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The cellular and molecular bases of leptin and ghrelin resistance in obesity

Key Points

  • The anorexigenic hormone leptin and the orexigenic hormone ghrelin are crucial for metabolic regulation and energy homeostasis

  • Obesity-associated resistance to leptin and ghrelin promotes adiposity and might contribute to the diseases that are associated with this condition beyond metabolic disorders

  • Resistance to leptin and ghrelin is a multifactorial process that involves changes at several levels: from disturbed hormonal production to altered receptor trafficking and signalling in the brain

  • Several molecules and signalling pathways associated with leptin and ghrelin receptors have been identified as potential targets to overcome resistance to these hormones, but none has reversed the energy imbalance in the long term

  • The identification of novel molecular targets and pathways that can be modulated to enhance sensitivity to leptin and ghrelin and restore energy homeostasis is necessary for the development of efficient pharmacological treatments for obesity

Abstract

Obesity, a major risk factor for the development of diabetes mellitus, cardiovascular diseases and certain types of cancer, arises from a chronic positive energy balance that is often due to unlimited access to food and an increasingly sedentary lifestyle on the background of a genetic and epigenetic vulnerability. Our understanding of the humoral and neuronal systems that mediate the control of energy homeostasis has improved dramatically in the past few decades. However, our ability to develop effective strategies to slow the current epidemic of obesity has been hampered, largely owing to the limited knowledge of the mechanisms underlying resistance to the action of metabolic hormones such as leptin and ghrelin. The development of resistance to leptin and ghrelin, hormones that are crucial for the neuroendocrine control of energy homeostasis, is a hallmark of obesity. Intensive research over the past several years has yielded tremendous progress in our understanding of the cellular pathways that disrupt the action of leptin and ghrelin. In this Review, we discuss the molecular mechanisms underpinning resistance to leptin and ghrelin and how they can be exploited as targets for pharmacological management of obesity.

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Figure 1: Physiological functions of leptin and ghrelin.
Figure 2: LepRb signalling and the molecular mechanisms contributing to leptin resistance in obesity.
Figure 3: Hypothalamic ghrelin signalling.
Figure 4: Hypothalamic ghrelin resistance.

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Acknowledgements

H.C. is funded by the US National Institutes of Health (HL127673 and MH109920). M.L.'s research is funded by the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement number 281854; the ObERStress project: Xunta de Galicia (2015-CP079); MINECO co-funded by the FEDER Program of EU (SAF2015-71026-R and BFU2015-70454-REDT/Adipoplast). Centro de Investigación Biomédica en Red (CIBER) de Fisiopatología de la Obesidad y Nutrición is an initiative of the Instituto de Salud Carlos III (ISCIII). K.R.'s research is supported by the US National Institutes of Health (HL084207); the American Heart Association (14EIA18860041); the University of Iowa Fraternal Order of Eagles Diabetes Research Center; and the University of Iowa Center for Hypertension Research.

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The authors contributed equally to all aspects of this manuscript. H.C. and M.L. have joint first authorship.

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Correspondence to Kamal Rahmouni.

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The authors declare no competing financial interests.

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Cui, H., López, M. & Rahmouni, K. The cellular and molecular bases of leptin and ghrelin resistance in obesity. Nat Rev Endocrinol 13, 338–351 (2017). https://doi.org/10.1038/nrendo.2016.222

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