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Department of Molecular Biology and Applied Physiology Tohoku University School of Medicine Sendai 980-8575, Japan
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{at}mail.cc.tohoku.ac.jp.
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 (3–36) 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 hypothalamo-pituitary 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 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 (3–36), and leptin, must be tackled.
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Received July 30, 2003.
Accepted for publication August 6, 2003.
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