Hypolipidemic, antiobesity, and hypoglycemic-hypoinsulinemic effects of beta,beta'-methyl-substituted hexadecanedioic acid in sand rats.

Abstract

Treatment of male sand rats kept on a balanced laboratory chow diet ad libitum with beta,beta'-tetramethyl-substituted hexadecanedioic acid (MEDICA 16) resulted in a hypolipidemic effect accompanied by an extensive reduction in adiposity, with a concomitant hypoglycemic-hypoinsulinemic effect. The overall effect was sustained as long as the drug was administered. The hypolipidemic effect of MEDICA 16 consisted of a 70 and 40% decrease in plasma triacylglycerols and cholesterol, respectively, and resulted from inhibition of liver lipogenesis and cholesterogenesis. Adipose reduction by MEDICA 16 treatment or calorie restriction consisted of a 75-90% decrease in the perirenal, omental, epididymal, and subcutaneous fat, with a 50% decrease in liver neutral lipids. The reduction in adiposity was accounted for by a respective decrease in the lipid content of individual adipocytes, with a concomitant decrease in the number of adipocytes of selected adipose tissues. The decrease induced in adiposity by MEDICA 16 treatment could not be accounted for by anorectic or cathartic effects of the drug. The hypoglycemic-hypoinsulinemic effect of MEDICA 16 consisted of amelioration of the tolerance of glucose with normalization of plasma insulin. It was accompanied by an eightfold increase in the number of insulin receptors in epididymal adipocytes, which was, however, counteracted by a decrease in their affinity for insulin. The receptor and postreceptor effects exerted by MEDICA 16 were similar to those of calorie restriction. The overall effect of MEDICA 16 in sand rats may reflect the pharmacological potential of MEDICA compounds in pathological hyperlipidemic-obesity-diabetic syndromes.