Abstract
Here we summarize recent progress in the biology of leptin, concentrating on its central nervous system (CNS) actions. The product of the ob gene, leptin is a circulating hormone produced by white adipose tissue that has potent effects on feeding behavior, thermogenesis and neuroendocrine responses. Leptin regulates energy homeostasis, as its absence in rodents and humans causes severe obesity. We consider the physiological mechanisms underlying leptin action, along with several novel hypothalamic neuropeptides that affect food intake and body weight. The molecular causes of several other obesity syndromes are discussed to illuminate how the CNS regulates body weight. We describe neural circuits that are downstream of leptin receptors and propose a model linking populations of leptin-responsive neurons with effector neurons underlying leptin's endocrine, autonomic and behavioral effects.
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References
Zhang, Y. et al. Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432 (1994).
Halaas, J. et al. Weight-reducing effects of the plasma protein encoded by the obese gene. Science 269, 543– 546 (1995).
Campfield, L. A., Smith, F. J., Guisez, Y., Devos, R. & Burn, P. Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks. Science 269, 546–549 (1995).
Pelleymounter, M. A. et al. Effects of the obese gene product on body weight regulation in ob/ob mice. Science 269, 540– 543 (1995).
Chehab, F. F., Lim, M. E. & Lu, R. Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin. Nat. Genet. 12, 318–320 (1996).
Tartaglia, L. A. et al. Identification and expression cloning of a leptin receptor, OB-R. Cell 83, 1263–1271 (1995).
Fei, H. et al. Anatomic localization of alternatively spliced leptin receptors (Ob-R) in mouse brain and other tissues. Proc. Natl. Acad. Sci. USA 94, 7001–7005 (1997).
Chen, H. et al. Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell 84, 491–495 (1996).
Lee, G. H. et al. Abnormal splicing of the leptin receptor in diabetic mice. Nature 379, 632–635 (1996).
White, D. W. et al. Constitutive and impaired signaling of leptin receptors containing the Gln → Pro extracellular domain fatty mutation. Proc. Natl Acad. Sci. USA 94, 10657–10662 (1997).
Ravussin, E. et al. Relatively low plasma leptin concentrations precede weight gain in Pima Indians. Nat. Med. 3, 238– 240 (1997).
Maffei, M. et al. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat. Med. 1, 1155–1161 (1995).
Considine, R. V. et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N. Engl. J. Med. 334, 292–295 (1996).
Van Heek, M. et al. Diet-induced obese mice develop peripheral, but not central, resistance to leptin. J. Clin. Invest. 99, 385–390 (1997).
Frederich, R. C. et al. Leptin levels reflect body lipid content in mice: evidence for diet-induced resistance to leptin action. Nat. Med. 1, 1311–1314 (1995).
Caro, J. F. et al. Decreased cerebrospinal-fluid/serum leptin ratio in obesity: a possible mechanism for leptin resistance. Lancet 348, 159–161 (1996).
Schwartz, M. W., Dallman, M. F. & Woods, S. C. Hypothalamic response to starvation: implications for the study of wasting disorders. Am. J. Physiol. 269, R949–957 (1995).
Flier, J. S. Clinical review.94: What's in a name? In search of leptin's physiologic role. J. Clin. Endocrinol. Metab. 83, 1407– 1413 (1998).
Ahima, R. S. et al. Role of leptin in the neuroendocrine response to fasting. Nature 382, 250–252 (1996).
Legradi, G., Emerson, C. H., Ahima, R. S., Flier, J. S. & Lechan, R. M. Leptin prevents fasting-induced suppression of prothyrotropin-releasing hormone messenger ribonucleic acid in neurons of the hypothalamic paraventricular nucleus. Endocrinology 138, 2569–2576 (1997).
Carro, E., Senaris, R., Considine, R. V., Casanueva, F. F. & Dieguez, C. Regulation of in vivo growth hormone secretion by leptin. Endocrinology 138, 2203–2206 (1997).
Laughlin, G. A. & Yen, S. S. Hypoleptinemia in women athletes: absence of a diurnal rhythm with amenorrhea. J. Clin. Endocrinol. Metab. 82, 318– 321 (1997).
Barash, I. A. et al. Leptin is a metabolic signal to the reproductive system. Endocrinology 137, 3144–3147 (1996).
Ahima, R. S., Dushay, J., Flier, S. N., Prabakaran, D. & Flier, J. S. Leptin accelerates the onset of puberty in normal female mice. J. Clin. Invest. 99, 391– 395 (1997).
Cheung, C. C. et al. Leptin is a metabolic gate for the onset of puberty n the female rat. Endocrinology 138, 855– 858 (1997).
Chehab, F. F., Mounzih, K., Lu, R. & Lim, M. E. Early onset of reproductive function in normal female mice treated with leptin. Science 275, 88–90 (1997).
Montague, C. T. et al. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 387, 903– 908 (1997).
Strobel, A., Issad, T., Camoin, L., Ozata, M. & Strosberg, A. D. A leptin missense mutation associated with hypogonadism and morbid obesity. Nat. Genet. 18, 213– 215 (1998).
Clement, K. et al. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 392, 398 –401 (1998).
Bi, S., Gavrilova, O., Gong, D. W., Mason, M. M. & Reitman, M. Identification of a placental enhancer for the human leptin gene. J. Biol. Chem. 272, 30583–30588 (1997).
Wang, J., Liu, R., Hawkins, M., Barzilai, N. & Rossetti, L. A nutrient-sensing pathway regulates leptin gene expression in muscle and fat. Nature 393, 684– 688 (1998).
Broadwell, R. D. & Brightman, M. W. Entry of peroxidase into neurons of the central and peripheral nervous systems from extracerebral and cerebral blood. J. Comp. Neurol. 166, 257–283 (1976).
Banks, W. A., Kastin, A. J., Huang, W., Jaspan, J. B. & Maness, L. M. Leptin enters the brain by a saturable system independent of insulin. Peptides 17, 305– 311 (1996).
Bjorbaek, C. et al. Expression of leptin receptor isoforms in rat brain microvessels. Endocrinology 139, 3485– 3491 (1998).
Elmquist, J. K., Bjorbaek, C., Ahima, R. S., Flier, J. S. & Saper, C. B. Distributions of leptin receptor mRNA isoforms in the rat brain. J. Comp. Neurol. 395 , 535–547 (1998).
Hetherington, A. W. & Ranson, S. W. Hypothalamic lesions and adiposity in the rat. Anat. Record 78, 149–172 (1940).
Mercer, J. G. et al. Localization of leptin receptor mRNA and the long form splice variant (Ob-Rb) in mouse hypothalamus and adjacent brain regions by in situ hybridization. FEBS Lett. 387, 113– 116 (1996).
Schwartz, M. W., Seeley, R. J., Campfield, L. A., Burn, P. & Baskin, D. G. Identification of targets of leptin action in rat hypothalamus. J. Clin. Invest. 98, 1101–1106 (1996).
White, D. W., Kuropatwinski, K. K., Devos, R., Baumann, H. & Tartaglia, L. A. Leptin receptor (OB-R) signaling. Cytoplasmic domain mutational analysis and evidence for receptor homo-oligomerization. J. Biol. Chem. 272, 4065– 4071 (1997).
Mercer, J. G. et al. Coexpression of leptin receptor and preproneuropeptide Y mRNA in arcuate nucleus of mouse hypothalamus. J. Neuroendocrinol. 8, 733–735 (1996).
Cheung, C. C., Clifton, D. K. & Steiner, R. A. Proopiomelanocortin neurons are direct targets for leptin in the hypothalamus. Endocrinology 138, 4489–4492 (1997).
Hakansson, M. L., Hulting, A. L. & Meister, B. Expression of leptin receptor mRNA in the hypothalamic arcuate nucleus--relationship with NPY neurones. Neuroreport 7, 3087–3092 (1996).
Satoh N. et al. Pathophysiological significance of the obese gene product, leptin, in ventromedial hypthalamus (VMH)-lesioned rats: evidence for loss of its satiety effect in VMH-lesioned rats. Endocrinology 138, 947–954 (1997).
Couce, M. E., Burguera, B., Parisi, J. E., Jensen, M. D. & Lloyd, R. V. Localization of leptin receptor in the human brain. Neuroendocrinology 66, 145–150 (1997).
Savioz, A. et al. Expression of leptin receptor mRNA (long splice form variant) in the human cerebellum. Neuroreport >, 3123– 3126 (1997).
Mercer, J. G., Moar, K. M. & Hoggard, N. Localization of leptin receptor (Ob-R) messenger ribonucleic acid in the rodent hindbrain. Endocrinology 139, 29–34 (1998).
Hakansson, M. L., Brown, H., Ghilardi, N., Skoda, R. C. & Meister, B. Leptin receptor immunoreactivity in chemically defined target neurons of the hypothalamus. J. Neurosci. 18 , 559–572 (1998).
Smedh, U., Hakansson, M. L., Meister, B. & Uvnas-Moberg, K. Leptin injected into the fourth ventricle inhibits gastric emptying. Neuroreport 9, 297–301 (1998).
Stephens, T. W. et al. The role of neuropeptide Y in the antiobesity action of the obese gene product. Nature 377, 530– 532 (1995).
Erickson, J. C., Hollopeter, G. & Palmiter, R. D. Attenuation of the obesity syndrome of ob/ob mice by the loss of neuropeptide Y. Science 274, 1704–1707 (1996).
Erickson, J. C., Clegg, K. E. & Palmiter, R. D. Sensitivity to leptin and susceptibility to seizures of mice lacking neuropeptide Y. Nature 381, 415–421 (1996).
Thornton, J. E., Cheung, C. C., Clifton, D. K. & Steiner, R. A. Regulation of hypothalamic proopiomelanocortin mRNA by leptin in ob/ob mice. Endocrinology 138, 5063– 5066 (1997).
Schwartz, M. W. et al. Leptin increases hypothalamic pro-opiomelanocortin mRNA expression in the rostral arcuate nucleus. Diabetes 46, 2119–2123 (1997).
Mizuno, T. M. et al. Hypothalamic pro-opiomelanocortin mRNA is reduced by fasting in ob/ob and db/db mice, but is stimulated by leptin. Diabetes 47, 294–297 (1998).
Fan, W., Boston, B. A., Kesterson, R. A., Hruby, V. J. & Cone, R. D. Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature 385, 165–168 (1997).
Shutter, J. R. et al. Hypothalamic expression of ART, a novel gene related to agouti, is up-regulated in obese and diabetic mutant mice. Genes Dev. 11, 593–602 (1997).
Ollmann, M. M. et al. Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science 278, 135–138 (1997).
Hahn, T., Breininger, J., Baskin, D. & Schwartz, M. Coexpression of Agrp and NPY in fasting-activated hypothalamic neurons. Nature Neurosci. 1, 271–272 (1998).
Seeley, R. J. et al. Melanocortin receptors in leptin effects. Nature 390, 349 (1997).
Huszar, D. et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88, 131– 141 (1997).
Mountjoy, K. G., Mortrud, M. T., Low, M. J., Simerly, R. B. & Cone, R. D. Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and autonomic control circuits in the brain. Mol. Endocrinol. 8, 1298– 1308 (1994).
Douglass, J., McKinzie, A. A. & Couceyro, P. PCR differential display identifies a rat brain mRNA that is transcriptionally regulated by cocaine and amphetamine. J. Neurosci. 15, 2471–2481 (1995).
Koylu, E. O. et al. Immunohistochemical localization of novel CART peptides in rat hypothalamus, pituitary and adrenal gland. J. Neuroendocrinol. 9, 823–833 (1997).
Koylu, E. O., Couceyro, P. R., Lambert, P. D. & Kuhar, M. J. Cocaine- and amphetamine-regulated transcript peptide immunohistochemical localization in the rat brain. J. Comp. Neurol. 391 , 115–132 (1998).
Kristensen, P. et al. Hypothalamic CART is a new anorectic peptide regulated by leptin. Nature 393, 72– 76 (1998).
Lambert, P. D. et al. CART peptides in the central control of feeding and interactions with neuropeptide Y. Synapse 29, 293– 298 (1998).
Lambert, P. D. et al. A role for novel CART peptide fragments in the central control of food intake. Neuropeptides 31, 620– 621 (1997).
Vaisse, C. et al. Leptin activation of Stat3 in the hypothalamus of wild-type and ob/ob mice but not db/db mice. Nat. Genet. 14, 95–97 (1996).
Elmquist, J. K., Ahima, R. S., Maratos-Flier, E., Flier, J. S. & Saper, C. B. Leptin activates neurons in ventrobasal hypothalamus and brainstem. Endocrinology 138, 839–842 (1997).
Woods, A. J. & Stock, M. J. Leptin activation in hypothalamus. Nature 381, 745 (1996).
Van Dijk, G. et al. Central infusions of leptin and GLP-1-(7-36) amide differentially stimulate c-FLI in the rat brain. Am. J. Physiol. 271 , R1096–1100 (1996).
Fulwiler, C. E. & Saper, C. B. Cholecystokinin-immunoreactive innervation of the ventromedial hypothalamus in the rat: possible substrate for autonomic regulation of feeding. Neurosci. Lett. 53, 289–296 (1985).
Barrachina, M. D., Mart'nez, V., Wang, L., Wei, J. Y. & Tach, Y. Synergistic interaction between leptin and cholecystokinin to reduce short-term food intake in lean mice. Proc. Natl Acad. Sci. USA 94, 10455–10460 (1997).
Bjorbaek, C., Elmquist, J. K., Frantz, J. D., Shoelson, S. E. & Flier, J. S. Identification of SOCS-3 as a potential mediator of central leptin resistance. Mol. Cell 1, 619–625 (1998).
Endo, T. A. et al. A new protein containing an SH2 domain that inhibits JAK kinases. Nature 387, 921–924 (1997).
Starr, R. et al. A family of cytokine-inducible inhibitors of signalling. Nature 387, 917–921 (1997).
Naka, T. et al. Structure and function of a new STAT-induced STAT inhibitor. Nature 387, 924–929 (1997).
Elmquist, J. K., Ahima, R. S., Elias, C. F., Flier, J. S. & Saper, C. B. Leptin activates distinct projections from the dorsomedial and ventromedial hypothalamic nuclei. Proc. Natl Acad. Sci. USA 95, 741–746 (1998).
Swanson, L. W. & Sawchenko, P. E. Hypothalamic integration: organization of the paraventricular and supraoptic nuclei. Annu. Rev. Neurosci. 6, 269–324 (1983).
Huang, Q., Rivest, R. & Richard, D. Effects of leptin on corticotropin-releasing factor (CRF) synthesis and CRF neuron activation in the paraventricular hypothalamic nucleus of obese (ob/ob) mice. Endocrinology 139, 1524–1532 (1998).
Gold, R. M. Hypothalamic obesity: the myth of the ventromedial nucleus. Science 182, 488–490 (1973).
Leibowitz, S. F. Specificity of hypothalamic peptides in the control of behavioral and physiological processes. Ann. NY Acad. Sci. 739, 12– 35 (1994).
Haynes, W. G., Morgan, D. A., Walsh, S. A., Mark, A. L. & Sivitz, W. I. Receptor-mediated regional sympathetic nerve activation by leptin. J. Clin. Invest. 100, 270–278 (1997).
Casto, R. M., VanNess, J. M. & Overton, J. M. Effects of central leptin administration on blood pressure in normotensive rats. >Neurosci. Lett. 246 , 29–32 (1998).
Bernardis, L. L. & Bellinger, L. L. The dorsomedial hypothalamic nucleus revisited: 1986 update. Brain Res. 434, 321–381 (1987).
Yoshimatsu, H., Niijima, A., Oomura, Y., Yamabe, K. & Katafuchi, T. Effects of hypothalamic lesion on pancreatic autonomic nerve activity in the rat. Brain Res. 303, 147–152 (1984).
Frohman, L. A. & Bernardis, L. L. Effect of hypothalamic stimulation on plasma glucose, insulin, and glucagon levels. Am. J. Physiol. 221, 1596– 1603 (1971).
DiMicco, J. A., Stotz-Potter, E. H., Monroe, A. J. & Morin, S. M. Role of the dorsomedial hypothalamus in the cardiovascular response to stress. Clin. Exp. Pharmacol. Physiol. 23, 171– 176 (1996).
Kesterson, R. A., Huszar, D., Lynch, C. A., Simerly, R. B. & Cone, R. D. Induction of neuropeptide Y gene expression in the dorsal medial hypothalamic nucleus in models of the agouti obesity syndrome. Mol. Endocrinol. 11, 630– 637 (1997).
Tritos, N. A., Elmquist, J. K., Mastaitis, J., Flier, J. S. & Maratos-Flier, E. Altered expression of multiple orexigenic peptide mRNAs in the hypothalamus of obese hyperleptinemic UCP-DTA mice. Endocrinology 139 (in press).
Watts, A. G., Swanson, L. W. & Sanchez-Watts, G. Efferent projections of the suprachiasmatic nucleus: I. Studies using anterograde transport of Phaseolus vulgaris leucoagglutinin in the rat. J. Comp. Neurol. 258, 204– 229 (1987).
Bellinger, L. L., Bernardis, L. L. & Mendel, V. E. Effect of ventromedial and dorsomedial hypothalamic lesions on circadian corticosterone rhythms. Neuroendocrinology 22, 216–225 (1976).
Choi, S., Horsley, C., Aguila, S. & Dallman, M. F. The hypothalamic ventromedial nuclei couple activity in the hypothalamo-pituitary-adrenal axis to the morning fed or fasted state. J. Neurosci. 16 , 8170–8180 (1996).
Suemaru, S., Darlington, D. N., Akana, S. F., Cascio, C. S. & Dallman, M. F. Ventromedial hypothalamic lesions inhibit corticosteroid feedback regulation of basal ACTH during the trough of the circadian rhythm. Neuroendocrinology 61, 453–463 (1995).
Licinio, J. et al. Human leptin levels are pulsatile and inversely related to pituitary-adrenal function. Nat. Med. 3, 575–579 (1997).
Ahima, R. S., Prabakaran, D. & Flier, J. S. Postnatal leptin surge and regulation of circadian rhythm of leptin by feeding. Implications for energy homeostasis and neuroendocrine function. J. Clin. Invest. 101, 1020– 1027 (1998).
Watts, A. G. IN Suprachiasmatic Nucleus: The Mind's Clock (eds Klein, D., Moore, R. Y. & Reppert, S. M.) 75–104 (Oxford Univ. Press, 1991).
Kalsbeek, A. et al. GABA receptors in the region of the dorsomedial hypothalamus of rats are implicated in the control of melatonin and corticosterone release. Neuroendocrinology 63, 69– 78 (1996).
Glaum, S. R. et al. Leptin, the obese gene product, rapidly modulates synaptic transmission in the hypothalamus. Mol. Pharmacol. 50, 230–235 (1996).
Spanswick, D., Smith, M. A., Groppi, V. E., Logan, S. D. & Ashford, M. L. Leptin inhibits hypothalamic neurons by activation of ATP-sensitive potassium channels. Nature 390, 521–525 (1997).
Bernardis, L. L. & Bellinger, L. L. The lateral hypothalamic area revisited: ingestive behavior. Neurosci. Biobehav. Rev. 20, 189–287 (1996).
Saper, C. B. Organization of cerebral cortical afferent systems in the rat. II. Hypothalamocortical projections. J. Comp. Neurol. 237, 21– 46 (1985).
Bittencourt, J. C. et al. The melanin-concentrating hormone system of the rat brain: an immuno- and hybridization histochemical characterization. J. Comp. Neurol. 319, 218–245 (1992).
Qu, D. et al. A role for melanin-concentrating hormone in the central regulation of feeding behaviour. Nature 380, 243– 247 (1996).
Sakurai, T. et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92, 573–585 (1998).
de Lecea, L. et al. The hypocretins: Hypothalamus-specific peptides with neuroexcitatory activity. Proc. Natl Acad. Sci. USA 95, 322–327 (1998).
Gerald, C. et al. A receptor subtype involved in neuropeptide-Y-induced food intake. Nature 382, 168–171 (1996).
Acknowledgements
The authors thank Quan Ha, Minh Ha, Charlotte Lee and Joseph Kelly for technical assistance and Carol Elias, Christian Bjørbæk and Rexford S. Ahima for discussions.
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Elmquist, J., Maratos-Flier, E., Saper, C. et al. Unraveling the central nervous system pathways underlying responses to leptin. Nat Neurosci 1, 445–450 (1998). https://doi.org/10.1038/2164
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DOI: https://doi.org/10.1038/2164
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