Increase of Neuronal Histamine in Obese Rats Is Associated with Decreases in Body Weight and Plasma Triglycerides
2006
Malmlöf, Kjell | Golozoubova, Valeria | Peschke, Bernd | Wulff, Birgitte S. | Refsgaard, Hanne H.F. | Johansen, Peter B. | Cremers, Thomas | Rimvall, Karin
OBJECTIVE: The purpose of the present study was to examine the metabolic effects of a specific histamine H₃ receptor antagonist, the cinnamic amide NNC 0038-0000-1202 (NNC 38-1202). RESEARCH METHODS AND PROCEDURES: 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 ~42%, in parallel with increases in plasma free fatty acids and β-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. DISCUSSION: The present study suggests that antagonistic targeting of the histamine H₃ receptor decreases food intake, body weight, and plasma TG levels and, thus, represents an interesting approach to treatment of obesity and associated hyperlipidemia.
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