Involvement of hypothalamic histamine H1 receptor in the regulation of feeding rhythm and obesity

Abstract

Histamine H1 receptors (H1-Rs) are found in peripheral tissues and in regions of the hypothalamus that are concerned with regulating body composition. In the present study, we. investigated the detailed mechanisms of histamine H1-Rs in the development of obesity. Histamine H1-R knockout (H1KO) mice gradually developed mature-onset obesity, which was accompanied by hyperphagia and decreased expression of uncoupling protein-1 (UCP-1) mRNA. Both younger nonobese (12-week-old) and older obese (48-week-old) H1KO mice exhibited impairment of the responsiveness to the leptin. In addition, disruption of the diurnal rhythm of feeding occurred before the onset-of obesity in. H1KO mice. Correction of these abnormal feeding rhythms- by means of scheduled feeding caused a reduction in obesity and associated metabolic disorders in H1KO mice. Furthermore, central administration of a histamine H1-R agonist affected feeding behavior, body weight, and c-fos-like immenoreactivity in the hypothalamus. Taken together, these findings suggest that histamine H1-Rs are crucial for the regulation of feeding rhythm and in mediating the effects of leptin. Early disruption of H1-R-mediated functions in H1KO mice may lead to hyperphagia and decreased expression of UCP-1 mRNA, which may contribute to the development of obesity in these animals. In addition, centrally acting histamine H 1-R may be a novel therapeutic target for the treatment of obesity and related metabolic disorders.