and female rats. Results of animal experiments revealed that estrogen (17-β-estradiol, E2) and androgen (dihydrotestosterone, DHT) had opposite effects on body weight gain as well as on the regulation of CAV1, hormone sensitive lipase (HSL) and uncoupling protein 1 (UCP1) in adipose tissues. Furthermore, sex hormone receptors and aromatase were differentially expressed in a sex-dependent manner in response to E2 and DHT treatments. In vivo data were confirmed using 3T3-L1 and HIB1B cell lines, where Cav1 knock down stimulated lipogenesis but suppressed sex hormone receptor signaling proteins. Most importantly, co-immunoprecipitation enabled the identification of previously unrecognized CAV1-interacting mitochondrial or lipid oxidative pathway proteins in adipose tissues. Taken together, current data showed that CAV1 may play important preventive role in the development of obesity, with more prominent effects in females, and proved to be an important target protein for the hormonal regulation of adipose tissue metabolism by manipulating sex hormone receptors and mitochondrial oxidative pathways. Therefore, we can report, for the first time, the molecular mechanism underlying the effects of sex steroid hormones in the sex-dimorphic regulation of CAV1.

小窝蛋白-1（Caveolin-1, CAV1）是一类保守的结构膜蛋白，可形成富含胆固醇与鞘磷脂的特殊膜结构域，尤其在脂肪细胞中富集。近期有研究表明，CAV1是性激素依赖调控多种代谢通路的重要靶蛋白，在癌症与糖尿病的发生发展中尤为关键。为阐明CAV1在性别依赖性肥胖发生中的差异化作用，本研究探究了高脂饮食（high fat diet, HFD）与性激素对雌雄大鼠脂肪组织中CAV1表达的影响。动物实验结果显示，雌激素（17-β-雌二醇，E2）与雄激素（二氢睾酮，DHT）对体重增加以及脂肪组织中CAV1、激素敏感性脂肪酶（hormone sensitive lipase, HSL）和解偶联蛋白1（uncoupling protein 1, UCP1）的调控作用截然相反。此外，经E2与DHT处理后，性激素受体（sex hormone receptors）与芳香化酶（aromatase）的表达呈现性别依赖性差异。本研究利用3T3-L1与HIB1B细胞系验证了体内实验结果，发现在上述细胞系中敲低Cav1可促进脂肪生成，但抑制性激素受体信号通路蛋白。尤为关键的是，通过免疫共沉淀（co-immunoprecipitation）实验，我们在脂肪组织中鉴定出此前未被报道的、可与CAV1相互作用的线粒体或脂质氧化通路相关蛋白。综上，本研究数据表明，CAV1可能在肥胖发生中发挥重要的预防作用，且在雌性个体中效果更为显著；同时证实，通过调控性激素受体与线粒体氧化通路，CAV1是脂肪组织代谢激素调控的重要靶蛋白。本研究首次阐明了性激素在性别二态性调控CAV1表达中的分子机制。