Effects of benfluorex on serum triacylglycerols and insulin sensitivity in the corpulent rat.
The JCR:LA-cp rat is obese, insulin resistant, and hyperlipidemic, and the males develop atherosclerosis and ischemic myocardial disease. Benfluorex at 35-40 mg.kg-1 body weight was administered in the food from 10 to 14 weeks of age and resulted in an initial 50% decrease in food consumption. Body weights of male and female rats initially decreased by about 7% and thereafter remained relatively constant, whereas control animals gained about 28% in weight over the treatment period. Pair-fed rats showed body weights virtually identical with those of benfluorex-treated animals. Benfluorex treatment and pair feeding decreased serum triacylglycerol concentrations by about 50%; there was a preferential loss of triacylglycerols containing longer chain fatty acids in the males, whereas this selectivity was not seen in the females. Hyperinsulinemic euglycemic insulin clamp studies were performed using [1-3H]glucose, a tracer that allows for the measurement of total glucose turnover, including hepatic uptake and release. In male cp/cp rats, hyperinsulinemia does not stimulate total glucose turnover, reflecting the very severe insulin resistance, and neither benfluorex treatment nor pair feeding increased total glucose turnover. Hyperinsulinemia in male cp/cp rats decreases hepatic glucose output, and benfluorex treatment or pair feeding reduced this insulin-mediated diversion of glucose to hepatic lipid synthesis. Hyperinsulinemia increases total glucose turnover in female cp/cp rats, and this was not increased further by benfluorex treatment or pair feeding. These effects emphasize the sex-specific differences in metabolic response of the rats to hyperinsulinemia and benfluorex treatment. Benfluorex ameliorates the obesity-insulin resistance-hyperlipidemia syndrome in this experimental model mainly by decreasing hyperphagia, with an accompanying improvement in hepatic glucose metabolism and a related reduction in hypertriglyceridemia.
Russell
J C
JC
Department of Surgery, University of Alberta, Edmonton, Canada.
Graham
S E
SE
Dolphin
P J
PJ
Brindley
D N
DN
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004195:Disease Models, Animal; D004435:Eating / Q000187:drug effects; D005260:Female; D005277:Fenfluramine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D008297:Male; D009765:Obesity / Q000097:blood* / Q000503:physiopathology; D051381:Rats; D011919:Rats, Inbred Strains; D012680:Sensitivity and Specificity; D014280:Triglycerides / Q000097:blood*
D000960:Hypolipidemic Agents; D007328:Insulin; D014280:Triglycerides; D005277:Fenfluramine; C001584:benfluorex