The arcuate nucleus of the hypothalamus (ARH) is a critical component of the neural circuits that regulate energy balance. However, little is known about how peripheral signals reach the ARH. The ARH is adjacent to the median eminence (ME), where highly specialized ependymal cells called tanycytes are found. Their privileged location at the interface between the blood and the brain suggests that these cells might be direct target for a variety of peripheral signals, including the adipocyte-derived hormone leptin. The understanding of leptin transport mechanisms is fundamental as it may provide new insights into cellular processes involved in leptin resistance linked to obesity.

The aim of this work was to determine wether tanycytes of the median eminence could be responsible for leptin entry in the hypothalamus and if they could be involved in the mechanisms responsible for obesity-associated leptin resistance.

In vivo experiments revealed that peripherally injected leptin is sequentially found in ME and later in MBH, leptin receptor activation following the same sequence. In contrast, we observed that leptin failed to reach the hypothalamus in obese mice and accumulates in ME. The use of fluorescent leptin demonstrated that leptin is internalized in ME tanycytes in a polarized manner. The use of a leptin antagonist showed the dependence of leptin receptor(s) activation for leptin internalization in tanycytes.

Experiments performed on cultured tanycytes confirmed our in vivo findings and showed that the release of leptin from tanycytes, which is blocked in obese mice, depends on the activation of ERK signaling pathway. The use of epidermal growth factor (EGF) to activate ERK signaling pathway in tanycytes can rescue leptin transport from ME to MBH in obese mice.

Altogether this data may provide valuable information in the understanding of central leptin transport and may help to explain mechanism underlying obesity-associated leptin resistance.