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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]

The hypothalamus has been identified as a main insulin target tissue for regulating normal body weight and glucose metabolism. Recent observations suggest that c-Jun-N-terminal kinase (JNK)-signalling plays a crucial role in the development of obesity and insulin resistance because neuronal JNK-1 ablation in the mouse prevented high-fat diet-induced obesity (DIO) and increased energy expenditure, as well as insulin sensitivity. In the present study, we investigated whether central JNK inhibition is associated with sensitisation of hypothalamic insulin signalling in mice fed a high-fat diet for 3 weeks and in leptin-deficient mice. We determined whether i.c.v. injection of a pharmacological JNK-inhibitor (SP600125) improved impaired glucose homeostasis. By immunohistochemistry, we first observed that JNK activity was increased in the arcuate nucleus (ARC) and the ventromedial hypothalamus (VMH) in both mouse models, relative to normoglycaemic controls. This suggests that up-regulation of JNK in these regions is associated with glucose intolerance and obesity, independent of leptin levels. Acute i.c.v. injection of SP600125 ameliorated glucose tolerance within 30 min in both leptin-deficient and DIO mice. Given the acute nature of i.c.v. injections, these effects cannot be attributed to changes in food intake or energy balance. In a hypothalamic cell line, and in the ARC and VMH of leptin-deficient mice, JNK inhibition by SP600125 consistently improved impaired insulin signalling. This was determined by a reduction of phospho-insulin receptor substrate-1 [IRS-1(Ser612)] protein in a hypothalamic cell line and a decline in the number of pIRS-1(Ser612) immunoreactive cells in the ARC and VMH. Serine 612 phosphorylation of IRS-1 is assumed to negatively regulate insulin signalling. In leptin-deficient mice, in both nuclei, central inhibition of JNK increased the number of cells immunoreactive for phospho-Akt (Ser473) and phospho-GSK-3β (Ser9), which are important markers of insulin signalling. Collectively, our data suggest that the acute inhibition of central JNK improves impaired glucose homeostasis and is associated with sensitisation of hypothalamic insulin signalling. [ABSTRACT FROM AUTHOR]