The occurrence of type II diabetes is highly correlated with obesity, but the mechanisms linking the two conditions are incompletely understood. Leptin is a potent insulin sensitizer and in leptin deficient, insulin insensitive, Lep(ob/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 hyperleptinemia and inflammation have been proposed as causative mechanisms. Scrutinizing the role of hyperleptinemia in this process, central hyperleptinemia in Lep(ob/ob) mice was induced by chronic (intracerebroventricular) ICV infusion of leptin (4.2μg/day) over 10 days. This treatment led to a dramatic decline in body weight and food intake as well as improvement in glucose tolerance. Transfer to HFD for 4 days markedly arrested the beneficial effects of leptin on these parameters. Since Lep(ob/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 Lep(ob/ob) mice were used as body weight matched controls. Mice in each group received either intraperitoneal leptin (ip 1.25 mg/kg) or vehicle and glucose tolerance, food intake and the number of phospho-STAT3 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 Lep(ob/ob) mice on LFD (P ≤ 0.001), but was ineffective in mice on HFD. Furthermore when leptin was administered centrally the glucose tolerance of Lep(ob/ob) mice on HFD was significantly impaired (p = 0.007). While leptin induced the number of phospho-STAT3 immunoreactive cells in the ARC and VMH of Lep(ob/ob) mice on LFD, HFD was associated with elevated phospho-STAT3 immunoreactivity in vehicle treated Lep(ob/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 Lep(ob/ob) mice develop leptin resistance on a HFD independent of hyperleptinemia and indicate that the JNK inflammatory pathway plays a key role in the induction of diet-induced glucose intolerance. This article is protected by copyright. All rights reserved.
- energy and glucose homeostasis
- JNK pathway