Increase of neuronal histamine in obese rats is associated with decreases in body weight and plasma triglycerides.
OBJECTIVE
The purpose of the present study was to examine the metabolic effects of a specific histamine H(3) receptor antagonist, the cinnamic amide NNC 0038-0000-1202 (NNC 38-1202).


METHODS
Effects of NNC 38-1202 on paraventricular levels of histamine and acute effects on food intake were followed in normal rats, whereas effects on body weight homeostasis and lipid metabolism were studied in a rat model of diet-induced obesity (DIO).


RESULTS
NNC 38-1202, administered as single oral doses of 15 and 30 mg/kg, significantly (p < 0.01) increased paraventricular histamine by 339 +/- 54% and 403 +/- 105%, respectively, compared with basal levels. The same doses produced significant (p < 0.01) reductions in food intake. In DIO rats receiving NNC 38-1202 in a daily dose of 5 mg/kg for 22 days, a decrease in food intake was associated with a significant (p < 0.001) net loss of body weight (-11.0 +/- 4.8 grams), compared with rats receiving vehicle, which gained 13.6 +/- 3.0 grams. Also, NNC 38-1202 significantly (p < 0.05) reduced plasma triglycerides by approximately 42%, in parallel with increases in plasma free fatty acids and beta-hydroxybutyrate levels. Despite reductions in food intake and body weight following administration of NNC 38-1202, no sign of a decrease in energy expenditure was observed, and whole-body lipid oxidation was significantly (p < 0.05) increased in the period after dosing.


CONCLUSIONS
The present study suggests that antagonistic targeting of the histamine H(3) receptor decreases food intake, body weight, and plasma TG levels and, thus, represents an interesting approach to treatment of obesity and associated hyperlipidemia.
Malmlöf
Kjell
K
Department of Diabetes Pharmacology, Novo Nordisk A/S, Novo Nordisk Park, 2760 Måløv, Denmark. kmal@novonordisk.com
Golozoubova
Valeria
V
Peschke
Bernd
B
Wulff
Birgitte S
BS
Refsgaard
Hanne H F
HH
Johansen
Peter B
PB
Cremers
Thomas
T
Rimvall
Karin
K
D000284:Administration, Oral; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects*; D006632:Histamine / Q000378:metabolism*; D006633:Histamine Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D009765:Obesity / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism*; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018100:Receptors, Histamine H3 / Q000187:drug effects* / Q000378:metabolism; D014280:Triglycerides / Q000097:blood*; D015431:Weight Loss
D006633:Histamine Antagonists; C510817:NNC 38-1049; D010879:Piperazines; D018100:Receptors, Histamine H3; D014280:Triglycerides; D006632:Histamine