Mutations in BSCL2 underlie human congenital generalized lipodystrophy. We inactivated Bscl2 in mice to examine the mechanisms whereby absence of Bscl2 leads to adipose tissue loss and metabolic disorders. Bscl2 ؊/؊ mice develop severe lipodystrophy of white adipose tissue (WAT), dyslipidemia, insulin resistance, and hepatic steatosis. In vitro differentiation of both Bscl2

Ginsenoside Re (Re), a compound derived from Panax ginseng, shows an antidiabetic effect. However, the molecular basis of its action remains unknown. We investigated insulin signaling and the antiinflammatory effect by Re in 3T3-L1 adipocytes and in high-fat diet (HFD) rats to dissect its anti-hyperglycemic mechanism. Glucose uptake was measured in 3T3-L1 cells and glucose infusion rate determined by clamp in HFD rats. The insulin signaling cascade, including insulin receptor (IR) beta-subunit, IR substrate-1, phosphatidylinositol 3-kinase, Akt and Akt substrate of 160 kDa, and glucose transporter-4 translocation are examined. Furthermore, c-Jun NH(2)-terminal kinase (JNK), MAPK, and nuclear factor (NF)-kappaB signaling cascades were also assessed. The results show Re increases glucose uptake in 3T3-L1 cells and glucose infusion rate in HFD rats. The activation of insulin signaling by Re is initiated at IR substrate-1 and further passes on through phosphatidylinositol 3-kinase and downstream signaling cascades. Moreover, Re demonstrates an impressive suppression of JNK and NF-kappaB activation and inhibitor of NF-kappaBalpha degradation. In conclusion, Re reduces insulin resistance in 3T3-L1 adipocytes and HFD rats through inhibition of JNK and NF-kappaB activation.

Glucagon-like peptide-1 (7-36) amide (GLP-1) is an insulin secretagogue. Recently, many studies have shown GLP-1 can improve insulin resistance in peripheral tissues. In the present study, we investigated glucose uptake in 3T3-L1 adipocytes in either basal or insulin resistant state and dissected insulin signaling pathway in order to elucidate the molecular mechanisms of GLP-1 mediated improvement of insulin resistance. We found GLP-1 and its long lasting analogue, exendin 4 up-regulated basal IR, IRS-1 and Glut 4 expressions although they did not increase basal glucose uptake alone. However, GLP-1 and exendin-4 increased insulin mediated glucose uptake in intact and TNF-alpha treated 3T3-L1 adipocytes by up-regulation of phophorylated IRbeta, IRS-1, Akt and GSK-3beta. These results indicate that GLP-1 and its analogue exendin-4 can amplify insulin signaling in 3T3-L1 adipocytes by up-regulation of some crucial insulin signaling molecules.