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, 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 hyperleptinaemia and
inflammation have been proposed as causative mechanisms. Scrutinising the role of hyperleptinaemia in this process, central hyperleptinaemia in Lep(ob/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 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 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 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). Although
leptin induced the number of pSTAT3 immunoreactive cells in the
ARC and VMH of Lep(ob/ob) mice on LFD, HFD was associated with elevated pSTAT3 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 hyperleptinaemia and also indicate that the JNK inflammatory pathway plays a key role in the induction of diet-induced
glucose intolerance.