부산대학교 도서관

The occurrence of type II diabetes is highly correlated with obesity, although the mechanisms linking the two conditions are incompletely understood. Leptin is a potent insulin sensitiser and, in leptin-deficient, insulin insensitive, Lepob/ob mice, leptin improves glucose tolerance, indicating that leptin resistance may link obesity to insulin insensitivity. Leptin resistance occurs in response to a high-fat diet ( HFD) and both hyperleptinaemia and inflammation have been proposed as causative mechanisms. Scrutinising the role of hyperleptinaemia in this process, central hyperleptinaemia in Lepob/ob mice was induced by chronic i.c.v. infusion of leptin (4.2 μg/day) over 10 days. This treatment led to a dramatic decline in body weight and food intake, as well as an improvement in glucose tolerance. Transfer to HFD for 4 days markedly arrested the beneficial effects of leptin on these parameters. Because Lepob/ob mice are exquisitely sensitive to leptin, the possibility that leptin could reverse HFD-induced glucose intolerance in these animals was investigated. HFD led to increased body weight and glucose intolerance compared to a low-fat diet ( LFD). Older and heavier Lepob/ob mice were used as body weight-matched controls. Mice in each group received either i.p. leptin (1.25 mg/kg) or vehicle, and glucose tolerance, food intake and the number of phosphorylated signal transducer and activator of transcription (pSTAT)3 immunoreactive cells in the arcuate nucleus ( ARC) and ventromedial hypothalamus ( VMH) were analysed. Leptin improved glucose tolerance (P = 0. 019) and reduced food intake in Lepob/ob mice on LFD (P ≤ 0.001) but was ineffective in mice on HFD. Furthermore, when leptin was administered centrally, the glucose tolerance of Lepob/ob mice on HFD was significantly impaired (P = 0.007). Although leptin induced the number of p STAT3 immunoreactive cells in the ARC and VMH of Lepob/ob mice on LFD, HFD was associated with elevated p STAT3 immunoreactivity in vehicle-treated Lepob/ob mice that was unaffected by leptin treatment, suggesting central leptin resistance. Negating central inflammation by co-administering a c-Jun n-terminal kinase ( JNK) inhibitor reinstated the glucose-lowering effects of leptin. These findings demonstrate that Lepob/ob mice develop leptin resistance on a HFD independent of hyperleptinaemia and also indicate that the JNK inflammatory pathway plays a key role in the induction of diet-induced glucose intolerance. [ABSTRACT FROM AUTHOR]