Hypothalamic neuronal histamine signaling in the estrogen deficiency‐induced obesity

Abstract

Menopause is one of the triggers that induce a variety of agerelated diseases such as osteoporosis, atherosclerosis, and obesity (Genazzani and Gambacciani 2001). The incidence of obesity is higher in post-menopausal women than in agematched pre-menopausal women; this increase is thought to be associated with the decline of estrogen levels after menopause. In fact, estrogen replacement therapy is an effective treatment to reduce body weight and fat accumulation in post-menopausal women (Svendsen et al. 1995). In rats, estrogen treatment reduces energy intake (Donohoe and Stevens 1983), and it has been demonstrated that ovariectomy (OVX) induces an increase in body weight, which can be reversed with estrogen replacement treatment (Wade et al. 1985). These studies suggest that estrogen plays an important role in the post-menopausal development of obesity.The paraventricular nucleus (PVN) within the hypothalamus is a major center of corticotropin-releasing hormone (CRH) neurons (Sawchenko and Swanson 1985). Previous research has demonstrated that estrogen receptors (ERs) and CRH neurons are co-localized within the PVN (Dagnault and Abbreviations used: a-hCRH, a-helical CRH; CRH, corticotropinreleasing hormone; DMSO, dimethylsulfoxide; DPN, 2,3-bis(4-hydroxyphenyl)-propionitrile; ER, estrogen receptor; FMH, a-fluoromethyl histidine; H1KO, histamine receptors knockout; H1-R, histamine receptors; HDC, histidine decarboxylase; i3vt, intra-3rd ventricular; OVX, ovariectomy; PBS, phosphate-buffered saline; PPT, 4,4¢,4¢¢-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol; PVN, paraventricular nucleus; SCN, suprachiasmatic nucleus; t-MH, tele-methylhistamine; TMN, tuberomammillary nucleus. AbstractMenopause is one of the triggers that induce obesity. Estradiol (E2), corticotropin-releasing hormone (CRH), and hypothalamic neuronal histamine are anorexigenic substances within the hypothalamus. This study examined the interactions among E2, CRH, and histamine during the regulation of feeding behavior and obesity in rodents. Food intake was measured in rats after the treatment of E2, a-fluoromethyl histidine, a specific suicide inhibitor of histidine decarboxylase that depletes hypothalamic neuronal histamine, or CRH antagonist. We measured food intake and body weight in wild-type mice or mice with targeted disruption of the histamine receptors (H1-R) knockout (H1KO mice). Furthermore, we investigated CRH content and histamine turnover in the hypothalamus after the E2 treatment or ovariectomy (OVX). We used immunohistochemical staining for estrogen receptors (ERs) in the histamine neurons. The E2-induced suppression of feeding was partially attenuated in rats pre-treated with a-fluoromethyl histidine or CRH antagonist and in H1KO mice. E2 treatment increased CRH content and histamine turnover in the hypothalamus. OVX increased food intake and body weight, and decreased CRH content and histamine turnover in the hypothalamus. In addition, E2 replacement reversed the OVX-induced changes in food intake and body weight in wild-type mic...

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