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Endocrinology 144(11):4690 4691 Copyright 2003 by The Endocrine Society doi: 10.1210/en.2003-0969

The Brainstem Is a Key Target for Neuroendocrine Research on Obesity

Obesity is one of the greatest and the most challenging problems in medicine of the 21st century, particularly in developed countries. Obesity is a common metabolic disease, with complex genetic traits, that is influenced by environmental factors. It constitutes an important risk factor for type 2 diabetes mellitus, hypertension, stroke, and coronary heart disease. The hypothalamus has been focused on as the center of the brain that controls appetite, energy expenditure, and body weight (1). During the last 25 yr, a great number of neuropeptides were discovered, for example, corticotropin-releasing factor, neuropeptide Y (NPY) and melanin-concentrating hormone (2, 3). These neuropeptides are present at high concentrations in the brain, particularly in the hypothalamus, and are presumed to act through neurotransmitter/neuromodulator roles as well as endocrine roles. Many of these neuropeptides are involved in the control of appetite and energy expenditure in the hypothalamus. Leptin, secreted by adipocytes, suppresses appetite and increases energy expenditure by acting on the brain, particularly on the complex networks of neuropeptides in the hypothalamus (4). The primary site of leptin action appears to be the arcuate nucleus (infundibular nucleus), where the leptin signal is transmitted to orexigenic (feeding-stimulating) neurons containing NPY and agouti-related protein (AGRP) and anorectic (feeding-inhibiting) neurons containing proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (5). Leptin signals are subsequently transmitted to other hypothalamic nuclei and extrahypothalamic brain areas. For example, axons from the arcuate nucleus innervate anorectic neurons containing TRH or corticotropin-releasing factor in the paraventricular nucleus and orexigenic neurons containing orexins (hypocretins) or melanin-concentrating hormone in the posterior lateral hypothalamic area. Moreover, at least two gastrointestinal hormones transmit peripheral signals of hunger or satiety from the gut to the brain; ghrelin secreted from the stomach stimulates appetite (6, 7) whereas peptide YY (336) secreted from the small intestine suppresses it (8). Importantly, the central control of body weight involves not only appetite but also energy expenditure, possibly through sympathetic nerve activation (9) and hypothalamopituitary thyroid axis stimulation (10). Leptin-overexpressing mice have increased sympathetic nerve activity and hypertension, as well as severe leanness (11). Melanocortin receptors, receptors for MSH and ACTH, form a subfamily of G protein-coupled receptors (12), consisting of at least five subtypes. -MSH secreted from POMC/cocaine- and amphetamine-regulated transcript
Abbreviations: AGRP, Agouti-related protein; NPY, neuropeptide Y; NTS, nucleus of the solitary tract; POMC, proopiomelanocortin.

neurons acts on melanocortin 3/4 receptors in the hypothalamus, whereas AGRP secreted from NPY/AGRP neurons acts on these receptors as an antagonist. Thus, melanocortin 3/4 receptors expressed in the hypothalamus are responsible for the central control of appetite and energy expenditure. When either melanocortin 4 or 3 receptor is knocked out in mice, obesity occurs (13, 14). Severe obesity is also reported in human subjects with mutation of the melanocortin 4 receptor gene (15). However, melanocortin 4 receptor is expressed not only in the hypothalamus but also in the brainstem, particularly in the dorsal motor nucleus of the vagus, lateral parabrachial nucleus, and nucleus of the solitary tract (NTS) (16, 17). In this issue of Endocrinology, Dr. D. L. Williams et al. (18) show that brainstem melanocortin 3/4 receptor stimulation increases uncoupling protein-1 gene expression in brown fat. Using surgically denervated and chronically decerebrate rats, they showed that this sympathetically stimulated elevation in uncoupling protein-1 gene expression is mediated by circuitry intrinsic to the caudal brainstem and spinal cord and independent of hypothalamic melanocortin receptors. As the authors discuss, there are two possible origins of endogenous -MSH, which acts on brainstem melanocortin receptors under physiological conditions: neurons in hypothalamus or in the NTS. The brainstem is also a target for the inhibitory effect of leptin on food intake (19, 20). Thus, melanocortin receptors in the brainstem and POMC neurons in the NTS are emerging as novel targets for neuroendocrine research on obesity and energy expenditure. Next their relationship to hypothalamic control, the sympathetic nervous system, and hormones, such as ghrelin, peptide YY (336), and leptin, must be tackled. Kazuhiro Takahashi Department of Molecular Biology and Applied Physiology Tohoku University School of Medicine Sendai 980-8575, Japan
Acknowledgments
Received July 30, 2003. Accepted August 6, 2003. Address all correspondence and requests for reprints to: Kazuhiro Takahashi, M.D., Department of Molecular Biology and Applied Physiology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan. E-mail: ktaka-md@mail.cc. tohoku.ac.jp.

References
1. Lawrence CB, Turnbull AV, Rothwell NJ 1999 Hypothalamic control of feeding. Curr Opin Neurobiol 9:778 783 2. Takahashi K, Satoh F, Totsune K, Sone M, Mizuno Y, Ohneda M, Murakami O, Mouri T 1996 Neuropeptides in the human brain. Funct Neurol 11:6598 3. Takahashi K 2001 Adrenomedullin from a pheochromocytoma to the eye: implications of the adrenomedullin research for endocrinology in the 21st century. Tohoku J Exp Med 193:79 114

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4. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM 1994 Positional cloning of the mouse obese gene and its human homologue. Nature 372:425 432 5. Schwartz MW, Woods SC, Porte Jr D, Seeley RJ, Baskin DG 2000 Central nervous system control of food intake. Nature 404:661 671 6. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K 1999 Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402:656 660 7. Tschop M, Smiley DL, Heiman ML 2000 Ghrelin induces adiposity in rodents. Nature 407:908 913 8. Batterham RL, Cowley MA, Small CJ, Herzog H, Cohen MA, Dakin CL, Wren AM, Brynes AE, Low MJ, Ghatei MA, Cone RD, Bloom SR 2002 Gut hormone PYY(336) physiologically inhibits food intake. Nature 418:650 654 9. Haynes WG, Morgan DA, Walsh SA, Mark AL, Sivitz WI 1997 Receptormediated regional sympathetic nerve activation by leptin. J Clin Invest 100: 270 278 10. Kim MS, Small CJ, Russell SH, Morgan DG, Abbott CR, AlAhmed SH, Hay DL, Ghatei MA, Smith DM, Bloom SR 2002 Effects of melanocortin receptor ligands on thyrotropin-releasing hormone release: evidence for the differential roles of melanocortin 3 and 4 receptors. J Neuroendocrinol 14:276 282 11. Aizawa-Abe M, Ogawa Y, Masuzaki H, Ebihara K, Satoh N, Iwai H, Matsuoka N, Hayashi T, Hosoda K, Inoue G, Yoshimasa Y, Nakao K 2000 Pathophysiological role of leptin in obesity-related hypertension. J Clin Invest 105:12431252 12. Adan RA, Gispen WH 1997 Brain melanocortin receptors: from cloning to function. Peptides 18:1279 1287 13. Huszar D, Lynch CA, Fairchild-Huntress V, Dunmore JH, Fang Q, Berke-

14.

15.

16.

17.

18.

19.

20.

meier LR, Gu W, Kesterson RA, Boston BA, Cone RD, Smith FJ, Campfield LA, Burn P, Lee F 1997 Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88:131141 Chen AS, Marsh DJ, Trumbauer ME, Frazier EG, Guan XM, Yu H, Rosenblum CI, Vongs A, Feng Y, Cao L, Metzger JM, Strack AM, Camacho RE, Mellin TN, Nunes CN, Min W, Fisher J, Gopal-Truter S, MacIntyre DE, Chen HY, Van der Ploeg LH 2000 Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass. Nat Genet 26:97102 Vaisse C, Clement K, Guy-Grand B, Froguel P 1998 A frameshift mutation in human MC4R is associated with a dominant form of obesity. Nat Genet 20:113114 Mountjoy KG, Mortrud MT, Low MJ, Simerly RB, Cone RD 1994 Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and autonomic control circuits in the brain. Mol Endocrinol 8:1298 1308 Kishi T, Aschkenasi CJ, Lee CE, Mountjoy KG, Saper CB, Elmquist JK 2003 Expression of melanocortin 4 receptor mRNA in the central nervous system of the rat. J Comp Neurol 457:213235 Williams DL, Bowers RR, Bartness TJ, Kaplan JM, Grill HJ 2003 Brainstem melanocortin 3/4 receptor stimulation increases uncoupling protein gene expression in brown fat. Endocrinology 144:4692 4697 Grill HJ, Schwartz MW, Kaplan JM, Foxhall JS, Breininger J, Baskin DG 2002 Evidence that the caudal brainstem is a target for the inhibitory effect of leptin on food intake. Endocrinology 143:239 246 Hosoi T, Kawagishi T, Okuma Y, Tanaka J, Nomura Y 2002 Brain stem is a direct target for leptins action in the central nervous system. Endocrinology 143:3498 3504