Disruption of the diurnal feeding rhythm in histamine H1 receptor knockout mice induces mature-onset obesity

Hypothalamic neuronal histamine and its H1 receptor (H1-R), one of leptin signaling pathways in the brain, regulate body weight and adiposity by affecting food intake and energy expenditure. Histamine H1-R knockout (H1KO) mice developed maturity-onset obesity, accompanied by hyperphagia and decreased energy expenditure assessed by the expression of uncoupling protein-1 (UCP-1) mRNA. Both younger non-obese (12 weeks old) and older obese (48 weeks old) H1KO mice exhibited impaired responsiveness to leptin. In addition, the diurnal feeding rhythm was disrupted before the onset of obesity in H1KO mice. Correction of these abnormal feeding rhythms with scheduled feeding improved the obesity and associated metabolic disorders in the H1KO mice. These findings suggest that histamine H1-R is crucial for regulating the 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 energy expenditure, which may contribute to the development of obesity in these animals.