20 YEARS OF LEPTIN: What we know and what the future holds

in Journal of Endocrinology
Author: Steve O'Rahilly
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  • MRC Metabolic Diseases Unit, Metabolic Research Laboratories, Wellcome Trust–MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK

Contributor Notes

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This special issue of Journal of Endocrinology celebrates the 20th anniversary of the discovery of leptin, a hormone produced by adipose tissue, which provides critical signals to the organism regarding the status of its energy stores. The discovery of leptin not only revolutionised our understanding of endocrine physiology but has also resulted in a registered medicinal product which is already improving the health of patients with serious metabolic diseases. In this issue, we have gathered together a group of essays by some of the world leaders in leptin research, including an overview by Dr Jeffrey Friedman who, in his seminal article in December 1994, described the adipocyte-derived hormone, the lack of which was responsible for the severe obesity in ob/ob mice and suggested that it should be named leptin.

Abstract

This special issue of Journal of Endocrinology celebrates the 20th anniversary of the discovery of leptin, a hormone produced by adipose tissue, which provides critical signals to the organism regarding the status of its energy stores. The discovery of leptin not only revolutionised our understanding of endocrine physiology but has also resulted in a registered medicinal product which is already improving the health of patients with serious metabolic diseases. In this issue, we have gathered together a group of essays by some of the world leaders in leptin research, including an overview by Dr Jeffrey Friedman who, in his seminal article in December 1994, described the adipocyte-derived hormone, the lack of which was responsible for the severe obesity in ob/ob mice and suggested that it should be named leptin.

I can recall, as if it was yesterday, my first sight of the 1st December 1994 copy of Nature with its now iconic cover image of an ob/ob mouse outweighing its two WT siblings (Zhang et al. 1994). I devoured the accompanying article with a growing sense of nuchal pilo-erection! Although I had been training as a clinical endocrinologist for almost a decade and had started research in type 2 diabetes, I had only very recently become aware of the long history of mechanistic research in obesity, reaching back to the hypothalamic lesioning experiments of Hetherington & Ranson (1940), the work of Kennedy on evaluating the response of rodents to fasting and overfeeding (Kennedy 1966), the classic parabiosis work of Hervey, which provided the first evidence for a circulating factor affecting body fat stores (Cummings & Hervey 1959), the descriptions of the ob/ob (Ingalls et al. 1950) and db/db (Hummel et al. 1966) mice by Snell, Coleman and colleagues at the Jackson Labs where Coleman subsequently undertook the renowned parabiosis experiments (Coleman 1973), establishing that the ob/ob mouse lacked a circulating factor to which the db/db mouse was resistant.

Given the limited technical resources available at the time, the identification of that circulating factor through positional genetic methods in the mouse was a tour de force requiring prodigious vision, courage, dedication and skill. I am delighted therefore that, in putting together this volume celebrating the discovery of leptin 20 years ago, Jeff Friedman has contributed a personal piece reflecting on the process of leptin's discovery and adumbrating the questions that remain (Friedman 2014).

The identification of the leptin receptor (Tartaglia et al. 1995) and its disruption in the db/db mouse (Chen et al. 1996, Chua et al. 1996) were major landmarks, and Jan Tavernier, whose laboratory has contributed much invaluable information about the relationships between structure and function of the leptin receptor, provides a scholarly overview of this aspect of leptin action (Peelman et al. 2014). Martin Myers has been at the forefront of using murine genetic manipulation to explore the physiological consequences of the perturbation of leptin signalling within the brain and provides an invaluable overview of the broader biology of leptin signalling (Allison & Myers 2014). The fall in circulating leptin levels upon starvation initiates a set of homeostatic responses far wider than those simply concerned with appetite and energy expenditure (Ahima et al. 1996). Among these are its profound effects on the reproductive system. Farid Chehab and Christos Mantzoros, who have made seminal contributions to this aspect of the field, in rodent models and humans respectively, provide thoughtful and insightful summaries of the current state-of-the-art of leptin and reproduction (Chebab 2014, Chou & Mantzoros 2014).

Leptin has recently been approved as a licensed, prescription medicine in both Japan and in the USA. It is therefore highly appropriate that our special issue should have a major focus on studies in humans. Sadaf Farooqi and I provide a perspective summarising the discovery of human genetic disorders of leptin secretion and action including our experience of witnessing, first-hand and for the first time, the dramatic effects of restoring leptin to humans who congenitally lacked the hormone (Farooqi & O'Rahilly 2014).

When leptin was first discovered, there was some understandable excitement about the possibility that it might be a widely applicable panacea for human obesity. To date, this has not proved to be the case, as obesity appears to be generally associated with reduced responsivity to leptin. Alex DePaoli has been intimately involved with leptin as a potential therapeutic from the earliest stage of its evolution and brings his unique insights to this volume (DePaoli 2014). Rosenbaum & Leibel (2014) have undertaken some of the most challenging but insightful studies of the human physiology of leptin and its potential relationship with weight regain after weight loss. In elegant studies of weight-reduced humans, they have shown that preventing the decrement in leptin induced by weight loss can abrogate some of the ‘energy-saving’ responses to weight loss. A deeper understanding of those effects of leptin may eventually result in a broadening of the therapeutic impact of this fascinating peptide.

There are many intriguing elements of leptin's biology and or pharmacology that we have not been able to cover in this volume. The examples include the effects of leptin on insulin sensitivity, blood pressure and the immune system. In the short space of 20 years, leptin has moved from the research journal to the canonical undergraduate physiology textbook as well as from the academic laboratory to the clinic. There is still much to do to illuminate the role of this fascinating adipose-derived hormone in biological functions and to optimise its use to benefit human health. The 30th anniversary issue will, I am sure, be a fascinating read.

Declaration of interest

I declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this editorial.

Funding

This piece is an overview of more than a century of research by many scientists around the world. As such this piece did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

Acknowledgements

The author thank the Medical Research Council, the Wellcome Trust and the NIHR Cambridge Biomedical research centre for continuing support of research in the area of obesity and related metabolic disease.

Reference

  • Ahima RS, Prabakaran D, Mantzoros C, Qu D, Lowell B, Maratos-Flier E & Flier JS 1996 Role of leptin in the neuroendocrine response to fasting. Nature 382 250252. (doi:10.1038/382250a0)

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  • Allison M & Myers M 2014 20 YEARS OF LEPTIN: Connecting leptin signaling to biological function. Journal of Endocrinology 223 T25T35. (doi:10.1530/JOE-14-0404)

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  • Chebab FF 2014 20 YEARS OF LEPTIN: Leptin and reproduction: past milestones, present undertakings and future endeavors. Journal of Endocrinology 223 T37T48. (doi:10.1530/JOE-14-0413)

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  • Chen H, Charlat O, Tartaglia LA, Woolf EA, Weng X, Ellis SJ, Lakey ND, Culpepper J, Moore KJ & Breitbart RE et al. 1996 Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell 84 491495. (doi:10.1016/S0092-8674(00)81294-5)

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  • Chua SC Jr, Chung WK, Wu-Peng XS, Zhang Y, Liu SM, Tartaglia L & Leibel RL 1996 Phenotypes of mouse diabetes and rat fatty due to mutations in the OB (leptin) receptor. Science 271 994996. (doi:10.1126/science.271.5251.994)

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    • Export Citation
  • Chou SH & Mantzoros C 2014 20 YEARS OF LEPTIN: Leptin in human reproductive disorders. Journal of Endocrinology 223 T49T62. (doi:10.1530/JOE-14-0245)

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  • Coleman DL 1973 Effects of parabiosis of obese with diabetes and normal mice. Diabetologia 9 294298. (doi:10.1007/BF01221857)

  • Cummings GR & Hervey J 1959 The effects of lesions in the hypothalamus in parabiotic rats. Physiology 145 336352.

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    • Search Google Scholar
    • Export Citation
  • Farooqi IS & O'Rahilly S 2014 20 YEARS OF LEPTIN: Human disorders of leptin action. Journal of Endocrinology 223 T63T70. (doi:10.1530/JOE-14-0480)

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    • Export Citation
  • Friedman J 2014 20 YEARS OF LEPTIN: Leptin at 20: an overview. Journal of Endocrinology 223 T1T8. (doi:10.1530/JOE-14-0405)

  • Hetherington AW & Ranson SW 1940 Hypothalamic lesions and adiposity in the rat. Anatomical Record 78 149172. (doi:10.1002/ar.1090780203)

  • Hummel KP, Dickie MM & Coleman DL 1966 Diabetes, a new mutation in the mouse. Science 153 11271128. (doi:10.1126/science.153.3740.1127)

  • Ingalls AM, Dickie MM & Snell GD 1950 Obese, a new mutation in the house mouse. Journal of Heredity 41 317318.

  • Kennedy GC 1966 Food intake, energy balance and growth. British Medical Bulletin 22 216220.

  • Peelman F, Zabeau L, Moharana K, Savvides SN & Tavernier J 2014 20 YEARS OF LEPTIN: Insights into signalling assemblies of the leptin receptor. Journal of Endocrinology 223 T9T23. (doi:10.1530/JOE-14-0264)

    • Search Google Scholar
    • Export Citation
  • Rosenbaum M & Leibel RL 2014 20 YEARS OF LEPTIN: Role of leptin in energy homeostasis in humans. Journal of Endocrinology 223 T83T95. (doi:10.1530/JOE-14-0358)

    • Search Google Scholar
    • Export Citation
  • Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R, Richards GJ, Campfield LA, Clark FT & Deeds J et al. 1995 Identification and expression cloning of a leptin receptor, OB-R. Cell 83 12631271. (doi:10.1016/0092-8674(95)90151-5)

    • Search Google Scholar
    • Export Citation
  • Zhang Y, Proenca R, Maffei M, Barone M, Leopold L & Friedman JM 1994 Positional cloning of the mouse obese gene and its human homologue. Nature 372 425432. (doi:10.1038/372425a0)

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This editorial accompanies a thematic review section on 20 Years of Leptin. The Guest Editor for this section was Sir Stephen O'Rahilly, University of Cambridge, Cambridge, UK.

 

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  • Ahima RS, Prabakaran D, Mantzoros C, Qu D, Lowell B, Maratos-Flier E & Flier JS 1996 Role of leptin in the neuroendocrine response to fasting. Nature 382 250252. (doi:10.1038/382250a0)

    • Search Google Scholar
    • Export Citation
  • Allison M & Myers M 2014 20 YEARS OF LEPTIN: Connecting leptin signaling to biological function. Journal of Endocrinology 223 T25T35. (doi:10.1530/JOE-14-0404)

    • Search Google Scholar
    • Export Citation
  • Chebab FF 2014 20 YEARS OF LEPTIN: Leptin and reproduction: past milestones, present undertakings and future endeavors. Journal of Endocrinology 223 T37T48. (doi:10.1530/JOE-14-0413)

    • Search Google Scholar
    • Export Citation
  • Chen H, Charlat O, Tartaglia LA, Woolf EA, Weng X, Ellis SJ, Lakey ND, Culpepper J, Moore KJ & Breitbart RE et al. 1996 Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell 84 491495. (doi:10.1016/S0092-8674(00)81294-5)

    • Search Google Scholar
    • Export Citation
  • Chua SC Jr, Chung WK, Wu-Peng XS, Zhang Y, Liu SM, Tartaglia L & Leibel RL 1996 Phenotypes of mouse diabetes and rat fatty due to mutations in the OB (leptin) receptor. Science 271 994996. (doi:10.1126/science.271.5251.994)

    • Search Google Scholar
    • Export Citation
  • Chou SH & Mantzoros C 2014 20 YEARS OF LEPTIN: Leptin in human reproductive disorders. Journal of Endocrinology 223 T49T62. (doi:10.1530/JOE-14-0245)

    • Search Google Scholar
    • Export Citation
  • Coleman DL 1973 Effects of parabiosis of obese with diabetes and normal mice. Diabetologia 9 294298. (doi:10.1007/BF01221857)

  • Cummings GR & Hervey J 1959 The effects of lesions in the hypothalamus in parabiotic rats. Physiology 145 336352.

  • DePaoli AM 2014 20 YEARS OF LEPTIN: Leptin in common obesity and associated disorders of metabolism. Journal of Endocrinology 223 T71T81. (doi:10.1530/JOE-14-0258)

    • Search Google Scholar
    • Export Citation
  • Farooqi IS & O'Rahilly S 2014 20 YEARS OF LEPTIN: Human disorders of leptin action. Journal of Endocrinology 223 T63T70. (doi:10.1530/JOE-14-0480)

    • Search Google Scholar
    • Export Citation
  • Friedman J 2014 20 YEARS OF LEPTIN: Leptin at 20: an overview. Journal of Endocrinology 223 T1T8. (doi:10.1530/JOE-14-0405)

  • Hetherington AW & Ranson SW 1940 Hypothalamic lesions and adiposity in the rat. Anatomical Record 78 149172. (doi:10.1002/ar.1090780203)

  • Hummel KP, Dickie MM & Coleman DL 1966 Diabetes, a new mutation in the mouse. Science 153 11271128. (doi:10.1126/science.153.3740.1127)

  • Ingalls AM, Dickie MM & Snell GD 1950 Obese, a new mutation in the house mouse. Journal of Heredity 41 317318.

  • Kennedy GC 1966 Food intake, energy balance and growth. British Medical Bulletin 22 216220.

  • Peelman F, Zabeau L, Moharana K, Savvides SN & Tavernier J 2014 20 YEARS OF LEPTIN: Insights into signalling assemblies of the leptin receptor. Journal of Endocrinology 223 T9T23. (doi:10.1530/JOE-14-0264)

    • Search Google Scholar
    • Export Citation
  • Rosenbaum M & Leibel RL 2014 20 YEARS OF LEPTIN: Role of leptin in energy homeostasis in humans. Journal of Endocrinology 223 T83T95. (doi:10.1530/JOE-14-0358)

    • Search Google Scholar
    • Export Citation
  • Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R, Richards GJ, Campfield LA, Clark FT & Deeds J et al. 1995 Identification and expression cloning of a leptin receptor, OB-R. Cell 83 12631271. (doi:10.1016/0092-8674(95)90151-5)

    • Search Google Scholar
    • Export Citation
  • Zhang Y, Proenca R, Maffei M, Barone M, Leopold L & Friedman JM 1994 Positional cloning of the mouse obese gene and its human homologue. Nature 372 425432. (doi:10.1038/372425a0)

    • Search Google Scholar
    • Export Citation