Involvement of hypothalamic histamine H1 receptor in the regulation of feeding rhythm and obesity.
Histamine H(1) receptors (H(1)-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 H(1)-Rs in the development of obesity. Histamine H(1)-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 H(1)-R agonist affected feeding behavior, body weight, and c-fos-like immunoreactivity in the hypothalamus. Taken together, these findings suggest that histamine H(1)-Rs are crucial for the regulation of feeding rhythm and in mediating the effects of leptin. Early disruption of H(1)-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.
Department of Internal Medicine, School of Medicine Oita University, Hasama, Oita, 879-5593 Japan. masaki@med.oita-u.ac.jp
Takayuki
T
Masaki
Seiichi
S
Chiba
Tohru
T
Yasuda
Hitoshi
H
Noguchi
Tetsuya
T
Kakuma
Takeshi
T
Watanabe
Toshiie
T
Sakata
Hironobu
H
Yoshimatsu
D002001:Adipose Tissue, Brown / Q000502:physiology; D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000502:physiology; D001786:Blood Glucose; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics; D004302:Dorsomedial Hypothalamic Nucleus / Q000502:physiology; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005247:Feeding Behavior / Q000187:drug effects / Q000502:physiology*; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D006632:Histamine / Q000494:pharmacology; D017442:Histamine Agonists / Q000494:pharmacology; D007026:Hypothalamic Area, Lateral / Q000502:physiology; D007031:Hypothalamus / Q000502:physiology*; D007328:Insulin / Q000097:blood; D007473:Ion Channels; D020738:Leptin / Q000097:blood / Q000235:genetics / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D024101:Mitochondrial Proteins; D009765:Obesity / Q000378:metabolism / Q000503:physiopathology*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D011969:Receptors, Histamine H1 / Q000235:genetics* / Q000378:metabolism*; D013493:Suprachiasmatic Nucleus / Q000502:physiology; D014280:Triglycerides / Q000378:metabolism; D000071256:Uncoupling Protein 1
D001786:Blood Glucose; D002352:Carrier Proteins; D005230:Fatty Acids, Nonesterified; D017442:Histamine Agonists; D007328:Insulin; D007473:Ion Channels; D020738:Leptin; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D016760:Proto-Oncogene Proteins c-fos; D011725:Pyridines; D012333:RNA, Messenger; D011969:Receptors, Histamine H1; D014280:Triglycerides; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; D006632:Histamine; C006183:2-(2-aminoethyl)pyridine