J Clin Invest 110(12): 1791-1799

Targeted disruption of H3 receptors results in changes in brain histamine tone leading to an obese phenotype

Functional Genomics, Banyu Tsukuba Research Institute in collaboration with Merck Research Laboratories, Tsukuba, Ibaraki, Japan

Address correspondence to: Hidehito Kotani, Banyu Tsukuba Research Institute, Okubu 3, Tsukuba, Ibaraki, 300-2611, Japan. Phone: 298-77-2202; Fax: 298-77-2027; E-mail: pj.oc.uynab@hhinatok.

Received 2002 Apr 24; Accepted 2002 Nov 6.

Abstract

Histamine is an aminergic neurotransmitter that is localized in the CNS and in peripheral tissues. To date, four histamine receptors have been identified, and the H3 receptor, which was recently cloned, is predominantly expressed in the CNS. The peripheral functions of histamine have been investigated intensively using available molecular and pharmacological tools, and the molecular identification of the H3 receptor opens up new possibilities for investigating the role of histamine in central tissues. To understand the biological function of the histamine presynaptic autoreceptor H3, we inactivated the receptor through homologous recombination. H3^{mice manifest mild obese phenotypes that are characterized by increases in body weight, food intake, and adiposity and by reductions in energy expenditure. Consistent with these observations, homozygous null mice have insulin and leptin resistance, increased levels of plasma leptin and insulin, and decreased levels of histamine in the hypothalamic/thalamic region of their brains coupled with increased histamine turnover. The expression of}UCP1 in brown adipose tissue and of UCP3 in brown adipose tissue, white adipose tissue, and skeletal muscle is decreased in H3^{mutants, and the anorexigenic activity of thioperamide is not observed. These results suggest that neuronal histamine is a mediator of body-weight homeostasis and that neuronal histamine functions through H3 receptors in mice.}

Abstract

Acknowledgments

We thank M. Yoshida, L. Van der Ploeg, D. Marsh, A. Kanatani, and S. Tokita for support and comments on the project; J. Winward and K. Marcopul for editorial assistance; H. Ohta, M. Maetani, S. Okuda, R. Yoshimoto, and A. Ishihara for technical work; and members of the Functional Genomics group for their informative discussions.

Acknowledgments

Footnotes

Conflict of interest: The authors have declared that no conflict of interest exists.

Nonstandard abbreviations used: tuberomammillary nucleus (TM); ventromedial nucleus (VMH); arcuate nucleus (ARH); embryonic stem (ES); neomycin (neo); N-α-methylhistamine (NAMHA); degradation per minute (dpm); brown adipose tissue (BAT); white adipose tissue (WAT); triacyl glycerol (TG); neuropeptide Y (NPY); histamine N-methyltransferase (HMT); melanin-concentrating hormone (MCH).

Footnotes

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