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Neuronal Histamine Regulates Food Intake, Adiposity, and Uncoupling Protein Expression in Agouti Yellow (A^y/a) Obese Mice

Department of Internal Medicine, School of Medicine, Oita Medical University, Oita 879-5593, Japan

Address all correspondence and requests for reprints to: Takayuki Masaki, Department of Internal Medicine, School of Medicine, Oita Medical University, Hasama, Oita 879-5593, Japan. E-mail: masaki{at}oita-med.ac.jp.

Hypothalamic neuronal histamine and its H₁ receptor (H₁-R) form a part of the leptin-signaling pathway in the brain and have been shown to regulate body weight and adiposity in diabetic (db/db) and diet-induced obese mice by affecting food intake and uncoupling protein mRNA expression. The proopiomelanocortin (POMC) melanocortin-4 receptor (MC-4R) is also important for leptin signaling. The present study had two aims: first, to clarify the antiobesity action of neuronal histamine in agouti yellow (A^y/a) obese mice, a model of obesity in which POMC/MC-4R signaling is disrupted by blockade of MC-4R and second, to investigate the functional relationship between neuronal histamine and POMC/MC-4R signaling. Central administration of histamine into the lateral cerebroventricle decreased cumulative food intake and body weight in A^y/a obese mice. Histamine treatment also decreased mRNA expression of ob gene in epididymal white adipose tissue and up-regulated uncoupling protein 1 mRNA expression in brown adipose tissue. These effects were attenuated in A^y/a obese mice with histamine H₁-receptor (H₁-R) knockout. Histamine treatment induced c-Fos-like immunoreactivity in both paraventricular and arcuate nucleus. There was no significant difference in histamine-induced c-Fos-like immunoreactivity in the hypothalamus between A^y/a obese mice and lean littermates, indicating histamine signaling was not disrupted at the hypothalamic level in A^y/a obese mice. These results suggest that neuronal histamine have an antiobese action, even in A^y/a obese mice despite a deficiency in POMC/MC-4R signaling. In addition, it appears that the histamine H₁-R signaling pathway may be independent or downstream of the POMC/MC-4R signaling.

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