Laboratory of Development and Plasticity of the Postnatal Brain, Inserm U837, Jean-Pierre Aubert Research Centre, Lille, France
5th HTRF Symposium, Avignon, France
Leptin, a 16 kDa peptide hormone primarily produced by adipocytes, is present in the serum at concentrations directly proportional to the amount of adipose tissue, and acts on its cognate receptor, LepR, in the brain to reduce food intake by regulating the activity of neurons in the mediobasal hypothalamus (MBH). In leptin-deficient humans and mice, the administration of leptin is highly effective in reducing hyperphagia and obesity. However, most cases of obesity are associated, paradoxically, with elevated circulating leptin levels that fail to reduce appetite or increase energy expenditure. The mechanisms underlying this resistance to leptin are poorly understood, but potentially involve defective leptin transport across the blood-brain barrier to the cerebrospinal fluid (CSF) or to its sites of action within the CNS, or the failure of the intracellular LepR signalling cascade. Here, we demonstrate that peripherally administered leptin sequentially activates LepR in median eminence tanycytes followed by MBH neurons in a process that requires tanycytic ERK signalling. In mice deficient in the signal-transducing LepRb isoform or with diet-induced obesity, leptin taken up by tanycytes, which form a barrier between the blood and the CSF, accumulates in the median eminence and fails to reach the MBH. Triggering ERK signalling in tanycytes with EGF reestablishes leptin transport and its activation of MBH neurons in obese animals and accelerates the restoration of leptin sensitivity upon the return to a normal-fat diet. Taken together, our findings indicate that the median eminence serves as the route through which leptin is transported into the hypothalamus, and that tanycytes act as a checkpoint along this route. ERK-dependent leptin transport by tanycytes could thus play a critical role in the pathophysiology of leptin resistance, and holds therapeutic potential for the treatment of obesity.