TROGLITAZONE ACTION IS INDEPENDENT OF ADIPOSE-TISSUE

We have investigated the antidiabetic action of troglitazone in aP2/DT A mice, whose white and brown fat was virtually eliminated by fat-spec ific expression of diphtheria toxin A chain. aP2/DTA mice had markedly suppressed serum leptin levels and were hyperphagic, but did not gain excess weight, aP2/DTA mice fed a control diet were hyperlipidemic, h yperglycemic, and had hyperinsulinemia indicative of insulin-resistant diabetes, Treatment with troglitazone alleviated the hyperglycemia, n ormalized the tolerance to intraperitoneally injected glucose, and sig nificantly decreased elevated insulin levels, Troglitazone also marked ly decreased the serum levels of cholesterol, triglycerides, and free fatty acids both in wild-type and aP2/DTA mice, The decrease in serum triglycerides in aP2/DTA mice was due to a marked reduction in VLDL- a nd LDL-associated triglyceride. In skeletal muscle, triglyceride level s were decreased in aP2/DTA mice compared with controls, but glycogen levels were increased, Troglitazone treatment decreased skeletal muscl e, but not hepatic triglyceride and increased hepatic and muscle glyco gen content: in wild-type mice. Troglitazone deer-eased muscle glycoge n content in aP2/DTA mice without affecting muscle triglyceride levels , The levels of peroxisomal proliferator-activated receptor gamma mRNA in liver increased slightly in aP2/DTA mice and were not changed by t roglitazone treatment, The results demonstrate that insulin resistance and diabetes can occur in animals without significant adipose deposit s. Furthermore, troglitazone can alter glucose and lipid metabolism in dependent of its effects on adipose tissue.