Estrogen and Raloxifene Modulate Leptin and Its Receptor in Hypothalamus and Adipose Tissue from Ovariectomized Rats

Abstract

Obesity, from declining estrogen levels after menopause, increases the risk of heart disease, diabetes, and hypertension. Ovariectomy (OVX) in rats is a good model of estrogen insufficiency. The ensuing mild obesity is useful to study how hypoestrogenism alters adiposity. This study examines the hypothesis that in ovariectomized (OVX) rats modification of estrogen levels or treatment with a selective estrogen receptor modulator, raloxifene (RAL), alters leptinemia and modulates leptin receptor (Ob-R) abundance in hypothalamus and white adipose tissue, similar to the modification of adipose status induced by hypoestrogenism. Mid- and long-term studies (7 and 22 wk) were conducted to monitor the change in leptinemia in rats after estrogen loss by OVX and after estrogen replacement by 17beta-estradiol (OVX+E(2)) or RAL treatment (OVX+RAL). Leptin was significantly higher in OVX rats vs. controls, in a time-dependent manner. This effect was reversed by both E(2) and RAL treatment at 7 wk (P < 0.05) and 22 wk (P < 0.001). Moreover, E(2) or RAL treatment reversed the OVX-induced increases in food intake, body weight, and fat mass content; the modifications of serum parameters were examined to evaluate the different lipid profiles. We also evaluated Ob-R expression in hypothalamus and adipose tissue by Western blot analysis. The expression of the long functional isoform (Ob-Rb) increased at 7 wk only in adipose tissue and decreased at 22 wk in OVX rats in both tissues; these effects were reversed by E(2) or RAL treatment. We provide evidence that central and peripheral Ob-Rb expression is related to modification of estrogen levels.

Ovariectomy and estrogen treatment modulate iron metabolism in rat adipose tissue

“…In the present study we have evaluated the binding activity of IRP1 and the expression of ferritin and TfR-1 in adipose tissue from rats having a mild obesity induced by seven-week ovariectomy, a model that mimics estrogen insufficiency [36]. We demonstrate for the first time, to our knowledge, that E 2 modulates the RNA binding activity of IRP1 and affect the ferritin and TfR-1 expression in adipose tissue.…”

“…Evidence suggests that seven-week ovariectomy increases fat mass and leptin serum content in rats, both features of estrogen loss [36]. Leptin might play a role in regulating iron metabolism in overweight status because it shares a number of common biological features with interleukin (IL)-6, a cytokine released in response to inflammation, a condition often associated with obesity [41].…”

“…Seven-week ovariectomy induced in rats a mild obesity that mimics estrogen insufficiency in human [36] and creates a useful in vivo experimental model of hypoestrogenism. All efforts were made to minimize animal suffering, and to reduce the number of animals used.…”

Evidence that oestrogen receptor-α plays an important role in the regulation of glucose homeostasis in mice: insulin sensitivity in the liver

“…While plasma leptin levels were significantly increased in ERKO mice, we also found a decreased hepatic expression of Lepr in ERKO mice. Similarly, ovariectomised rats demonstrated increased plasma leptin levels, as well as a decrease in the expression of leptin receptor in the hypothalamus and adipose tissues, which was normalised by oestradiol treatment [37]. Oestradiol treatment of ovariectomised mice significantly increased hepatic Lepr mRNA level, even after 2 h, suggesting a direct role of estrogens on the regulation of Lepr (Gao H, Dahlman-Wright K, Gustaffson J-Å, unpublished results).…”

Ovariohysterectomy alters body composition and adipose and skeletal muscle gene expression in cats fed a high-protein or moderate-protein diet

“…Estrogen plays a key role in adipose tissue deposition and function (Cooke and Naaz, 2004), and decreases leptin receptor expression in the hypothalamus and adipose tissue (Meli et al, 2004). Estrogen plays a role in spontaneous physical activity, and therefore, its removal can lead to decreased muscle mass and strength (Brown, 2008).…”