Cell Metab. 2014 Feb 4;19(2):293-301.

Hypothalamic tanycytes are an ERK-gated conduit for leptin into the brain.

Balland E1, Dam J2, Langlet F1, Caron E1, Steculorum S1, Messina A1, Rasika S1, Falluel-Morel A3, Anouar Y3, Dehouck B1, Trinquet E4, Jockers R2, Bouret SG5, Prévot V6.

  • 1Inserm UMR837, Jean-Pierre Aubert Research Centre, UDSL, IMPRT, 59000 Lille, France.
  • 2Inserm U1016, CNRS UMR 8104, Institut Cochin, Université Paris Descartes, 75000 Paris, France.
  • 3Inserm U982, University of Rouen, 76821 Mont-Saint-Aignan, France.
  • 4Cisbio Bioassays, Parc Technologique Marcel Boiteux, BP84175, 30200 Codolet, France.
  • 5Inserm UMR837, Jean-Pierre Aubert Research Centre, UDSL, IMPRT, 59000 Lille, France; Neuroscience Program, The Saban Research Institute, Children’s Hospital Los Angeles, University of Southern California, Los Angeles, CA 90027, USA.
  • 6Inserm UMR837, Jean-Pierre Aubert Research Centre, UDSL, IMPRT, 59000 Lille, France. Electronic address: vincent.prevot@inserm.fr.

 

ABSTRACT:

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.

PMID: 24506870

 

SUPPLEMENT:

In leptin-deficient humans and mice, leptin administration effectively reduces hyperphagia and obesity. Paradoxically, most cases of obesity display high circulating leptin levels that fail to reduce appetite or increase energy expenditure. The mechanisms underlying this leptin resistance are unclear, but potentially include its defective transport across the blood-brain barrier to the cerebrospinal fluid (CSF) or to its sites of action within the CNS, and failure of the LepR signaling cascade.

Our findings show that blood-borne leptin enters the brain through the hypothalamic median eminence, and that tanycytes, which capture leptin from the bloodstream, act as a checkpoint along this route. Once past this tanycytic checkpoint and in the CSF, leptin appears to reach the mediobasal hypothalamus and, subsequently, other brain regions, by volume-based transmission (Figure 1). Results intriguingly show that this shuttling of peripheral leptin into the CSF requires activation of tanycytic ERK signaling by the LepRb isoform of the leptin receptor (schematic diagram).
In diet-induced obese animals, circulating leptin accumulates into the median eminence and its access to the mediobasal hypothalamus is disrupted. Epidermal growth factor treatment, which markedly activates ERK signaling in median eminence tanycytes, restores hypothalamic leptin signaling (Figure 2) and function in obese mice with diet-induced leptin resistance, and hastens weight loss when they return to a normal diet.

Figure-12Fig 1. Leptin transported from the periphery into the CSF reaches target areas both in the hypothalamus and in non-hypothalamic areas bordering the ventricles. Fluorescent bioactive leptin was injected intravenously in wild-type mice. Ten minutes later, fluorescent leptin (white labelling) was found not only in downstream hypothalamic neurons (arrows in B and C), but also in other leptin target regions contacting the CSF, such as the hippocampus (D), the cerebral cortex (E), and the medial nucleus of the amygdala (MEA) (F), suggesting that leptin release by tanycytes (arrowheads in B) mediates its access to both metabolic and cognitive brain circuits. Similar results were obtained when fluorescent leptin was injected directly into the CSF (data not shown). Dotted lines in A delineate the ventricles. 3V, third ventricle; VL, lateral ventricle; DG, dentate gyrus, CP, caudate-putamen. In all panels, cell nuclei are counterstained with Hoechst. The scale bar in F indicates the scale for B to F.

 

Figure-21Fig 2. EGF-mediated activation of ERK signaling in the median eminence (ME) restores hypothalamic leptin signaling in diet-induced obese (DIO) mice. The images show representative photomicrographs of phosphorylated STAT3 (pSTAT3) immunofluorescence after intraperitoneal administration of leptin (3 mg/kg, 45 min) or vehicle (45 min) along with EGF treatment 15 min before sacrifice. VMH, ventromedial nucleus of the hypothalamus; DMH, dorsomedial nucleus of the hypothalamus. Scale bar: 200 μm.

 

Schematic-diagram  Fig 3. Schematic diagram 

 

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