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 sub(3) 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 plus or minus 54% and 403 plus or minus 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 plus or minus 4.8 grams), compared with rats receiving vehicle, which gained 13.6 plus or minus 3.0 grams. Also, NNC 38-1202 significantly (p < 0.05) reduced plasma triglycerides by similar to 42%, in parallel with increases in plasma free fatty acids and {szligbeta}-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 H sub(3) receptor decreases food intake, body weight, and plasma TG levels and, thus, represents an interesting approach to treatment of obesity and associated hyperlipidemia.