Abstract
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.
Highlights
Interest in factors that regulate adipose tissue function has increased due to concerns over excess fat consumption in Western diets, which may mainly contribute to obesity and other metabolic diseases [1]
We found that numerous metabolic proteins in white adipose tissue (WAT), brown adipose tissue (BAT), and other metabolic tissues are regulated in a sexdependent manner [28,29,30,31,32]
As abdominal WAT and BAT showed the most interesting fat pad weight patterns, we studied the histological characteristics of these tissues by immunoflourescence using CAV1-FITC followed by quantification of adipocyte area and lipid area in abdominal WAT and BAT, respectively
Summary
Interest in factors that regulate adipose tissue function has increased due to concerns over excess fat consumption in Western diets, which may mainly contribute to obesity and other metabolic diseases [1]. Previous studies using Cav1-null mice have demonstrated reduced whole body fat mass and adiponectin levels, elevated triglycerides (TG) and free fatty acids (FFA), as well as blunted responses to b3-adrenergic receptor stimulation [2,4]. The lean phenotype of Cav1-null mice is primarily related to the inability of adipose tissue to store lipids, which remain in the circulation and cause massive elevation of free fatty acids and hypertriglycerides [11,12]. Despite this recent progress, the precise roles of CAV1 remain unclear, especially in the development of obesity. It is not well established whether or not CAV1 exerts its effects in a sex-dependent manner as well as in response to sex steroid hormones
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