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

Departments of Experimental Pharmacology and Obstetrics and Gynecology (A.N., C.D.C., C.N.), University of Naples Federico II, 80131 Naples, Italy

Address all correspondence and requests for reprints to: Prof. Rosaria Meli, Department of Experimental Pharmacology, via D. Montesano 49, 80131 Naples, Italy. E-mail: meli{at}unina.it.

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 17ß-estradiol (OVX+E₂) 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 E₂ and RAL treatment at 7 wk (P < 0.05) and 22 wk (P < 0.001). Moreover, E₂ 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 E₂ or RAL treatment. We provide evidence that central and peripheral Ob-Rb expression is related to modification of estrogen levels.

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