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Leptin Receptors and Mechanism of Action

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Leptin

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Abstract

The phenotypic exploration of obesity mutant mice in the 1950s was the starting point of a long scientific journey, which climaxed more than 40 years later with the identification of leptin and its receptor LepR. This was rapidly followed by the discovery of rare congenital leptin deficiency and mutations in LEPR in subjects with strikingly similar early-onset and massive obesity phenotypes as in obese mutant mice. In this chapter, we describe several genetic abnormalities found in human LEPR and their dramatic clinical consequences. We address the question of the difficult management of patients with LEPR mutation. Additionally, a wealth of information on LEPR structure and mechanism of action has been produced through molecular, biochemical, and modeling studies. However, as discussed in the first part of this chapter, deciphering the molecular mechanisms underlying resistance to leptin, which occur in the vast majority of obese subjects, remains a challenge.

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Acknowledgements 

Teams are supported by grants from the European Union’s Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 241592 (to R.J.), the Agence Nationale de la Recherche ANR-12-JSV1-0011 (to J.D.), the “Who am I?” laboratory of excellence no. ANR-11-LABX-0071 funded by the French government through its “Investments for the Future” program operated by the French National Research Agency (ANR) under grant no. ANR-11-IDEX-0005-01 (to J.D. and R.J.) as well as the IHU University/Hospital Institute of Cardiometabolism and Nutrition (ICAN no. ANR-10-IAHU). Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS), and Programme Hospitalier de Recherche Clinique (AP/HP). The authors thank Mr. Ludovic Le Chat in helping for iconography and paper formatting.

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  1. Inserm U1016, Institut Cochin, Université Paris Descartes, Sorbonne Paris Cite, Paris, France

    Julie Dam Ph.D. & Ralf Jockers Ph.D.

  2. Institute of Cardiometabolism and Nutrition, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Inserm UMR-S1166, Université Pierre et Marie Curie-Paris6, Sorbonne University, Paris, France

    Michèle Guerre-Millo Ph.D. & Karine Clément M.D., Ph.D.

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  1. Julie Dam Ph.D.
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  3. Michèle Guerre-Millo Ph.D.
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Correspondence to Karine Clément M.D., Ph.D. .

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  1. Division of Endocrinology, Diabetes and Metabolism, University of Tennessee Health Science Center, Memphis, Tennessee, USA

    Sam Dagogo-Jack, MD

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Dam, J., Jockers, R., Guerre-Millo, M., Clément, K. (2015). Leptin Receptors and Mechanism of Action. In: Dagogo-Jack, MD, S. (eds) Leptin. Springer, Cham. https://doi.org/10.1007/978-3-319-09915-6_2

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