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

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.

Effect of estrogen on expression of prohibitin in white adipose tissue and liver of diet-induced obese rats

“…Thus, we hypothesized that the various expression patterns of those proteins are the result of differential hormonal regulation, specifically estrogen. More recently, we found that exogenous estrogen significantly reduced body weight in HFD-fed male and female rats [28].…”

Lactobionic acid reduces body weight gain in diet-induced obese rats by targeted inhibition of galectin-1

“…3T3-L1 and HIB1B preadipocytes were cultured and differentiated using previously described protocols [16]. For LBA treatment, both adipocytes were separately treated with LBA (250 or 500 mM in PBS or vehicle) in maturation medium for 4 days before further analysis.…”

“…3T3-LI and HIB1B adipocytes were matured for 4 days and used for Oil Red O staining as well as quantification of TG according to previously described methods [16].…”

“…Lysates from both white adipose tissue (WAT) and brown adipose tissue (BAT) were prepared in RIPA buffer (Sigma), followed by immunoblotting using monoclonal/polyclonal antibodies against GAL1, PPARg, SREBP-1c, C/EBPa, COX IV, HSL, ATP5B, UCP1, and b-actin (Santa Cruz Biotechnology Inc., Santa Cruz, CA, USA) according to common laboratory protocols [16].…”

Membrane lipid rafts and estrogenic signalling: a functional role in the modulation of cell homeostasis

“…The relationships between ERa and caveolin, even if partially known and studied only in some cell types, appear to be important for E2 action. Moreover, E2 play a role in the regulation of caveolin-1 expression, increasing its level in adipose tissues and skeletal muscle, and decreasing its expression in the liver [17]. It has been demonstrated that ERa localized to caveolae is coupled to specific G-proteins, endothelial nitric oxide synthase (eNOS), Src-kinase, phosphoinositide 3-kinase (PI3K)/ AKT, JAK/STAT, and extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinases (MAPK) [6,18,19].…”