Cell Metabolism
Volume 19, Issue 2, 4 February 2014, Pages 293-301
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Short Article
Hypothalamic Tanycytes Are an ERK-Gated Conduit for Leptin into the Brain

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Highlights

  • Blood-borne leptin enters the hypothalamus through the median eminence

  • Tanycytes act as a checkpoint in the entry of leptin into the brain

  • LepRb-ERK signaling is required for hypothalamic leptin uptake

  • Triggering ERK signaling in tanycytes rescues leptin function in obese mice

Summary

Leptin secreted by adipocytes acts on the brain to reduce food intake by regulating neuronal activity in the mediobasal hypothalamus (MBH). Obesity is associated with resistance to high circulating leptin levels. Here, we demonstrate that peripherally administered leptin activates its receptor (LepR) in median eminence tanycytes followed by MBH neurons, a process requiring tanycytic ERK signaling and the passage of leptin through the cerebrospinal fluid. In mice lacking the signal-transducing LepRb isoform or with diet-induced obesity, leptin taken up by tanycytes accumulates in the median eminence and fails to reach the MBH. Triggering ERK signaling in tanycytes with EGF reestablishes leptin transport, elicits MBH neuron activation and energy expenditure in obese animals, and accelerates the restoration of leptin sensitivity upon the return to a normal-fat diet. ERK-dependent leptin transport by tanycytes could thus play a critical role in the pathophysiology of leptin resistance, and holds therapeutic potential for treating obesity.

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These authors contributed equally to this work