Review The role of hypothalamic estrogen receptors in metabolic regulation Aaron Frank b , Lynda M. Brown a , Deborah J. Clegg b,⇑ a Food and Nutrition Sciences Program, North Carolina Agricultural and Technical State University, Greensboro, NC 27411-0002, USA b Department of Internal Medicine, Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, TX 75390-8854, USA article info Article history: Available online xxxx Keywords: Body weight Energy balance Hypothalamus 17b-Estradiol Estrogen receptor alpha (ERS1) Estrogen receptor beta (ERS2) G protein-coupled estrogen receptor (GPER) Neuropeptides abstract Estrogens regulate key features of metabolism, including food intake, body weight, energy expenditure, insulin sensitivity, leptin sensitivity, and body fat distribution. There are two ‘classical’ estrogen receptors (ERs): estrogen receptor alpha (ERS1) and estrogen receptor beta (ERS2). Human and murine data indicate ERS1 contributes to metabolic regulation more so than ESR2. For example, there are human inac- tivating mutations of ERS1 which recapitulate aspects of the metabolic syndrome in both men and women. Much of our understanding of the metabolic roles of ERS1 was initially uncovered in estrogen receptor a-null mice (ERS1 À/À ); these mice display aspects of the metabolic syndrome, including increased body weight, increased visceral fat deposition and dysregulated glucose intolerance. Recent data further implicate ERS1 in specific tissues and neuronal populations as being critical for regulating food intake, energy expenditure, body fat distribution and adipose tissue function. This review will focus predominantly on the role of hypothalamic ERs and their critical role in regulating all aspects of energy homeostasis and metabolism. Ó 2014 Elsevier Inc. All rights reserved. 1. Introduction The brain is the central integration site for body weight regula- tion. Within the brain, the hypothalamus is a complex structure of nuclei, pathways and neurotransmitter systems that controls food intake and energy expenditure (Zhang et al., 2008; Grill and Kaplan, 2002; Williams et al., 2001; Xu et al., 2011). Early interest in the hypothalamus stemmed from findings that lesioning specific hypothalamic nuclei produced dramatic changes in food intake and energy homeostasis. In 1954, Dr. Stellar suggested the hypothala- mus was the central neural structure involved in the control of food intake (Stellar, 1954). The so-called ‘‘Dual-Center Hypothesis’’ was based on earlier experiments by Hetherington and Ranson where electrolytic lesions were placed in two brain regions of rats. Lesions of the ventral medial hypothalamus (VMH) increased food intake and induced obesity (Hetherington and Ranson, 1942, 1940). It was hypothesized the lesions affected satiety, leading the VMH to be dubbed the ‘satiety center’ (Weingarten et al., 1985; Vilberg and Keesey, 1984). In contrast, lesions of the lateral hypothalamic area (LHA) decreased food intake and provoked weight loss (Anand and Brobeck, 1951); this region became known as the ‘hunger center’ (Ungan and Karakas, 1989). Electrical stimu- lation of the two hypothalamic centers supported the hypothesis: stimulation of the VMH caused rats to stop eating (Saito et al., 1988), while stimulation of the LHA caused sated rats to eat (Bernardis and Bellinger, 1996). Thus, the Dual-Center Hypothesis became the dominant theory of how the central nervous system (CNS) controls food intake (Stellar, 1954; Elmquist et al., 1999; Jeanrenaud and Rohner-Jeanrenaud, 2000). Recently, elegant stud- ies using viral vector technology and generation of transgenic mice with selective deletions or targets of specific brain regions have substantiated these original findings and clearly demonstrated that http://dx.doi.org/10.1016/j.yfrne.2014.05.002 0091-3022/Ó 2014 Elsevier Inc. All rights reserved. Abbreviations: AgRP, agouti-related peptide; Akt/PKB, protein kinase B; ARC, arcuate nucleus; CCK, cholecystokinin; CNS, central nervous system; E2, 17b-estradiol; ER, estrogen receptor; ERE, estrogen response element; ERS1, ER alpha; ERS1 À/À , ER alpha null mouse; ERKO, ER knock-out mouse; ERaKO, ER alpha knockout mouse; ERS2, ER beta; HPG, hypothalamic pituitary gonadal axis; Ghsr À/À , GHSR null mice; GHSRs, growth hormone secretagogue receptors; GPCR, G protein- coupled receptor; GPER, G protein-coupled ER; i3vt, intra-third ventricular; leprb, long form of the leptin receptor; LHA, lateral hypothalamic area; aMSH, alpha melanocyte stimulating hormone; MAP, mitogen-activated protein; MC3/MC4, melanocortin-3, -4 receptors; MCH, melanin-concentrating hormone; MNAR, modulator of nongenomic activity of ER; MPOA, medial preoptic area; NERKI, nuclear ERa knock-in mouse; NPY, neuropeptide Y; NTS, nucleus of the solitary tract; OVX, ovariectomy; PI3K, phosphatidylinositol 3-kinase; POMC, pro-opiomelanocortin; PVN, paraventricular nucleus; SF1, steroidogenic factor-1; sh, short hairpin; VMH, ventromedial hypothalamus; ZI, zona incerta. ⇑ Corresponding author. Address: Department of Internal Medicine, Touchstone Diabetes Center, UT Southwestern Medical Center, 5323 Harry Hines Blvd., K5.252, Dallas, TX 75390-8854, USA. Fax: +1 214 648 8720. E-mail address: deborah.clegg@utsouthwestern.edu (D.J. Clegg). Frontiers in Neuroendocrinology xxx (2014) xxx–xxx Contents lists available at ScienceDirect Frontiers in Neuroendocrinology journal homepage: www.elsevier.com/locate/yfrne Please cite this article in press as: Frank, A., et al. The role of hypothalamic estrogen receptors in metabolic regulation. Front. Neuroendocrinol. (2014), http://dx.doi.org/10.1016/j.yfrne.2014.05.002