Temporal and regional onset of leptin resistance in diet-induced obese mice

Abstract

In common forms of obesity, leptin fails to convey its regulatory effect. This so called "leptin resistance", is not well understood, and solving this puzzle is a key to understanding how obesity develops. Here, we investigated the temporal and regional onset of leptin resistance in response to a diet enriched with long-chain saturated fatty acids (HFD) in mice. Mice were exposed to either low-fat diet (LFD) or HFD for 4hr, 24hr, 10d and 28d. Mice in each group received an i.p injection of either PBS or leptin and the number of phosphorylated signal transducer and activator of transcription-3 (pSTAT3) immunoreactive (ir) cells in the ARC, VMH and DMH were analysed 30- or 120 min after treatment. In the ARC, as soon as 24hrs of HFD the molecular leptin response was reduced by 40% (p<0.01). Compared with 24hr, after 10d the number of leptin-induced pSTAT3-ir cells was elevated after 120 min suggesting a sustained response and a partial return of leptin sensitivity. After 28d, leptin failed to induce the number of pSTAT3-ir over control levels, suggesting markedly reduced sensitivity to leptin. In the VMH after 24hrs we observed a 50% reduction in leptin-induced pSTAT-3-ir cells, followed by a further decline after 10d. However, after 28d there was a significant increase in pSTAT-3-ir cells (p<0.05) indicating partial recovery of leptin sensitivity. In contrast to these two regions, in the DMH no loss of leptin sensitivity was observed at any time-point. These findings demonstrate that a loss of sensitivity to leptin occurs rapidly after exposure to HFD in the ARC and VMH but not the DMH. However, there seems to be a biphasic pattern of leptin responsiveness, with a partial return of leptin sensitivity occurring after 10 days in the arcuate nucleus, and after 28 days in the VMH. By 28 days, the response to leptin in the arcuate nucleus was completely lost. These findings suggest that molecular responses to leptin are altered after high fat feeding in a time- and region-specific manner.

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