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The Journal of Neuroscience, November 1, 2006, 26(44):11255-11256; doi:10.1523/JNEUROSCI.3717-06.2006

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Journal Club

Editor's Note: These short reviews of a recent paper in the Journal, written exclusively by graduate students or postdoctoral fellows, are intended to mimic the journal clubs that exist in your own departments or institutions. For more information on the format and purpose of the Journal Club, please see http://www.jneurosci.org/misc/ifa_features.shtml.

Membrane Estrogen Receptors and Energy Homeostasis

Lori Asarian

Swiss Federal Institute of Technology Zürich, Institute of Animal Science, CH-8603 Schwerzenbach, Switzerland

Review of Qiu et al. (http://www.jneurosci.org/cgi/content/full/26/21/5649)

The actions of gonadal steroid hormones in the brain produce myriad physiological and behavioral effects. One of the most potent gonadal steroids is estradiol (E₂), which, in addition to positive and negative feedback effects on gonadotropin-releasing hormone release, affects sexual and social behavior, food intake, locomotor activity, and many other brain functions. The site(s) and the estrogen receptor (ER) species involved in most of these effects remain unknown. The vast majority of investigations have focused on the classical nuclear ERs, which are now known to have at least two subtypes, ER and ER. Both ER and ER are present in the cytosol, membrane, or other cellular compartments and, after binding E₂, initiate gene transcription by either nuclear translocation or activating second-messenger pathways (Fig. 1). (Lagrange et al. 1997) identified a different, membrane-associated ER (mER) on hypothalamic neural membranes. Binding of E₂ to this mER results in increases in cAMP levels and rapid activation of phospholipase C/protein kinase C/protein kinase A (PLC/PKC/PKA) pathways that can immediately desensitize µ-opioid and GABA_B receptors. In a recent issue of The Journal of Neuroscience, (Qiu et al., 2006) reported exciting additional investigations of this mER.

View larger version (34K): [in this window] [in a new window]   Figure 1. Schematic of intracellular mechanisms underlying E2 effects on sexual and social behavior, energy homeostasis, and many other brain-mediated functions. Most of these functions occur as a result of gene transcription elicited by binding of E2 to the classic ER and ER. The newly characterized mER (Qiu et al., 2006) that seems to mediate some of the effects of E2 on energy homeostasis opens new possibilities in the investigation of the role of E2 in normal physiology.

 
The new results are based mainly on studies of the newly developed compound STX, a novel ER antagonist that does not bind to ER or ER. Remarkably, 75% of neurons in the hypothalamic arcuate nucleus, including all of the pro-opiomelanocortin (POMC)-expressing neurons, were found to be 40% less sensitive to the GABA_B agonist baclofen after STX treatment [(Qiu et al., 2006), their Fig. 2 (http://www.jneurosci.org/cgi/content/full/26/21/5649/F2)]. The initial experiments in female guinea pigs were replicated in female ER and ER knock-out (KO) mice and male ER KO mice, indicating that these electrophysiological responses do not require classical ER, occur in other species, and occur in both sexes [(Qiu et al., 2006), their Fig. 3 (http://www.jneurosci.org/cgi/content/full/26/21/5649/F3)]. Additional pharmacological tests indicated that this response is mediated by a G_q-coupled PLC/PKC/PKA pathway. These data open up exciting new frontiers in the molecular pharmacology of the arcuate nucleus and E₂ in general. Finally, the finding that STX potently reduced the excess body weight gain of ovariectomized guinea pigs links the in vitro findings to in vivo, physiological functions [(Qiu et al., 2006), their Fig. 4a,b (http://www.jneurosci.org/cgi/content/full/26/21/5649/F4)]. The authors suggest that E₂ is likely to inhibit feeding via mER-mediated maintenance of normal excitability of POMC, in particular, melanocortinergic, neurons in the arcuate nucleus, which are considered to be critical elements of the neural network controlling feeding.

Because estradiol appears to play a physiological role in the regulation of eating, energy homeostasis, and adiposity in both animals and women (Geary, 2004; Asarian and Geary, 2006), this functional conclusion deserves close scrutiny. Several issues require additional evaluation. First, of course, it will be important in future work to measure food intake directly, not just body weight. Although the effect of E₂ on energy homeostasis is mediated mainly by changes in food intake, effects on physical activity and metabolic energy expenditure can also be important, especially in rodents. Second, because STX was given systemically in the energy balance tests, the site of action is uncertain. (Qiu et al., 2006) cite (Butera and Cjaza 1984) to support the idea that the anorexigenic effects of E₂ originate in the arcuate/ventromedial hypothalamus; in fact, those authors found that paraventricular nucleus E₂ administration was more effective than arcuate administration. The same is true in rats (for review, see Geary, 2004). Moreover, since that time, many investigators have shown that implantation of pure E₂, as done by (Butera and Cjaza 1984), does not lead to a localized action of the hormone (for review, see Geary, 2004).

A third critical issue regards the involvement of ER in body weight regulation: E₂ treatment does not normalize food intake or body weight gain in ER KO mice (Geary et al., 2001), indicating that ER is necessary for this effect of E₂. This, of course, does not eliminate the possibility that mER are also involved but does indicate that the relative contributions of the E₂ receptors require additional work. A fourth and related point concerns the latency of the effect of E₂ on feeding in ovariectomized animals, which is normally over 24 h. For example, the subcutaneous injection of a physiological dose of E₂ (2 µg) in ovariectomized rats does not affect food intake for over 1 d (Asarian and Geary, 2002). This long latency seems inconsistent with the hypothesis that immediate mER signaling in the arcuate mediates the effect of E₂ on feeding. It is possible, of course, that other, slower effects of mER activation do contribute.

Finally, the hypothesis that hypothalamic melanocortinergic neurons are involved in the feeding-inhibitory effect of E₂ also deserves additional testing in light of several apparently inconsistent reports. For example, E₂ treatment failed to affect the feeding response to intracerebroventricular injections of either the melanocortin 3/4 receptor agonist melanotan II or the melanocortin 3/4 receptor antagonists SHU9119 [acetyl-(Nle⁴,Asp⁵,D-2-Nal⁷,Lys¹⁰)-cyclo--MSH(4:10)amide] and agouti-related protein (for review, see Asarian and Geary, 2006). If E₂ were to act, as hypothesized, by affecting the tone of hypothalamic melanocortinergic neurons, one would predict that E₂ would indirectly affect the response of their postsynaptic neurons to melanocortin 3/4 agonists or antagonists. Furthermore, the feeding-inhibitory effect of leptin, which directly activates arcuate melanocortinergic neurons, is also not affected by E₂ treatment in ovariectomized rats (for review, see Geary, 2004; Asarian and Geary, 2006).

Received Aug. 25, 2006; revised Sept. 18, 2006; accepted Sept. 18, 2006.

Correspondence should be addressed to Lori Asarian, Swiss Federal Institute of Technology Zürich, Institute of Animal Science, Schorenstrasse 16, CH-8603 Schwerzenbach, Switzerland. Email: lasarian{at}ethz.ch

Copyright © 2006 Society for Neuroscience 0270-6474/06/2611255-02$15.00/0

References

Asarian L, Geary N (2002) Cyclic estradiol treatment normalizes body weight and restores physiological patterns of spontaneous feeding and sexual receptivity in ovariectomized rats. Horm Behav 42:461–471.[CrossRef][Medline]

Asarian L, Geary N (2006) Modulation of appetite by gonadal steroid hormones. Philos Trans R Soc Lond B Biol Sci 361:1251–1263.[Abstract/Free Full Text]

Butera PC, Cjaza JA (1984) Intracranial estradiol in ovariectomized guinea pigs: effects on ingestive behaviors and body weight. Brain Res 19:41–48.

Geary N (2004) The estrogenic inhibition of eating. In: Handbook of behavioral neurobiology, Vol 14, Neurobiology of food and fluid intake (Stricker EM, Woods SC, eds) Ed 2 pp. 307–345. New York: Kluwer Academic/Plenum.

Geary N, Asarian L, Korach KS, Pfaff DW, Ogawa S (2001) Deficits in E2-dependent control of feeding, weight gain, and cholecystokinin satiation in ER-alpha null mice. Endocrinology 142:4751–4757.[Abstract/Free Full Text]

Lagrange AH, Ronnekleiv OK, Kelly MJ (1997) Modulation of G-protein-coupled receptors by an estrogen receptor that activates protein kinase A. Mol Pharmacol 51:605–612.[Abstract/Free Full Text]

Qiu J, Bosch MA, Tobias SC, Krust A, Graham SM, Murphy SJ, Korach KS, Chambon P, Scanlon TS, Ronnekleiv OK, Kelly MJ (2006) A G-protein-coupled estrogen receptor is involved in hypothalamic control of energy homeostasis. J Neurosci 26:5649–5655.[Abstract/Free Full Text]

Related articles in J. Neurosci.:

A G-Protein-Coupled Estrogen Receptor Is Involved in Hypothalamic Control of Energy Homeostasis

Jian Qiu, Martha A. Bosch, Sandra C. Tobias, Andree Krust, Sharon M. Graham, Stephanie J. Murphy, Kenneth S. Korach, Pierre Chambon, Thomas S. Scanlan, Oline K. Rønnekleiv, and Martin J. Kelly
J. Neurosci. 2006 26: 5649-5655. [Abstract] [Full Text]  

This Article Full Text (PDF) Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Email this article to a friend Related articles in J. Neurosci. Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Asarian, L. Search for Related Content PubMed PubMed Citation Articles by Asarian, L.

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