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    Loss of leptin entry into the brain leads to obesity and type 2 diabetes

    Leptin entry into the brain via a tanycytic shuttle, mediated by leptin Receptor-EGF receptor molecular complex, controls lipid metabolism and pancreas function.

    A close collaboration between the teams of Vincent Prévot (INSERM UMR-S 1172, Lille), Julie Dam/Ralf Jockers (Institut Cochin, INSERM U1016, CNRS, Université de Paris) and Stéphane Gasman (INCI, CNRS UPR3212, Strasbourg), in an article published in the journal Nature Metabolism, highlights a key communication point between peripheral tissues and the brain. Leptin, produced by the adipose tissue, is a hormone which circulates in the bloodstream and informs the hypothalamus in the brain about the level of energy stores. In this new study, the authors reveal the molecular mechanisms and the consequences of impaired leptin entry into the brain in the development of obesity and diabetes, opening important therapeutic perspectives in metabolic disorders.

    Deficits in leptin receptor signaling are well-known to cause obesity. Secreted in the bloodstream by the adipose tissue, leptin is an anorectic hormone decreasing satiety and regulating energy expenditure but also glucose homeostasis. To exert this action, leptin must be transported from the bloodstream to the arcuate nucleus of the hypothalamus, located in the brain, crossing a very special barrier, called the median eminence, which is formed of glial cells, the tanycytes. The expression of the leptin receptor in this area has so far remained controversial, and the mechanisms and implications of an alteration of this local leptin transport and entry into the brain are unknown.
    A consortium formed by the teams of Stéphane Gasman, Julie Dam/Ralf Jockers and Vincent Prévot has shed light on the molecular mechanisms involved and the importance of leptin entry into the brain on metabolic regulation. Using a multidisciplinary approach, at the molecular, cellular and in vivo level, the authors show that tanycytes, expressing the functional leptin receptor (LepRb), respond to leptin, and that the transcytotic transport of leptin requires a coordinated activation of a molecular complex between LepR and the EGF receptor (EGFR). Selective suppression of LepR (or EGFR) in tanycytes blocks the entry of leptin to a very specific site in the brain, and is thought to trigger an alteration in sympathetic tone. The loss of leptin transport specifically at the level of the tanycytic gate, not only induces an increase in food intake and fat mass, but results also in fasting hyperglycaemia and glucose intolerance by modification of the physiology of the pancreas and attenuation of insulin secretion by beta-cells.

    By suppressing the LepR receptor at the gates of leptin entry into the brain, the animal model obtained intriguingly exhibits the characteristics of the type 2 diabetes known as “East Asian” (Korea and Japan) still poorly studied by researchers. While the so-called "Western" diabetes is mainly associated with significant overweight or morbid obesity, this other type of type 2 diabetes is characterized by a slight overweight with an increase in abdominal fat, and is rather specified by an early failure of pancreatic insulin secretion, as seen in the animal model where LepR is absent in tanycytes. The development of this new animal model will perhaps allow to advance research on this particular form of type 2 diabetes which affects millions of people.

    The transport of leptin through tanycytes regulated by LepR/EGFR could therefore be crucial for the pathophysiology of type 2 diabetes in addition to obesity, with therapeutic implications.

    This study was funded by ANR (GlioShuttles4Metabolism), was chosen for the cover of the issue of Nature Metabolism published in August 2021, and was highlighted by a News & Views of the same issue.

    Figure legend

    Leptin is shuttled from the bloodstream to the arcuate nucleus of the hypothalamus, located in the brain, by tanycytic cells of the median eminence barrier. This transport is regulated by the molecular complex formed between the leptin receptor (LepR) and the EGF receptor (EGFR). Suppression of LepR or EGFR specifically in tanycytes results in elevated food intake, increased fat mass and glucose intolerance related to change in pancreatic function with decreased glucose-induced insulin secretion. These results suggest that the altered entry of leptin via the tanycytes could contribute to the development of obesity and type 2 diabetes.

     

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    Duquenne M, Folgueira C*, Bourouh C*, Millet M*, Silva A*, Clasadonte J*, Imbernon M, Fernandois D, Martinez-Corral I, Kusumakshi S, Caron E, Rasika S, Deliglia E, Jouy N, Oishi A, Mazzone M, Trinquet E, Tavernier J, Kim YB, Ory S, Jockers R, Schwaninger M, Boehm U, Nogueiras R, Annicotte JS, Gasman S#, Dam J# and Prévot V#. Leptin brain entry via a tanycytic LepR-EGFR shuttle controls lipid metabolism and pancreas function. Nat Metab. 2021 Aug 2.
    PMID: 34341568; DOI: 10.1038/s42255-021-00432-5
    * These authors contributed equally
    # These authors jointly supervised this work

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