Dissection of the Mechanism of Obesity-induced Insulin Resistance

Troglitazone (CS-045) is one of the thiazolidinediones that activate the peroxisomeproliferator-activated receptor γ （PPARγ）这是被禁止的，primarily in adipose tissues To eluciadate the mechanism by which troglitazonerelieves insulin resistance in vivo，我们studied its effects on the white adipose tissues of an obese animal model （obese Zucker rat）Administration of troglitazone for 15d normalized mild hyperglycemia and marked hyperinsulinemia in 15d normalized mild hyperglycemia这些rats. Plasma triglyceride level was decreased by troglitazone in both obese and lean rats.Troglitazone did not change the total weight of white adipose tissues but increased the number ofsmall adipocytes (<2,500μm - D12 - D1) approximately fourfold in both retroperitoneal and subcutaneousadipose tissues of肥胖rats. It also decreased the number of large adipocytesD12) by ~ 50%. In fact，the percentage of apoptotic nuclei was ~ 2.5-fold higher in the troglitazone-treated retroperitonealwhite adipose tissue, tha…More n, control. Concomitantly, troglitazone normalized the，表达式水平TNF- α which were elevated by 2-and 1.4-fold in the retroperitoneal andmesenteric white adipose tissues of the obese ratsTroglitazone also caused a dramatic decrease in the expression leptin leptin，which were increased by 4-10-fold in the white adipose tissues of肥胖rats. These results suggestthe primary action of troglitazone may be to increase the number of small adipocytes in whiteadipose tissues,The increase number of small adipocytes and The decreased number of largeadipocytes in white adipose tissues of troglitazone-treated肥胖rats appear to be an importantmechanism by which increased expression levels of TNF- α and higher levels of plasma lipids are规范化，leading to alleviation of insulin resistance(Okuno et al.， J. Clin. Invest. 101，1354-1361, 1998). Furthermore，we made PPARγ deficient mice. Under high diet PPARγ(+/-) mice have been shown to be protectedfrom肥胖和insulin resistance with higher serum levels of leptin compared with those inwild-type mice(Kubota et al, Mol. Cell. 4, 597-609，1999年suggesting that PPAR - activity promotes increased obesity and insulin resistance under highfat diet. Furthermore, through the search of diabetic patients，number of the 5ubJects with PPARγ Prol2Ala allele(less activity form of PPARγ2) in diabeticgroup are less than that in control non-diabetic group(Hara et al, diabetologia in press). less

Troglitazone (CS-045) is one of the thiazolidinediones that activate the peroxisome proliferator-activated receptor γ (PPARγ), which is expressed primarily in adipose tissues. To eluciadate the mechanism by which troglitazone relieves insulin resistance in vivo, we studied its effects on the white adipose tissues of an obese animal model (obese Zucker rat). Administration of troglitazone for 15 d normalized mild hyperglycemia and marked hyperinsulinemia in these rats. Plasma triglyceride level was decreased by troglitazone in both obese and lean rats. Troglitazone did not change the total weight of white adipose tissues but increased the number of small adipocytes (<2,500μmィイD12ィエD1) approximately fourfold in both retroperitoneal and subcutaneous adipose tissues of obese rats. It also decreased the number of large adipocytes (> 5,000μmィイD12ィエD1) by〜50%. In fact, the percentage of apoptotic nuclei was 〜2.5-fold higher in the troglitazone-treated retroperitoneal white adipose tissue, tha … More n, control. Concomitantly, troglitazone normalized the, expression levels of TNF- α which were elevated by 2-and 1.4-fold in the retroperitoneal and mesenteric white adipose tissues of the obese rats, respectively. Troglitazone also caused a dramatic decrease in the expression levels of leptin, which were increased by 4-10-fold in the white adipose tissues of obese rats. These results suggest that the primary action of troglitazone may be to increase the number of small adipocytes in white adipose tissues, presumably via PPARγ. The increase number of small adipocytes and the decreased number of large adipocytes in white adipose tissues of troglitazone-treated obese rats appear to be an important mechanism by which increased expression levels of TNF- α and higher levels of plasma lipids are normalized, leading to alleviation of insulin resistance(Okuno et al., J. Clin. Invest. 101, 1354-1361, 1998). Furthermore, we have made PPARγ deficient mice. Under high diet PPARγ(+/-) mice have been shown to be protected from obesity and insulin resistance with higher serum levels of leptin compared with those in wild-type mice(Kubota et al, Mol. Cell. 4, 597-609, 1999). suggesting that PPARγ activity promotes increased obesity and insulin resistance under high fat diet. Furthermore, through the search of diabetic patients, the number of the 5ubJects with PPARγ Prol2Ala allele(less activity form of PPARγ2) in diabetic group are less than that in control non-diabetic group(Hara et al, diabetologia in press). Less