- Email: [email protected]
20 years of leptin: From the discovery of the leptin gene to leptin in our therapeutic armamentarium
ME TA BOL I SM C LI N I CA L A ND E XP E RI ME N TAL 64 (2 0 1 5 ) 1 –4
Available online at www.sciencedirect.com
Metabolism www.metabolismjournal.com
Leptin in the 21st Century
20 years of leptin: From the discovery of the leptin gene to leptin in our therapeutic armamentarium 1.
Introduction
This issue of the journal Metabolism celebrates the 20 years since the discovery of the prototypical adipose tissue secreted hormone leptin [1–9]. Leptin has proven to be a key marker of the amount of energy stores in the body, and leptin levels circulate at levels proportional to the amount of the amount of body fat, signaling available energy stores [10]. Leptin levels also decrease in response to acute caloric deprivation, suggesting a role for leptin in the broader context of regulating energy homeostasis [11]. In the spirit of science, leptin has proven to be unpredictable and truly fascinating—a system worth exploring and understanding. Indeed, the discovery of leptin has changed our understanding of adipose tissue and energy regulation and has provided a much better understanding of the connection between energy reserves and several physiological functions including but not limited to metabolism, reproductive function and immune function. At this twentieth anniversary of its discovery, papers to be published in this special issue on leptin present the wealth of knowledge that has been gained in this field and also highlight the many questions that remain to be answered. Leptin, originally developed as a potential therapy for obesity, was recently approved by the Food and Drug Administration (FDA) for the treatment of lipodystrophy. In the meantime, we realized that although its usefulness as a pharmacotherapy for obesity was limited, leptin may still be useful as a combination therapy with other medications to treat obesity and/or as a potentially effective medication in other disorders. Perhaps, even more importantly, the discovery of leptin has opened the way to critical discoveries about energy homeostasis and adipose tissues. Knowledge about how energy intake and expenditure are regulated has grown exponentially since the discovery of leptin and has furthered significantly the understanding of many critical neuroendocrine pathways with which leptin interacts and/or modulates to control body weight and energy intake/expenditure [1–3].
2.
Leptin as a complex signal
Mice which are ob/ob, lacking leptin, and db/db, lacking a functional leptin receptor, have given us novel insights into http://dx.doi.org/10.1016/j.metabol.2014.10.023 0026-0495/© 2015 Published by Elsevier Inc.
the physiology of leptin. In addition to their most obvious obesity phenotype, these animals have a unique behavioral profile that lends more credence to the function of leptin in regulating other key cognitive and behavioral processes. These ob/ob or db/db mice are non-aggressive, have very little locomotor activity, and are not sexually active [8,9,12]. These findings present a unique avenue of understanding how deeply the impacts of leptin are to the general system as well the cognitive impacts of leptin on complex behaviors, currently a very active field for research [13]. One of the main targets of leptin in the brain is the hypothalamus and neurons which express proopiomelanocortin (POMC) [13–15], which are activated by leptin, as well as agouti-related peptide (AgRP) and neuropeptide Y (NPY) neurons [16,17] which are inhibited by leptin. In turn, these neurons influence the activity of many other neurons in the brain [13,18] creating a key neural circuitry controlling energy intake and expenditure. The critical understanding of this circuitry, which has been growing in size and complexity with time, is expected to not only help us form a better understanding of the complex system regulating energy homeostasis but also how leptin influences other neural circuits to alter behavior and cognition. For example, disease states such as depression [13,19] as well as physiological functions such as reward processing through dopaminergic neurons in the midbrain have been shown to be influenced by hormones like leptin [15,20].
3.
Leptin and neuroendocrine function
We have also learned that leptin, particularly in states associated with energy deficiency and hypoleptinemia, influences several neuroendocrine axes, including the thyroid, gonadal, cortisol and growth hormone axes to regulate reproduction and reproductive behaviors and capacity, activity, thermoregulation and stress [21–25]. Detailed information about this physiological role of leptin with direct translational implications and therapeutic potential will be covered in subsequent articles of this special edition. Under normal conditions, leptin acts as a key signal to the brain conveying information that there is adequate energy available for normal physiologic processes, such as fertility, bone health, and cognition [13,15]. In contrast, even with
2
ME TAB O L IS M C LI N IC A L A N D E XP E RI ME N TAL 6 4 (2 0 1 5 ) 1–4
acute energy restriction, leptin levels decrease abruptly and several neuroendocrine responses are affected in animals [26] and humans [11]. In leptin deficient states, such as in exercise-induced hypothalamic amenorrhea, where individuals suffer from infertility and/or delayed puberty, decreased bone density, and other developmental and stress-related problems [27], it has been clearly proven that the lack of appropriate leptin levels is directly linked with the abnormal phenotype [23,28,29]. In proof of concept studies, leptin has been proven to normalize neuroendocrine and immune function [23,28,29] and to improve bone density [30] in these women. Other leptin deficient states include lipodystrophy, i.e. congenital or acquired absence of fat, for which leptin was recently approved in the USA and Japan [31–33].
4.
Leptin in obesity
Physiologic increases in plasma leptin levels in leptin deficient and wild type mice lead to a dose dependent reduction of food intake and loss of weight [34]. While leptin has potent effects on reducing food intake and body weight in ob and wild type animals, its efficacy in obese animals is variable and often reduced [34]. The extreme case of leptin resistance can be observed in the db mouse model which has a mutation in the leptin receptor [8,9]. In the absence of leptin's actions, these mice become obese and secondarily overproduce the hormone. In other animal models of obesity, leptin resistance or tolerance is more complex, and can in principle develop at many points in the neural circuitry that regulates feeding. In humans, leptin is highly potent in patients with low endogenous levels but its effects in lean normoleptinemic patients have not been studied extensively [22,28,30,32,35]. We have shown that in hypoleptinemic subjects, leptin administration alters appetite and activates several brain centers in comparison to control subjects [36] and that in extremely lean hypoleptinemic subjects with exercise-induced amenorrhea, treatment with leptin may result in weight loss when circulating leptin levels exceed the normal physiological range, an effect that is completely reversible with altering leptin dose to result in physiological circulating leptin levels [23,29]. In contrast, leptin has variable effects at very high doses (0.3 mg/kg bid) as monotherapy for obesity in the general population whereas a lower dose (0.1 mg/kg bid) did not show efficacy [37]. Whether garden variety obesity is a leptin tolerant or resistant state in humans or whether higher doses of leptin lead to tachyphylaxis remains to be studied in detail [38]. In addition, whether the efficacy of leptin for the treatment of obesity may increase when it is combined with other agents that cause weight loss, such as with amylin (pramlintide), a pancreatic peptide that is approved for the treatment of diabetes, and whether the combination may have additive or synergistic effects when co-administered remains to be studied in detail by future studies [38].
5.
Future directions
While much has been learned, the road ahead is wide open and still likely to lead to new advances since several key
questions remain unanswered. What regulates leptin gene expression and can this be leveraged to alter circulating leptin levels without encountering neutralizing antibodies? How is leptin transported into the central nervous system (CNS) and is leptin transport into the CNS a potential locus of leptin tolerance? How does leptin control energy homeostasis and metabolism? What signaling pathways are activated by leptin in humans [3,31,39,40] and what is the physiological role of leptin signaling in peripheral tissues? Are some of leptin's effects peripherally mediated or are most or all of its effects mediated by the CNS? What are the physiologic and cellular mechanisms by which leptin reduces adipose deposits in fat and other tissues and what is the nature of leptin tolerance? What are the physiologic and cellular mechanisms by which leptin improves insulin resistance, hyperlipidemia and glucose metabolism in lipodystrophic subjects and beyond? Does leptin act to a large extent by suppressing glucagon or are there other novel mechanisms also at play and what are the translational implications of such mechanisms? [41] Finally, how does leptin modulate the complex physiology of the behavioral/motivational system and what are the clinical implications of such regulation in disease states such as depression? Thus, beyond feeding and energy homeostasis, it is now understood that leptin's effects are much further reaching and may impact many other systems as well. The papers of this volume of Metabolism have been carefully selected to present an authoritative account of the biology and clinical applications of leptin that expands on all these themes.
Funding None.
Disclosure The authors have no conflicts of interest to disclose.
Jeffrey M. Friedman Howard Hughes Medical Institute, Rockefeller University New York, NY Corresponding author at: The Rockefeller University, 1230 York Avenue, New York, NY 10065 Christos S. Mantzoros Section of Endocrinology, VA Boston Healthcare System/Harvard Medical School, Boston, MA Division of Endocrinology, Beth-Israel Deaconess Medical Center/Harvard Medical School, Boston, MA
REFERENCES
[1] Ingalls AM, Dickie MM, Snell GD. Obese, a new mutation in the house mouse. Obes Res 1996;4(1):101 [Epub 1996/01/01, PubMed PMID: 8787944]. [2] Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human
ME TA BOL I SM C LI N I CA L A ND E XP E RI ME N TAL 64 (2 0 1 5 ) 1 –4
[3]
[4]
[5] [6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
homologue. Nature 1994;372(6505):425–32. http://dx.doi.org/ 10.1038/372425a0 [Epub 1994/12/01, PubMed PMID: 7984236]. Moon BC, Friedman JM. The molecular basis of the obese mutation in ob2j mice. Genomics 1997;42(1):152–6. http://dx. doi.org/10.1006/geno.1997.4701 [Epub 1997/05/15, PubMed PMID: 9177786]. Coleman DL. Obese and diabetes: two mutant genes causing diabetes-obesity syndromes in mice. Diabetologia 1978;14(3): 141–8 [Epub 1978/03/01, PubMed PMID: 350680]. Hervey GR. Regulation of energy balance. Nature 1969;222 (5194):629–31 [Epub 1969/05/17, PubMed PMID: 5768271]. Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals. Nature 1998;395(6704):763–70. http://dx. doi.org/10.1038/27376 [Epub 1998/10/31, PubMed PMID: 9796811]. Halaas JL, Gajiwala KS, Maffei M, Cohen SL, Chait BT, Rabinowitz D, Lallone RL, Burley SK, Friedman JM. Weightreducing effects of the plasma protein encoded by the obese gene. Science 1995;269(5223):543–6 [Epub 1995/07/28, PubMed PMID: 7624777]. Lee GH, Proenca R, Montez JM, Carroll KM, Darvishzadeh JG, Lee JI, Friedman JM. Abnormal splicing of the leptin receptor in diabetic mice. Nature 1996;379(6566):632–5. http://dx.doi.org/ 10.1038/379632a0 [Epub 1996/02/15, PubMed PMID: 8628397]. Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R, Richards GJ, Campfield LA, Clark FT, Deeds J, Muir C, Sanker S, Moriarty A, Moore KJ, Smutko JS, Mays GG, Wool EA, Monroe CA, Tepper RI. Identification and expression cloning of a leptin receptor, OB-R. Cell 1995;83(7):1263–71 Epub 1995/ 12/29, PubMed PMID: 8548812. Maffei M, Halaas J, Ravussin E, Pratley RE, Lee GH, Zhang Y, Fei H, Kim S, Lallone R, Ranganathan S, et al. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat Med 1995;1(11): 1155–61 [Epub 1995/11/01, PubMed PMID: 7584987]. Chan JL, Heist K, DePaoli AM, Veldhuis JD, Mantzoros CS. The role of falling leptin levels in the neuroendocrine and metabolic adaptation to short-term starvation in healthy men. J Clin Invest 2003;111(9):1409–21. http://dx.doi.org/10.1172/jci17490 [Epub 2003/05/03, PubMed PMID: 12727933; PubMed Central PMCID: PMCPMC154448]. Bray GA. Obesity, a disorder of nutrient partitioning: the Mona Lisa hypothesis. J Nutr 1991;121(8):1146–62 [Epub 1991/ 08/01. PubMed PMID: 1861165]. Farr OM, Tsoukas MA, Mantzoros CS. Leptin and the brain: Influences on brain development, cognitive functioning and psychiatric disorders. Metabolism 2014. http://dx.doi.org/10. 1016/j.metabol.2014.07.004 [Epub 2014/08/06, PubMed PMID: 25092133]. Lu D, Willard D, Patel IR, Kadwell S, Overton L, Kost T, Luther M, Chen W, Woychik RP, Wilkison WO, et al. Agouti protein is an antagonist of the melanocyte-stimulating-hormone receptor. Nature 1994;371(6500):799–802. http://dx.doi.org/10. 1038/371799a0 [Epub 1994/10/27, PubMed PMID: 7935841]. Stieg MR, Sievers C, Farr O, Stalla GK, Mantzoros CS. Leptin: a hormone linking activation of neuroendocrine axes with neuropathology. Psychoneuroendocrinology 2014;51C:47–57. http://dx.doi.org/10.1016/j.psyneuen.2014.09.004 [Epub 2014/ 10/08, PubMed PMID: 25290346]. Ollmann MM, Wilson BD, Yang YK, Kerns JA, Chen Y, Gantz I, Barsh GS. Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science 1997;278 (5335):135–8 [Epub 1997/10/06, PubMed PMID: 9311920]. Stephens TW, Basinski M, Bristow PK, Bue-Valleskey JM, Burgettx SG, Craft L, Hale J, Hoffmann J, Hsiung HM, Kriauciunas A, et al. The role of neuropeptide y in the antiobesity action of the obese gene product. Nature 1995;377 (6549):530–2. http://dx.doi.org/10.1038/377530a0 [Epub 1995/ 10/12, PubMed PMID: 7566151].
3
[18] Friedman JM. The alphabet of weight control. Nature 1997; 385(6612):119–20. http://dx.doi.org/10.1038/385119a0 [Epub 1997/01/09, PubMed PMID: 8990109]. [19] Lu XY, Kim CS, Frazer A, Zhang W. Leptin: a potential novel antidepressant. Proc Natl Acad Sci U S A 2006;103(5):1593–8. http://dx.doi.org/10.1073/pnas.0508901103 [Epub 2006/01/21, PubMed PMID: 16423896; PubMed Central PMCID: PMCPMC1360555]. [20] Domingos AI, Vaynshteyn J, Voss HU, Ren X, Gradinaru V, Zang F, Deisseroth K, de Araujo IE, Friedman J. Leptin regulates the reward value of nutrient. Nat Neurosci 2011;14(12):1562–8. http://dx.doi.org/10.1038/nn.2977 [Epub 2011/11/15, PubMed PMID: 22081158]. [21] Strobel A, Issad T, Camoin L, Ozata M, Strosberg AD. A leptin missense mutation associated with hypogonadism and morbid obesity. Nat Genet 1998;18(3):213–5. http://dx.doi.org/ 10.1038/ng0398-213 [Epub 1998/03/21, PubMed PMID: 9500540]. [22] Farooqi IS, Jebb SA, Langmack G, Lawrence E, Cheetham CH, Prentice AM, Hughes IA, McCamish MA, O'Rahilly S. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med 1999;341(12):879–84. http://dx.doi. org/10.1056/NEJM199909163411204 [Epub 1999/09/16, PubMed PMID: 10486419]. [23] Chou SH, Chamberland JP, Liu X, Matarese G, Gao C, Stefanakis R, Brinkoetter MT, Gong H, Arampatzi K, Mantzoros CS. Leptin is an effective treatment for hypothalamic amenorrhea. Proc Natl Acad Sci U S A 2011;108(16): 6585–90. http://dx.doi.org/10.1073/pnas.1015674108 [Epub 2011/04/06, PubMed PMID: 21464293; PubMed Central PMCID: PMCPMC3080974]. [24] Audi L, Mantzoros CS, Vidal-Puig A, et al. Leptin in relation to resumption of menses in women with anorexia nervosa. Mol Psychiatry 1998;3(6):544–7. [25] Dalamaga M, Chou SH, Shields K, Papageorgiou P, Polyzos SA, Mantzoros CS. Leptin at the intersection of neuroendocrinology and metabolism: current evidence and therapeutic perspectives. Cell Metab 2013;18(1):29–42. http://dx.doi.org/10.1016/j.cmet. 2013.05.010 [Epub 2013/06/19, S1550-4131(13)00200-3 [pii]. PubMed PMID: 23770129]. [26] Ahima RS, Prabakaran D, Mantzoros C, Qu D, Lowell B, Maratos-Flier E, Flier JS. Role of leptin in the neuroendocrine response to fasting. Nature 1996;382(6588):250–2. http://dx. doi.org/10.1038/382250a0 [Epub 1996/07/18, PubMed PMID: 8717038]. [27] Chan JL, Mantzoros CS. Role of leptin in energy-deprivation states: normal human physiology and clinical implications for hypothalamic amenorrhoea and anorexia nervosa. Lancet 2005;366(9479):74–85. http://dx.doi.org/10.1016/s0140-6736 (05)66830-4 [Epub 2005/07/05, PubMed PMID: 15993236]. [28] Welt CK, Chan JL, Bullen J, Murphy R, Smith P, DePaoli AM, Karalis A, Mantzoros CS. Recombinant human leptin in women with hypothalamic amenorrhea. N Engl J Med 2004; 351(10):987–97. http://dx.doi.org/10.1056/NEJMoa04038351/10/ 987 [Epub 2004/09/03, [pii]. PubMed PMID: 15342807]. [29] Matarese G, La Rocca C, Moon HS, Huh JY, Brinkoetter MT, Chou S, Perna F, Greco D, Kilim HP, Gao C, Arampatzi K, Wang Z, Mantzoros CS, et al. Selective capacity of metreleptin administration to reconstitute CD4 + T-cell number in females with acquired hypoleptinemia. Proc Natl Acad Sci U S A 2013;110(9):E818–27. http://dx.doi.org/10.1073/pnas. 1214554110 [Epub 2013/02/06, PubMed PMID: 23382191; PubMed Central PMCID: PMCPMC3587204]. [30] Sienkiewicz E, Magkos F, Aronis KN, Brinkoetter M, Chamberland JP, Chou S, Arampatzi KM, Gao C, Koniaris A, Mantzoros CS. Long-term metreleptin treatment increases bone mineral density and content at the lumbar spine of lean hypoleptinemic women. Metabolism 2011;60(9): 1211–21. http://dx.doi.org/10.1016/j.metabol.2011.05.016
4
[31]
[32]
[33]
[34]
[35]
ME TAB O L IS M C LI N IC A L A N D E XP E RI ME N TAL 6 4 (2 0 1 5 ) 1–4
[Epub 2011/07/12, S0026-0495(11)00156-9 [pii]. PubMed PMID: 21741057]. Moon HS, Dalamaga M, Kim SY, Polyzos SA, Hamnvik OP, Magkos F, Paruthi J, Mantzoros CS. Leptin's role in lipodystrophic and nonlipodystrophic insulin-resistant and diabetic individuals. Endocr Rev 2013;34(3):377–412. http://dx. doi.org/10.1210/er.2012-1053 [Epub 2013/03/12, PubMed PMID: 23475416; PubMed Central PMCID: PMCPMC3660716]. Tsoukas MA, Farr OM, Mantzoros CS. Leptin in congenital and hiv-associated lipodystrophy. Metabolism 2014. http://dx.doi. org/10.1016/j.metabol.2014.07.017 [Epub 2014/10/01, PubMed PMID: 25267014]. Fiorenza CG, Chou SH, Mantzoros CS. Lipodystrophy: pathophysiology and advances in treatment. Nat Rev Endocrinol 2011;7(3):137–50. http://dx.doi.org/10.1038/ nrendo.2010.199 Epub 2010/11/17, PubMed PMID: 21079616; PubMed Central PMCID: PMCPmc3150735. Halaas JL, Boozer C, Blair-West J, Fidahusein N, Denton DA, Friedman JM. Physiological response to long-term peripheral and central leptin infusion in lean and obese mice. Proc Natl Acad Sci U S A 1997;94(16):8878–83 [Epub 1997/08/05. PubMed PMID: 9238071; PubMed Central PMCID: PMCPMC23177]. Oral EA, Simha V, Ruiz E, Andewelt A, Premkumar A, Snell P, Wagner AJ, DePaoli AM, Reitman ML, Taylor SI, Gorden P, Garg A. Leptin-replacement therapy for lipodystrophy. N Engl J Med 2002;346(8):570–8. http://dx.doi.org/10.1056/ NEJMoa012437 [Epub 2002/02/22, PubMed PMID: 11856796].
[36] Farr OM, Fiorenza C, Papageorgiou P, Brinkoetter M, Ziemke F, Koo BB, Rojas R, Mantzoros CS. Leptin therapy alters appetite and neural responses to food stimuli in brain areas of leptin sensitive subjects without altering brain structure. J Clin Endocrinol Metab 2014:jc20142774. http://dx.doi.org/10.1210/ jc.2014-2774 [Epub 2014/10/04, PubMed PMID: 25279500]. [37] Heymsfield SB, Greenberg AS, Fujioka K, Dixon RM, Kushner R, Hunt T, Lubina JA, Patane J, Self B, Hunt P, McCamish M. Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. JAMA 1999;282(16):1568–75. [38] Roth JD, Roland BL, Cole RL, Trevaskis JL, Weyer C, Koda JE, Anderson CM, Parkes DG, Baron AD. Leptin responsiveness restored by amylin agonism in diet-induced obesity: evidence from nonclinical and clinical studies. Proc Natl Acad Sci U S A 2008;105(20):7257–62. [39] Moon HS, Dincer F, Mantzoros CS. Amylin-induced downregulation of hippocampal neurogenesis is attenuated by leptin in a STAT3/AMPK/ERK-dependent manner in mice. Diabetologia 2013;56(3):627–34. [40] Moon HS, Chamberland JP, Diakopoulos KN, Fiorenza CG, Ziemke F, Schneider B, Mantzoros CS, et al. Leptin and amylin act in an additive manner to activate overlapping signaling pathways in peripheral tissues: in vitro and ex vivo studies in humans. Diabetes Care 2011;34(1):132–8. [41] Unger RH, Cherrington AD. Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover. J Clin Invest 2012;122(1):4–12.
Available online at www.sciencedirect.com
Metabolism www.metabolismjournal.com
Leptin in the 21st Century
20 years of leptin: From the discovery of the leptin gene to leptin in our therapeutic armamentarium 1.
Introduction
This issue of the journal Metabolism celebrates the 20 years since the discovery of the prototypical adipose tissue secreted hormone leptin [1–9]. Leptin has proven to be a key marker of the amount of energy stores in the body, and leptin levels circulate at levels proportional to the amount of the amount of body fat, signaling available energy stores [10]. Leptin levels also decrease in response to acute caloric deprivation, suggesting a role for leptin in the broader context of regulating energy homeostasis [11]. In the spirit of science, leptin has proven to be unpredictable and truly fascinating—a system worth exploring and understanding. Indeed, the discovery of leptin has changed our understanding of adipose tissue and energy regulation and has provided a much better understanding of the connection between energy reserves and several physiological functions including but not limited to metabolism, reproductive function and immune function. At this twentieth anniversary of its discovery, papers to be published in this special issue on leptin present the wealth of knowledge that has been gained in this field and also highlight the many questions that remain to be answered. Leptin, originally developed as a potential therapy for obesity, was recently approved by the Food and Drug Administration (FDA) for the treatment of lipodystrophy. In the meantime, we realized that although its usefulness as a pharmacotherapy for obesity was limited, leptin may still be useful as a combination therapy with other medications to treat obesity and/or as a potentially effective medication in other disorders. Perhaps, even more importantly, the discovery of leptin has opened the way to critical discoveries about energy homeostasis and adipose tissues. Knowledge about how energy intake and expenditure are regulated has grown exponentially since the discovery of leptin and has furthered significantly the understanding of many critical neuroendocrine pathways with which leptin interacts and/or modulates to control body weight and energy intake/expenditure [1–3].
2.
Leptin as a complex signal
Mice which are ob/ob, lacking leptin, and db/db, lacking a functional leptin receptor, have given us novel insights into http://dx.doi.org/10.1016/j.metabol.2014.10.023 0026-0495/© 2015 Published by Elsevier Inc.
the physiology of leptin. In addition to their most obvious obesity phenotype, these animals have a unique behavioral profile that lends more credence to the function of leptin in regulating other key cognitive and behavioral processes. These ob/ob or db/db mice are non-aggressive, have very little locomotor activity, and are not sexually active [8,9,12]. These findings present a unique avenue of understanding how deeply the impacts of leptin are to the general system as well the cognitive impacts of leptin on complex behaviors, currently a very active field for research [13]. One of the main targets of leptin in the brain is the hypothalamus and neurons which express proopiomelanocortin (POMC) [13–15], which are activated by leptin, as well as agouti-related peptide (AgRP) and neuropeptide Y (NPY) neurons [16,17] which are inhibited by leptin. In turn, these neurons influence the activity of many other neurons in the brain [13,18] creating a key neural circuitry controlling energy intake and expenditure. The critical understanding of this circuitry, which has been growing in size and complexity with time, is expected to not only help us form a better understanding of the complex system regulating energy homeostasis but also how leptin influences other neural circuits to alter behavior and cognition. For example, disease states such as depression [13,19] as well as physiological functions such as reward processing through dopaminergic neurons in the midbrain have been shown to be influenced by hormones like leptin [15,20].
3.
Leptin and neuroendocrine function
We have also learned that leptin, particularly in states associated with energy deficiency and hypoleptinemia, influences several neuroendocrine axes, including the thyroid, gonadal, cortisol and growth hormone axes to regulate reproduction and reproductive behaviors and capacity, activity, thermoregulation and stress [21–25]. Detailed information about this physiological role of leptin with direct translational implications and therapeutic potential will be covered in subsequent articles of this special edition. Under normal conditions, leptin acts as a key signal to the brain conveying information that there is adequate energy available for normal physiologic processes, such as fertility, bone health, and cognition [13,15]. In contrast, even with
2
ME TAB O L IS M C LI N IC A L A N D E XP E RI ME N TAL 6 4 (2 0 1 5 ) 1–4
acute energy restriction, leptin levels decrease abruptly and several neuroendocrine responses are affected in animals [26] and humans [11]. In leptin deficient states, such as in exercise-induced hypothalamic amenorrhea, where individuals suffer from infertility and/or delayed puberty, decreased bone density, and other developmental and stress-related problems [27], it has been clearly proven that the lack of appropriate leptin levels is directly linked with the abnormal phenotype [23,28,29]. In proof of concept studies, leptin has been proven to normalize neuroendocrine and immune function [23,28,29] and to improve bone density [30] in these women. Other leptin deficient states include lipodystrophy, i.e. congenital or acquired absence of fat, for which leptin was recently approved in the USA and Japan [31–33].
4.
Leptin in obesity
Physiologic increases in plasma leptin levels in leptin deficient and wild type mice lead to a dose dependent reduction of food intake and loss of weight [34]. While leptin has potent effects on reducing food intake and body weight in ob and wild type animals, its efficacy in obese animals is variable and often reduced [34]. The extreme case of leptin resistance can be observed in the db mouse model which has a mutation in the leptin receptor [8,9]. In the absence of leptin's actions, these mice become obese and secondarily overproduce the hormone. In other animal models of obesity, leptin resistance or tolerance is more complex, and can in principle develop at many points in the neural circuitry that regulates feeding. In humans, leptin is highly potent in patients with low endogenous levels but its effects in lean normoleptinemic patients have not been studied extensively [22,28,30,32,35]. We have shown that in hypoleptinemic subjects, leptin administration alters appetite and activates several brain centers in comparison to control subjects [36] and that in extremely lean hypoleptinemic subjects with exercise-induced amenorrhea, treatment with leptin may result in weight loss when circulating leptin levels exceed the normal physiological range, an effect that is completely reversible with altering leptin dose to result in physiological circulating leptin levels [23,29]. In contrast, leptin has variable effects at very high doses (0.3 mg/kg bid) as monotherapy for obesity in the general population whereas a lower dose (0.1 mg/kg bid) did not show efficacy [37]. Whether garden variety obesity is a leptin tolerant or resistant state in humans or whether higher doses of leptin lead to tachyphylaxis remains to be studied in detail [38]. In addition, whether the efficacy of leptin for the treatment of obesity may increase when it is combined with other agents that cause weight loss, such as with amylin (pramlintide), a pancreatic peptide that is approved for the treatment of diabetes, and whether the combination may have additive or synergistic effects when co-administered remains to be studied in detail by future studies [38].
5.
Future directions
While much has been learned, the road ahead is wide open and still likely to lead to new advances since several key
questions remain unanswered. What regulates leptin gene expression and can this be leveraged to alter circulating leptin levels without encountering neutralizing antibodies? How is leptin transported into the central nervous system (CNS) and is leptin transport into the CNS a potential locus of leptin tolerance? How does leptin control energy homeostasis and metabolism? What signaling pathways are activated by leptin in humans [3,31,39,40] and what is the physiological role of leptin signaling in peripheral tissues? Are some of leptin's effects peripherally mediated or are most or all of its effects mediated by the CNS? What are the physiologic and cellular mechanisms by which leptin reduces adipose deposits in fat and other tissues and what is the nature of leptin tolerance? What are the physiologic and cellular mechanisms by which leptin improves insulin resistance, hyperlipidemia and glucose metabolism in lipodystrophic subjects and beyond? Does leptin act to a large extent by suppressing glucagon or are there other novel mechanisms also at play and what are the translational implications of such mechanisms? [41] Finally, how does leptin modulate the complex physiology of the behavioral/motivational system and what are the clinical implications of such regulation in disease states such as depression? Thus, beyond feeding and energy homeostasis, it is now understood that leptin's effects are much further reaching and may impact many other systems as well. The papers of this volume of Metabolism have been carefully selected to present an authoritative account of the biology and clinical applications of leptin that expands on all these themes.
Funding None.
Disclosure The authors have no conflicts of interest to disclose.
Jeffrey M. Friedman Howard Hughes Medical Institute, Rockefeller University New York, NY Corresponding author at: The Rockefeller University, 1230 York Avenue, New York, NY 10065 Christos S. Mantzoros Section of Endocrinology, VA Boston Healthcare System/Harvard Medical School, Boston, MA Division of Endocrinology, Beth-Israel Deaconess Medical Center/Harvard Medical School, Boston, MA
REFERENCES
[1] Ingalls AM, Dickie MM, Snell GD. Obese, a new mutation in the house mouse. Obes Res 1996;4(1):101 [Epub 1996/01/01, PubMed PMID: 8787944]. [2] Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human
ME TA BOL I SM C LI N I CA L A ND E XP E RI ME N TAL 64 (2 0 1 5 ) 1 –4
[3]
[4]
[5] [6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
homologue. Nature 1994;372(6505):425–32. http://dx.doi.org/ 10.1038/372425a0 [Epub 1994/12/01, PubMed PMID: 7984236]. Moon BC, Friedman JM. The molecular basis of the obese mutation in ob2j mice. Genomics 1997;42(1):152–6. http://dx. doi.org/10.1006/geno.1997.4701 [Epub 1997/05/15, PubMed PMID: 9177786]. Coleman DL. Obese and diabetes: two mutant genes causing diabetes-obesity syndromes in mice. Diabetologia 1978;14(3): 141–8 [Epub 1978/03/01, PubMed PMID: 350680]. Hervey GR. Regulation of energy balance. Nature 1969;222 (5194):629–31 [Epub 1969/05/17, PubMed PMID: 5768271]. Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals. Nature 1998;395(6704):763–70. http://dx. doi.org/10.1038/27376 [Epub 1998/10/31, PubMed PMID: 9796811]. Halaas JL, Gajiwala KS, Maffei M, Cohen SL, Chait BT, Rabinowitz D, Lallone RL, Burley SK, Friedman JM. Weightreducing effects of the plasma protein encoded by the obese gene. Science 1995;269(5223):543–6 [Epub 1995/07/28, PubMed PMID: 7624777]. Lee GH, Proenca R, Montez JM, Carroll KM, Darvishzadeh JG, Lee JI, Friedman JM. Abnormal splicing of the leptin receptor in diabetic mice. Nature 1996;379(6566):632–5. http://dx.doi.org/ 10.1038/379632a0 [Epub 1996/02/15, PubMed PMID: 8628397]. Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R, Richards GJ, Campfield LA, Clark FT, Deeds J, Muir C, Sanker S, Moriarty A, Moore KJ, Smutko JS, Mays GG, Wool EA, Monroe CA, Tepper RI. Identification and expression cloning of a leptin receptor, OB-R. Cell 1995;83(7):1263–71 Epub 1995/ 12/29, PubMed PMID: 8548812. Maffei M, Halaas J, Ravussin E, Pratley RE, Lee GH, Zhang Y, Fei H, Kim S, Lallone R, Ranganathan S, et al. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat Med 1995;1(11): 1155–61 [Epub 1995/11/01, PubMed PMID: 7584987]. Chan JL, Heist K, DePaoli AM, Veldhuis JD, Mantzoros CS. The role of falling leptin levels in the neuroendocrine and metabolic adaptation to short-term starvation in healthy men. J Clin Invest 2003;111(9):1409–21. http://dx.doi.org/10.1172/jci17490 [Epub 2003/05/03, PubMed PMID: 12727933; PubMed Central PMCID: PMCPMC154448]. Bray GA. Obesity, a disorder of nutrient partitioning: the Mona Lisa hypothesis. J Nutr 1991;121(8):1146–62 [Epub 1991/ 08/01. PubMed PMID: 1861165]. Farr OM, Tsoukas MA, Mantzoros CS. Leptin and the brain: Influences on brain development, cognitive functioning and psychiatric disorders. Metabolism 2014. http://dx.doi.org/10. 1016/j.metabol.2014.07.004 [Epub 2014/08/06, PubMed PMID: 25092133]. Lu D, Willard D, Patel IR, Kadwell S, Overton L, Kost T, Luther M, Chen W, Woychik RP, Wilkison WO, et al. Agouti protein is an antagonist of the melanocyte-stimulating-hormone receptor. Nature 1994;371(6500):799–802. http://dx.doi.org/10. 1038/371799a0 [Epub 1994/10/27, PubMed PMID: 7935841]. Stieg MR, Sievers C, Farr O, Stalla GK, Mantzoros CS. Leptin: a hormone linking activation of neuroendocrine axes with neuropathology. Psychoneuroendocrinology 2014;51C:47–57. http://dx.doi.org/10.1016/j.psyneuen.2014.09.004 [Epub 2014/ 10/08, PubMed PMID: 25290346]. Ollmann MM, Wilson BD, Yang YK, Kerns JA, Chen Y, Gantz I, Barsh GS. Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science 1997;278 (5335):135–8 [Epub 1997/10/06, PubMed PMID: 9311920]. Stephens TW, Basinski M, Bristow PK, Bue-Valleskey JM, Burgettx SG, Craft L, Hale J, Hoffmann J, Hsiung HM, Kriauciunas A, et al. The role of neuropeptide y in the antiobesity action of the obese gene product. Nature 1995;377 (6549):530–2. http://dx.doi.org/10.1038/377530a0 [Epub 1995/ 10/12, PubMed PMID: 7566151].
3
[18] Friedman JM. The alphabet of weight control. Nature 1997; 385(6612):119–20. http://dx.doi.org/10.1038/385119a0 [Epub 1997/01/09, PubMed PMID: 8990109]. [19] Lu XY, Kim CS, Frazer A, Zhang W. Leptin: a potential novel antidepressant. Proc Natl Acad Sci U S A 2006;103(5):1593–8. http://dx.doi.org/10.1073/pnas.0508901103 [Epub 2006/01/21, PubMed PMID: 16423896; PubMed Central PMCID: PMCPMC1360555]. [20] Domingos AI, Vaynshteyn J, Voss HU, Ren X, Gradinaru V, Zang F, Deisseroth K, de Araujo IE, Friedman J. Leptin regulates the reward value of nutrient. Nat Neurosci 2011;14(12):1562–8. http://dx.doi.org/10.1038/nn.2977 [Epub 2011/11/15, PubMed PMID: 22081158]. [21] Strobel A, Issad T, Camoin L, Ozata M, Strosberg AD. A leptin missense mutation associated with hypogonadism and morbid obesity. Nat Genet 1998;18(3):213–5. http://dx.doi.org/ 10.1038/ng0398-213 [Epub 1998/03/21, PubMed PMID: 9500540]. [22] Farooqi IS, Jebb SA, Langmack G, Lawrence E, Cheetham CH, Prentice AM, Hughes IA, McCamish MA, O'Rahilly S. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med 1999;341(12):879–84. http://dx.doi. org/10.1056/NEJM199909163411204 [Epub 1999/09/16, PubMed PMID: 10486419]. [23] Chou SH, Chamberland JP, Liu X, Matarese G, Gao C, Stefanakis R, Brinkoetter MT, Gong H, Arampatzi K, Mantzoros CS. Leptin is an effective treatment for hypothalamic amenorrhea. Proc Natl Acad Sci U S A 2011;108(16): 6585–90. http://dx.doi.org/10.1073/pnas.1015674108 [Epub 2011/04/06, PubMed PMID: 21464293; PubMed Central PMCID: PMCPMC3080974]. [24] Audi L, Mantzoros CS, Vidal-Puig A, et al. Leptin in relation to resumption of menses in women with anorexia nervosa. Mol Psychiatry 1998;3(6):544–7. [25] Dalamaga M, Chou SH, Shields K, Papageorgiou P, Polyzos SA, Mantzoros CS. Leptin at the intersection of neuroendocrinology and metabolism: current evidence and therapeutic perspectives. Cell Metab 2013;18(1):29–42. http://dx.doi.org/10.1016/j.cmet. 2013.05.010 [Epub 2013/06/19, S1550-4131(13)00200-3 [pii]. PubMed PMID: 23770129]. [26] Ahima RS, Prabakaran D, Mantzoros C, Qu D, Lowell B, Maratos-Flier E, Flier JS. Role of leptin in the neuroendocrine response to fasting. Nature 1996;382(6588):250–2. http://dx. doi.org/10.1038/382250a0 [Epub 1996/07/18, PubMed PMID: 8717038]. [27] Chan JL, Mantzoros CS. Role of leptin in energy-deprivation states: normal human physiology and clinical implications for hypothalamic amenorrhoea and anorexia nervosa. Lancet 2005;366(9479):74–85. http://dx.doi.org/10.1016/s0140-6736 (05)66830-4 [Epub 2005/07/05, PubMed PMID: 15993236]. [28] Welt CK, Chan JL, Bullen J, Murphy R, Smith P, DePaoli AM, Karalis A, Mantzoros CS. Recombinant human leptin in women with hypothalamic amenorrhea. N Engl J Med 2004; 351(10):987–97. http://dx.doi.org/10.1056/NEJMoa04038351/10/ 987 [Epub 2004/09/03, [pii]. PubMed PMID: 15342807]. [29] Matarese G, La Rocca C, Moon HS, Huh JY, Brinkoetter MT, Chou S, Perna F, Greco D, Kilim HP, Gao C, Arampatzi K, Wang Z, Mantzoros CS, et al. Selective capacity of metreleptin administration to reconstitute CD4 + T-cell number in females with acquired hypoleptinemia. Proc Natl Acad Sci U S A 2013;110(9):E818–27. http://dx.doi.org/10.1073/pnas. 1214554110 [Epub 2013/02/06, PubMed PMID: 23382191; PubMed Central PMCID: PMCPMC3587204]. [30] Sienkiewicz E, Magkos F, Aronis KN, Brinkoetter M, Chamberland JP, Chou S, Arampatzi KM, Gao C, Koniaris A, Mantzoros CS. Long-term metreleptin treatment increases bone mineral density and content at the lumbar spine of lean hypoleptinemic women. Metabolism 2011;60(9): 1211–21. http://dx.doi.org/10.1016/j.metabol.2011.05.016
4
[31]
[32]
[33]
[34]
[35]
ME TAB O L IS M C LI N IC A L A N D E XP E RI ME N TAL 6 4 (2 0 1 5 ) 1–4
[Epub 2011/07/12, S0026-0495(11)00156-9 [pii]. PubMed PMID: 21741057]. Moon HS, Dalamaga M, Kim SY, Polyzos SA, Hamnvik OP, Magkos F, Paruthi J, Mantzoros CS. Leptin's role in lipodystrophic and nonlipodystrophic insulin-resistant and diabetic individuals. Endocr Rev 2013;34(3):377–412. http://dx. doi.org/10.1210/er.2012-1053 [Epub 2013/03/12, PubMed PMID: 23475416; PubMed Central PMCID: PMCPMC3660716]. Tsoukas MA, Farr OM, Mantzoros CS. Leptin in congenital and hiv-associated lipodystrophy. Metabolism 2014. http://dx.doi. org/10.1016/j.metabol.2014.07.017 [Epub 2014/10/01, PubMed PMID: 25267014]. Fiorenza CG, Chou SH, Mantzoros CS. Lipodystrophy: pathophysiology and advances in treatment. Nat Rev Endocrinol 2011;7(3):137–50. http://dx.doi.org/10.1038/ nrendo.2010.199 Epub 2010/11/17, PubMed PMID: 21079616; PubMed Central PMCID: PMCPmc3150735. Halaas JL, Boozer C, Blair-West J, Fidahusein N, Denton DA, Friedman JM. Physiological response to long-term peripheral and central leptin infusion in lean and obese mice. Proc Natl Acad Sci U S A 1997;94(16):8878–83 [Epub 1997/08/05. PubMed PMID: 9238071; PubMed Central PMCID: PMCPMC23177]. Oral EA, Simha V, Ruiz E, Andewelt A, Premkumar A, Snell P, Wagner AJ, DePaoli AM, Reitman ML, Taylor SI, Gorden P, Garg A. Leptin-replacement therapy for lipodystrophy. N Engl J Med 2002;346(8):570–8. http://dx.doi.org/10.1056/ NEJMoa012437 [Epub 2002/02/22, PubMed PMID: 11856796].
[36] Farr OM, Fiorenza C, Papageorgiou P, Brinkoetter M, Ziemke F, Koo BB, Rojas R, Mantzoros CS. Leptin therapy alters appetite and neural responses to food stimuli in brain areas of leptin sensitive subjects without altering brain structure. J Clin Endocrinol Metab 2014:jc20142774. http://dx.doi.org/10.1210/ jc.2014-2774 [Epub 2014/10/04, PubMed PMID: 25279500]. [37] Heymsfield SB, Greenberg AS, Fujioka K, Dixon RM, Kushner R, Hunt T, Lubina JA, Patane J, Self B, Hunt P, McCamish M. Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. JAMA 1999;282(16):1568–75. [38] Roth JD, Roland BL, Cole RL, Trevaskis JL, Weyer C, Koda JE, Anderson CM, Parkes DG, Baron AD. Leptin responsiveness restored by amylin agonism in diet-induced obesity: evidence from nonclinical and clinical studies. Proc Natl Acad Sci U S A 2008;105(20):7257–62. [39] Moon HS, Dincer F, Mantzoros CS. Amylin-induced downregulation of hippocampal neurogenesis is attenuated by leptin in a STAT3/AMPK/ERK-dependent manner in mice. Diabetologia 2013;56(3):627–34. [40] Moon HS, Chamberland JP, Diakopoulos KN, Fiorenza CG, Ziemke F, Schneider B, Mantzoros CS, et al. Leptin and amylin act in an additive manner to activate overlapping signaling pathways in peripheral tissues: in vitro and ex vivo studies in humans. Diabetes Care 2011;34(1):132–8. [41] Unger RH, Cherrington AD. Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover. J Clin Invest 2012;122(1):4–12.