Energy intake and expenditure is regulated by a complex interplay between peripheral and central factors. An exhaustive list of peptides and neurotransmitters taking part in this complex regulation of body weight exists. Among these is histamine, which acts as a central neurotransmitter. In the present article we review current evidence pointing at an important role of histamine in the regulation of appetite and metabolism. Studies using both knockout mouse models as well as pharmacological studies have revealed that histamine acts as an anorexigenic agent via stimulation of histamine H1 receptors. One effect of histamine in the regulation of appetite is to act as a mediator of the inhibitory effect of leptin on appetite. It seems that histamine may attenuate and delay the development of leptin resistance in high-fat-diet-induced obesity. Furthermore, histamine may also act to accelerate lipolysis. Based on the current evidence of the involvement of histamine in the regulation of body weight, the histaminergic system is an obvious target for the development of pharmacological agents to control obesity. At present, H3 receptor antagonists that stimulate the histaminergic system may be the most promising histaminergic drugs for antiobesity therapy.

Flegal KM: Epidemiologic aspects of overweight and obesity in the United States. Physiol Behav 2005;86:599–602.
Wada H, Yamatodani A, Inagaki N, Itowi N, Wang NP, Fukui H: Histaminergic neuron system and its function. Adv Exp Med Biol 1988;236:343–357.
Kalucy RS: Drug-induced weight gain. Drugs 1980;19:268–278.
Arrang JM, Garbarg M, Lancelot JC, Lecomte JM, Pollard H, Robba M, et al: Highly potent and selective ligands for histamine H3-receptors. Nature 1987;327:117–123.
Berne RM, Levy MN, Koeppen BM, Stanton BA: Physiology, ed 5. St Louis, Mosby, 2004.
Knigge U, Warberg J: The role of histamine in the neuroendocrine regulation of pituitary hormone secretion. Acta Endocrinol (Copenh) 1991;124:609–619.
Schwartz JC: Histamine receptors in the brain and their possible functions; in Ganellin CR, Parsons ME (eds): Pharmacology of Histamine Receptors, ed 1. Bristol, Wright, 1982, p 353.
Schwartz JC, Arrang JM, Garbarg M, Pollard H, Ruat M: Histaminergic transmission in the mammalian brain. Physiol Rev 1991;71:1–51.
Palacios JM, Wamsley JK, Kuhar MJ: The distribution of histamine H1-receptors in the rat brain: an autoradiographic study. Neuroscience 1981;6:15–37.
Ruat M, Traiffort E, Bouthenet ML, Schwartz JC, Hirschfeld J, Buschauer A, et al: Reversible and irreversible labeling and autoradiographic localization of the cerebral histamine H2 receptor using [125I]iodinated probes. Proc Natl Acad Sci USA 1990;87:1658–1662.
Smits R, Mulder A: Inhibitory effects of histamine on the release of serotonin and noradrenaline from rat brain slices. Neurochem Int 1991;18:215–220.
Clineschmidt BV, Lotti VJ: Histamine: intraventricular injection suppresses ingestive behavior of the cat. Arch Int Pharmacodyn Ther 1973;206:288–298.
Itowi N, Nagai K, Nakagawa H, Watanabe T, Wada H: Changes in the feeding behavior of rats elicited by histamine infusion. Physiol Behav 1988;44:221–226.
Lecklin A, Etu-Seppala P, Stark H, Tuomisto L: Effects of intracerebroventricularly infused histamine and selective H1, H2 and H3 agonists on food and water intake and urine flow in Wistar rats. Brain Res 1998;793:279–288.
Orthen-Gambill N: Antihistaminic drugs increase feeding, while histidine suppresses feeding in rats. Pharmacol Biochem Behav 1988;31:81–86.
Sheiner JB, Morris P, Anderson GH: Food intake suppression by histidine. Pharmacol Biochem Behav 1985;23:721–726.
Vaziri P, Dang K, Anderson GH: Evidence for histamine involvement in the effect of histidine loads on food and water intake in rats. J Nutr 1997;127:1519–1526.
Lecklin A, Tuomisto L, MacDonald E: Metoprine, an inhibitor of histamine N-methyltransferase but not catechol-O-methyltransferase, suppresses feeding in sated and in food deprived rats. Methods Find Exp Clin Pharmacol 1995;17:47–52.
Lecklin A, Tuomisto L: The blockade of H1 receptors attenuates the suppression of feeding and diuresis induced by inhibition of histamine catabolism. Pharmacol Biochem Behav 1998;59:753–758.
Doi T, Sakata T, Yoshimatsu H, Machidori H, Kurokawa M, Jayasekara LA, et al: Hypothalamic neuronal histamine regulates feeding circadian rhythm in rats. Brain Res 1994;641:311–318.
Ookuma K, Sakata T, Fukagawa K, Yoshimatsu H, Kurokawa M, Machidori H, et al: Neuronal histamine in the hypothalamus suppresses food intake in rats. Brain Res 1993;628:235–242.
Orthen-Gambill N, Salomon M: FMH-induced decrease in central histamine levels produces increased feeding and body weight in rats. Physiol Behav 1992;51:891–893.
Sakata T, Fukagawa K, Ookuma K, Fujimoto K, Yoshimatsu H, Yamatodani A, et al: Hypothalamic neuronal histamine modulates ad libitum feeding by rats. Brain Res 1990;537:303–306.
Tuomisto L, Yamatodani A, Jolkkonen J, Sainio EL, Airaksinen MM: Inhibition of brain histamine synthesis increases food intake and attenuates vasopressin response to salt loading in rats. Methods Find Exp Clin Pharmacol 1994;16:355–359.
Fukagawa K, Sakata T, Shiraishi T, Yoshimatsu H, Fujimoto K, Ookuma K, et al: Neuronal histamine modulates feeding behavior through H1-receptor in rat hypothalamus. Am J Physiol 1989;256:R605–R611.
Machidori H, Sakata T, Yoshimatsu H, Ookuma K, Fujimoto K, Kurokawa M, et al: Zucker obese rats: defect in brain histamine control of feeding. Brain Res 1992;590:180–186.
Mercer LP, Kelley DS, Humphries LL, Dunn JD: Manipulation of central nervous system histamine or histaminergic receptors (H1) affects food intake in rats. J Nutr 1994;124:1029–1036.
Ookuma K, Yoshimatsu H, Sakata T, Fujimoto K, Fukagawa F: Hypothalamic sites of neuronal histamine action on food intake by rats. Brain Res 1989;490:268–275.
Sakata T, Ookuma K, Fukagawa K, Fujimoto K, Yoshimatsu H, Shiraishi T, et al: Blockade of the histamine H1-receptor in the rat ventromedial hypothalamus and feeding elicitation. Brain Res 1988;441:403–407.
Merali Z, Banks K: Does the histaminergic system mediate bombesin/GRP-induced suppression of food intake? Am J Physiol 1994;267:R1589–R1595.
Jørgensen EA, Knigge U, Watanabe T, Warberg J, Kjær A: Histaminergic neurons are involved in the orexigenic effect of orexin-A. Neuroendocrinology 2006;82:70–77.
Itoh E, Fujimiya M, Inui A: Thioperamide, a histamine H3 receptor antagonist, suppresses NPY-but not dynorphin A-induced feeding in rats. Regul Pept 1998;75–76:373–376.
Itoh E, Fujimiya M, Inui A: Thioperamide, a histamine H3 receptor antagonist, powerfully suppresses peptide YY-induced food intake in rats. Biol Psychiatry 1999;45:475–481.
Schwartz MW, Woods SC, Porte D Jr, Seeley RJ, Baskin DG: Central nervous system control of food intake. Nature 2000;404:661–671.
Morimoto T, Yamamoto Y, Mobarakeh JI, Yanai K, Watanabe T, Watanabe T, et al: Involvement of the histaminergic system in leptin-induced suppression of food intake. Physiol Behav 1999;67:679–683.
Masaki T, Yoshimatsu H, Chiba S, Watanabe T, Sakata T: Targeted disruption of histamine H1-receptor attenuates regulatory effects of leptin on feeding, adiposity, and UCP family in mice. Diabetes 2001;50:385–391.
Masaki T, Chiba S, Yasuda T, Noguchi H, Kakuma T, Watanabe T, et al: Involvement of hypothalamic histamine H1 receptor in the regulation of feeding rhythm and obesity. Diabetes 2004;53:2250–2260.
Jørgensen EA, Vogelsang TW, Knigge U, Watanabe T, Warberg J, Kjær A: Increased susceptibility to diet-induced obesity in histamine-deficient mice. Neuroendocrinology 2006;83:289–294.
Toftegaard CL, Knigge U, Kjær A, Warberg J: The role of hypothalamic histamine in leptin-induced suppression of short-term food intake in fasted rats. Regul Pept 2003;111:83–90.
Yoshimatsu H, Itateyama E, Kondou S, Tajima D, Himeno K, Hidaka S, et al: Hypothalamic neuronal histamine as a target of leptin in feeding behavior. Diabetes 1999;48:2286–2291.
Morimoto T, Yamamoto Y, Yamatodani A: Leptin facilitates histamine release from the hypothalamus in rats. Brain Res 2000;868:367–369.
Itateyama E, Chiba S, Sakata T, Yoshimatsu H: Hypothalamic neuronal histamine in genetically obese animals: its implication of leptin action in the brain. Exp Biol Med (Maywood ) 2003;228:1132–1137.
Bugajski J, Janusz Z: Lipolytic responses induced by intracerebroventricular administration of histamine in the rat. Agents Actions 1981;11:147–150.
Tsuda K, Yoshimatsu H, Niijima A, Chiba S, Okeda T, Sakata T: Hypothalamic histamine neurons activate lipolysis in rat adipose tissue. Exp Biol Med (Maywood ) 2002;227:208–213.
Yoshimatsu H, Hidaka S, Niijima A, Sakata T: Histamine neurons down-regulate ob gene expression in rat white adipose tissue. Inflamm Res 2001;50(suppl 2):S72–S73.
Fulop AK, Foldes A, Buzas E, Hegyi K, Miklos IH, Romics L, et al: Hyperleptinemia, visceral adiposity, and decreased glucose tolerance in mice with a targeted disruption of the histidine decarboxylase gene. Endocrinology 2003;144:4306–4314.
Takahashi K, Suwa H, Ishikawa T, Kotani H: Targeted disruption of H3 receptors results in changes in brain histamine tone leading to an obese phenotype. J Clin Invest 2002;110:1791–1799.
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