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Yonsei Med J. Jul 1, 2012; 53(4): 671–679.
Published online May 22, 2012. doi:  10.3349/ymj.2012.53.4.671
PMCID: PMC3381496
Leptin as a Modulator of Neuroendocrine Function in Humans
Sami M. Khan,1 Ole-Petter R. Hamnvik,1,2,3 Mary Brinkoetter,1,2 and Christos S. Mantzoroscorresponding author1,2
1Division of Endocrinology, Diabetes & Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
2Section of Endocrinology, Boston VA Healthcare System, Boston, MA, USA.
3Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
corresponding authorCorresponding author.
Corresponding author: Dr. Christos S. Mantzoros, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA. Tel: 617-667-8630, Fax: 617-667-8634, cmantzor/at/bidmc.harvard.edu
Received April 10, 2012
Leptin, a peptide hormone secreted by adipocytes in proportion of the amount of energy stored in fat, plays a central role in regulating human energy homeostasis. In addition, leptin plays a significant permissive role in the physiological regulation of several neuroendocrine axes, including the hypothalamic-pituitary-gonadal, -thyroid, -growth hormone, and -adrenal axes. Decreased levels of leptin, also known as hypoleptinemia, signal to the brain a state of energy deprivation. Hypoleptinemia can be a congenital or acquired condition, and is associated with alterations of the aforementioned axes aimed at promoting survival. More specifically, gonadotropin levels decrease and become less pulsatile under conditions of energy deprivation, and these changes can be at least partially reversed through leptin administration in physiological replacement doses. Similarly, leptin deficiency is associated with thyroid axis abnormalities including abnormal levels of thyrotropin-releasing hormone, and leptin administration may at least partially attenuate this effect. Leptin deficiency results in decreased insulin-like growth factor 1 levels which can be partially ameliorated through leptin administration, and leptin appears to have a much more pronounced effect on the growth of rodents than that of humans. Similarly, adrenal axis function is regulated more tightly by low leptin in rodents than in humans. In addition to congenital leptin deficiency, conditions that may be associated with decreased leptin levels include hypothalamic amenorrhea, anorexia nervosa, and congenital or acquired lipodystrophy syndromes. Accumulating evidence from proof of concept studies suggests that leptin administration, in replacement doses, may ameliorate neuroendocrine abnormalities in individuals who suffer from these conditions.
Keywords: Leptin, leptin deficiency, amenorrhea
Leptin, an adipocyte-secreted hormone, was first discovered in 1994 through positional cloning of the ob/ob mouse model of obesity.1 Since then, much has been discovered about leptin's role in regulating energy homeostasis, neuroendocrine, and immune functions. Leptin is secreted in direct proportion to the amount of energy stored in adipose tissue, and circulating leptin levels serve as a peripheral signal to the central nervous system about the amount of energy reserves available for reproductive and other essential functions.2 Thus, circulating leptin levels dictate the body's energy homeostasis and neuroendocrine, immune as well as metabolic function.3-5 More recently, human and rodent studies have demonstrated that leptin plays an important role in regulating neuroendocrine axes such as the hypothalamic-pituitary-gonadal axis,6-8 the thyroid axis,6,7 the growth hormone axis,7,9 and the adrenal axis.10,11 Leptin levels are also influenced by several other factors including acute change in energy intake; leptin levels decrease in response to acute and chronic energy deprivation.7,8,12 It appears that leptin may be especially important in mediating neuroendocrine adaptations that act in a concerted manner to conserve energy.6-8 We review herein the current state of knowledge about the effects of leptin, leptin deprivation, and leptin replacement on these neuroendocrine axes.
Biology of leptin; an overview
Leptin, the product of the ob gene in rodents1 and the LEP gene in humans, is a 167-amino acid, 16 kDalton, adipocyte-secreted hormone. It structurally resembles a cytokine and as it was one of the first adipocyte-secreted hormones to be discovered with this cytokine-like structure, it is the prototype of the adipocytokine proteins. Orthologs of leptin with slightly varied amino acid sequences but conserved functional properties and tertiary structure have been found in several species including fish and reptiles.13 Leptin is produced primarily by the white adipose tissue, but is also expressed in other tissues such as the brown adipose tissue,14 the primary and secondary lymphoid organs,15 the bone marrow, the mammary epithelium, the ovaries, the skeletal muscle, and the placenta to mention a few.16 Leptin levels in humans are secreted in proportion to energy stored in fat (total body fat mass).17,18 Acute changes in caloric intake, mainly acute decreases in food intake, have been shown to have a dramatic effect on circulating leptin concentrations. For example, fasting for one or three days results in a marked decrease of leptin levels (by 50% and 80% respectively).7,8,12 Leptin levels in humans are also influenced by sex steroid levels,3,19-21 thyroid hormones, cytokines, and other factors to a lesser degree than the factors mentioned above.22-24
Leptin exerts its effects through binding and activating specific leptin receptors, which are coded for by the db gene in mice25 and the LEPR gene in humans.26 These receptors exist both in the central nervous system, especially the hypothalamus,27,28 kidneys, lungs,29 lymphocytes,28,30-32 adipose tissue,21,33,34 prostate, ovaries, liver, small intestines, and heart.16,35 There are at least six isoforms of the murine leptin receptor,36 whereas in humans, only four alternatively spliced isoforms have been described.37,38 The ObRb receptor, the long form of the leptin receptor, is considered the active leptin receptor and is highly expressed in the hypothalamus, including in nuclei associated with body weight control.29
Circulating leptin levels in humans
Leptin levels in the blood stream display a circadian pattern such that leptin concentration is at the lowest point between early afternoon and mid-afternoon and is at its highest point between midnight and early morning.39,40 Furthermore, leptin secretion appears to be pulsatile.11 Though the pulsatility of leptin secretion is similar in obese and in lean individuals, the amplitude of leptin pulses is greater among obese individuals.11
Several factors contribute to the inter-individual variability of leptin levels in humans, including gender and total body fat mass.41 Leptin levels display sexual dimorphism, with women having higher levels than men even after controlling for adiposity.42 Sex hormones such as testosterone43 and estrogen44,45 explain some of the gender variation in leptin levels. Among women, leptin levels appear to be at their highest level during the luteal phase of the menstrual cycle.46 Distribution of fat also plays a role in variability of leptin levels; subcutaneous fat appears to produce more leptin than omental fat.47
Data on the neuroendocrine functions of leptin in humans emanate mainly from case reports of congenital leptin deficiency and leptin administration to these individuals,48-50 as well as from observational and interventional physiology studies involving fasting and/or weight loss in normal subjects followed by leptin administration.7,8,51,52 In a direct extension of these studies, leptin physiology and pathophysiology has also been studied using various disease states as experimental models. These include conditions associated with relative leptin deficiency, such as hypothalamic amenorrhea and lipodystrophies.48,53,54 We summarize findings from these studies in the following paragraphs.
Humans with genetic mutations that lead to congenital leptin deficiency experience hypogonadotropic hypogonadism and failure to undergo puberty;55 the latter is restored by leptin administration in replacement doses.48,49,56 These data in the extremely rare subjects with congenital leptin deficiency are consistent with our finding that a rise in leptin levels precedes the onset of puberty in normal boys.57 Even in rodents, exogenous leptin administration results in earlier onset of markers of puberty including vaginal opening,58 and leptin antibodies appear to inhibit pubertal onset in female rats.59 Although ob/ob mice have complete leptin deficiency and are infertile, female ob/ob mice can ovulate and give birth if they are treated with leptin in replacement doses,60 which stimulates the secretion of luteinizing hormone (LH) in vivo.61 In mice, fasting-induced hypoleptinemia also diminishes the levels of gonadotropins and impairs the reproductive function and sex hormone levels of these mice; however, leptin administration restores testosterone levels in male mice, estrous cycles in female mice, and LH levels in both.6
In a follow-up to our rodent experiments and observational studies in humans, we have also demonstrated that caloric deprivation of normal-weight men decreases testosterone levels as well as LH pulsatility, effects that can be fully normalized by administering leptin in physiological replacement doses.7,62 Similarly, caloric deprivation that leads to partial leptin deficiency in normal-weight women decreases their LH peak frequency, and this effect can be reversed through leptin administration.8 Leptin's effect on luteinizing hormone secretion appears to proceed via an indirect mechanism, as neurons that secrete gonadotropin-releasing hormone (GnRH) do not have leptin receptors.63 There is evidence that leptin may act on groups of neurons that in turn provide input to populations of GnRH secreting neurons in regions of the brain such the preoptic area.21,64,65 These groups of neurons may include agouti-related peptide/neuropeptide Y and proopiomelanocortin neurons64 as well as neurons in the arcuate nucleus that express kisspeptin, bradykinin, and dynorphin, that regulate GnRH secreting neurons66 either directly or through KiSS-1 neurons.67
A well-studied mediator of the relationship between leptin and reproduction is kisspeptin. This protein is a product of the Kiss1 gene.68 Kiss1 mRNA expression is reduced in the caudal hypothalamus of fasting female rats69,70 and ob/ob mice express Kiss1 mRNA to a lesser degree than do their wild-type counterparts.67 The expression of Kiss1 mRNA is partially restored with the administration of exogenously administered leptin67 whereas exogenously administered kisspeptin to rodents that are relatively leptin deficient stimulates the secretion of GnRH71 and increases levels of LH, follicle-stimulating hormone,72,73 and testosterone.73 Populations of neurons with leptin receptors in brain regions such as the hypothalamic ventral premammillary nucleus and the preoptic region have been found in close proximity to both Kiss1 and GnRH neurons.74 Although leptin's initiation of puberty in mice requires a functional ventral premammillary nucleus, this does not appear to require the action of Kiss1 mRNA expressing neurons.75
Similar to leptin, thyroid-stimulating hormone (TSH) has a pulsatile and circadian pattern of secretion, and we have found that both hormones have similar circadian patterns.76 In congenitally leptin-deficient individuals, we have observed that TSH secretion is disorganized.76 It has also been reported that leptin-deficient children exhibit an increase in triiodothyronine (T3) and thyroxine (T4), though not in TSH, after leptin therapy in an uncontrolled interventional study;49 however, one boy, one man, and two women, all of whom had congenital leptin-deficiency, demonstrated normal thyroid function whether or not they were undergoing leptin replacement.50
In rodents, leptin deficient ob/ob mice demonstrate much more pronounced thyroid disorders, including hypothalamic hypothyroidism since birth.77 Similarly, fasting decreases serum levels of T4 in mice, though this effect can be ameliorated through leptin administration.6 Leptin regulates thyrotropin-releasing hormone levels by increasing pro-TRH gene expression in neurons in the paraventricular nucleus of the hypothalamus,78 probably through the central melanocortin system.79 Leptin also stimulates the expression of prohormone convertases 1 and 2, which cleave pro-TRH in order to produce TRH in the paraventricular nucleus.80
To directly test the role of leptin in regulating thyroid function in humans, we administered leptin in the context of a randomized, placebo controlled interventional study involving fasting of normal-weight men for 72 hours. Fasting-induced hypoleptinemia resulted in altered TSH levels and secretion patterns and leptin administration ameliorated the degree to which caloric deprivation altered TSH secretion patterns and levels.7 In contrast to men, in whom significant hypoleptinemia was induced (levels less than 2-3 ng/mL), similarly pronounced effects of leptin administration were not seen in a similar study on normal-weight women8 in whom leptin levels were decreased but remained within normal limits. We proposed that the reason for the discrepant results between these two otherwise similar studies could be the fact that men experienced a decrease in leptin levels to an average of 0.27 ng/mL (much lower than the lower normal level in our laboratory, 3 ng/mL).7 In contrast, leptin levels dropped to an average level of approximately 3 ng/mL in women8 and thus we suggested that leptin appears to have a threshold level for regulation of TSH.81 In contrast to TSH, T3 and T4 were much less regulated in humans than in rodents.
These data, taken together, suggest that although leptin may have a significant effect in regulating the secretion pattern of TSH in humans, its role in regulating circulating levels of T3 and T4 may not be as important in humans as it is in rodents and may be different in complete leptin deficiency than in relative, acute hypoleptinemia.21,65,81
A subsequent interventional but non-randomized study focused on both lean and obese participants who were studied before and after they had lost 10% of their body weight (and thus became relatively hypoleptinemic) over the course of an average of eight weeks.51 Though all participants experienced decreased levels of leptin, obese subjects still had relatively higher levels, which ranged from 10 ng/mL up to 60 ng/mL.51 Levels of TSH, T3, and T4 were reportedly all decreased, though leptin replacement only increased T3 and T4 levels in these subjects.51 The authors of this study suggest that leptin may increase the bioactivity of TSH or stimulate T4 secretion, but these results from this non-randomized study remain to be replicated by future randomized studies involving administration of leptin in physiological replacement doses.51 We have recently reported that administering leptin in pharmacological doses to subjects undergoing a 6-month-long mild hypocaloric diet does not appear to alter levels of the circulating hormones of the thyroid axis but doses administered were supraphysiological and may have thus suppressed leptin receptors leading to suboptimal results.82
Humans who are leptin-deficient due to mutations of the leptin gene demonstrate normal growth velocity in childhood48,49 although their final height is decreased due to the lack of pubertal growth spurt.83 We have proposed on the basis of the above and other experimental data from our own physiology studies in humans that leptin may regulate growth hormone's ability to stimulate the secretion of insulin-like growth factor 1 (IGF-1) as well as the corresponding binding proteins in the periphery as opposed to acting directly on pituitary secretion of growth hormone itself.84
We have shown by studying a group of normal-weight men who became truly hypoleptinemic through prolonged fasting that leptin administration tends to restore total IGF-1 levels, which are decreased due to caloric deprivation.7 In normal weight women, though, we found that leptin replacement did not significantly normalize IGF-1 levels.8 Again, this was interpreted as illustrative of leptin having a threshold for neuroendocrine regulation as the men's leptin levels dropped below 3 ng/mL whereas the women's average leptin level did not.81 Similarly, administering leptin to euleptinemic subjects undergoing a 6-month-long mild hypocaloric diet did not appear to alter levels of the circulating levels of IGF-1 or other hormones in the IGF axis.82
In vitro evidence indicates that corticotropin-releasing hormone is released in response to leptin in a dose-dependent manner10 and suggests that leptin decreases the secretion of corticosterone from cells of rat adrenal cortex.85 Additionally, leptin decreases the degree to which stress increases ACTH and corticosterone levels.86
On the basis of very small and non-randomized studies, it has been suggested that the adrenal axis of individuals with mutated leptin or leptin receptor genes may not be significantly impaired.26,48,49 Similarly, leptin administration in a group of men who became hypoleptinemic in response to fasting for 72 hours did not appear to have a major effect on cortisol secretion.7 Likewise, leptin administration did not attenuate significantly the activation of the adrenal axis in a similar study of fasting women.8 In contrast, in the context of a larger randomized placebo-controlled study, we found that women with hypothalamic amenorrhea who were hypercortisolemic did experience a statistically significant decrease in cortisol levels after they were treated with replacement doses of metreleptin.87 Along the same lines, we have reported that there appears to be an inverse relationship between healthy men's fluctuations in circulating levels of leptin and both cortisol and ACTH.11 Thus, the effect of leptin to regulate the adrenal axis in humans is rather small in magnitude and thus can be detected only in larger, randomized studies.
Congenital leptin deficiency
Mutations of the leptin gene result in congenital leptin deficiency, a rare condition in humans seen more commonly in populations where consanguineous marriage is relatively more common.88 Congenital leptin deficiency leads to obesity, which arises early in life, due to uncontrollable hyperphagia.89 It is also accompanied by neuroendocrine abnormalities such hypothalamic hypogonadism and pubertal failure55 which can be treated with leptin administration in replacement doses.48,49,56 As mentioned above, these individuals may have an impaired pituitary-thyroid axis (though one case series did not find abnormal thyroid function50), with increased T3 and T4 levels and unchanged TSH levels after leptin replacement.49 Leptin is currently available on a compassionate basis for the treatment of morbid obesity and hypothalamic hypogonadism of these subjects.
Hypothalamic amenorrhea
Hypothalamic amenorrhea (HA) caused by an imbalance between energy expenditure and energy intake associated with excessive stress, excessive exercise, or inadequate food intake leads to significant neuroendocrine abnormalities, infertility and osteoporosis/stress fractures.90 In association with low fat mass, women with HA have abnormally low levels of leptin.91 We have reported that administration of leptin, in replacement doses, may lead to normalization of neuroendocrine action in women with hypothalamic amenorrhea.54 Leptin replacement normalized LH levels and pulsatility within weeks and ovulation within months in an open label study with a course of treatment of ten weeks.54 Moreover, in a subsequent placebo-controlled, double-blind, randomized study with a larger sample size we confirmed these results using a course of treatment of nine months.92
The aforementioned ten-week study of leptin replacement in women with hypothalamic amenorrhea yielded increased levels of bone-specific alkaline phosphatase and osteocalcin, two bone formation markers.54 More definitive results in terms of changes in overall or regional bone mineral content or density were reported in the nine-month long randomized placebo-controlled study.87 In this study, six women underwent nine months of double-blind leptin administration and then elected to receive an additional year of open-label leptin administration; these women experienced significant gains in bone mineral content and density.87
Anorexia nervosa
Anorexia nervosa is associated with hypoleptinemia.53 Among amenorrheic anorexic women with who have gained weight, circulating leptin levels are higher in those whose menses had resumed than in those who had remained amenorrheic.93 Unfortunately, there may be mild weight and/or fat loss with leptin replacement in lean women,54,92 which may be a potential reason not to administer leptin to anorexic women.
Lipodystrophy
Lipodystrophy is a condition characterized by abnormal distribution of adipose tissue. It is either inherited, in a very small number of patients, or can be acquired. The latter is much more frequent and most often occurs in HIV-positive subjects being treated with highly-active antiretroviral therapy for human immunodeficiency virus (HIV) infection.94 Subjects with significant degrees of lipodystrophy have lower leptin levels than unaffected subjects.95,96 Leptin administration in replacement doses is associated with normalization of neuroendocrine parameters in subjects who have lipodystrophy.97 Additionally, and probably even more importantly, leptin administration in replacement doses to subjects with lipodystrophy improves their metabolic abnormalities; including hypertriglyceridemia and impaired glucose control which often are resistant to maximum doses of insulin sensitizers or very high doses of insulin.98,99 The development of anti-leptin antibodies has been considered by many as a factor that may limit the use of this medication in humans but data remain inconclusive.100,101
In conclusion, it appears that leptin regulates neuroendocrine function in humans and has a special role in mediating the neuroendocrine response to energy deprivation. Directions for future research include further elucidating the anatomical connections between energy homeostasis and neuroendocrine functions and the specific molecular mechanisms underlying these connections.
Additionally, it appears that leptin levels are decreased in conditions such as congenital leptin deficiency, hypothalamic amenorrhea, anorexia nervosa, and lipoatrophy, conditions in which a leptin measurement in the blood could provide important novel diagnostic information. Small-scale proof-of-concept studies have shown that several of the neuroendocrine and other abnormalities associated with these conditions can be ameliorated via leptin therapy in replacement doses. Future research should involve larger-scale phase III placebo-controlled leptin administration trials to fully establish leptin's therapeutic role in disease states associated with leptin deficiency.
Footnotes
The authors have no financial conflicts of interest.
1. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994;372:425–432. [PubMed]
2. Moschos S, Chan JL, Mantzoros CS. Leptin and reproduction: a review. Fertil Steril. 2002;77:433–444. [PubMed]
3. Blüher S, Mantzoros CS. Leptin in humans: lessons from translational research. Am J Clin Nutr. 2009;89:991S–997S. [PubMed]
4. Hamnvik OP, Liu X, Petrou M, Gong H, Chamberland JP, Kim EH, et al. Soluble leptin receptor and leptin are associated with baseline adiposity and metabolic risk factors, and predict adiposity, metabolic syndrome, and glucose levels at 2-year follow-up: the Cyprus Metabolism Prospective Cohort Study. Metabolism. 2011;60:987–993. [PubMed]
5. Matarese G, Mantzoros C, La Cava A. Leptin and adipocytokines: bridging the gap between immunity and atherosclerosis. Curr Pharm Des. 2007;13:3676–3680. [PubMed]
6. Ahima RS, Prabakaran D, Mantzoros C, Qu D, Lowell B, Maratos-Flier E, et al. Role of leptin in the neuroendocrine response to fasting. Nature. 1996;382:250–252. [PubMed]
7. 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;111:1409–1421. [PMC free article] [PubMed]
8. Chan JL, Matarese G, Shetty GK, Raciti P, Kelesidis I, Aufiero D, et al. Differential regulation of metabolic, neuroendocrine, and immune function by leptin in humans. Proc Natl Acad Sci U S A. 2006;103:8481–8486. [PubMed]
9. Luque RM, Huang ZH, Shah B, Mazzone T, Kineman RD. Effects of leptin replacement on hypothalamic-pituitary growth hormone axis function and circulating ghrelin levels in ob/ob mice. Am J Physiol Endocrinol Metab. 2007;292:E891–E899. [PubMed]
10. Costa A, Poma A, Martignoni E, Nappi G, Ur E, Grossman A. Stimulation of corticotrophin-releasing hormone release by the obese (ob) gene product, leptin, from hypothalamic explants. Neuroreport. 1997;8:1131–1134. [PubMed]
11. Licinio J, Mantzoros C, Negrão AB, Cizza G, Wong ML, Bongiorno PB, et al. Human leptin levels are pulsatile and inversely related to pituitary-adrenal function. Nat Med. 1997;3:575–579. [PubMed]
12. Boden G, Chen X, Mozzoli M, Ryan I. Effect of fasting on serum leptin in normal human subjects. J Clin Endocrinol Metab. 1996;81:3419–3423. [PubMed]
13. Denver RJ, Bonett RM, Boorse GC. Evolution of leptin structure and function. Neuroendocrinology. 2011;94:21–38. [PubMed]
14. Trayhurn P, Duncan JS, Hoggard N, Rayner DV. Regulation of leptin production: a dominant role for the sympathetic nervous system? Proc Nutr Soc. 1998;57:413–419. [PubMed]
15. Matarese G, Moschos S, Mantzoros CS. Leptin in immunology. J Immunol. 2005;174:3137–3142. [PubMed]
16. Margetic S, Gazzola C, Pegg GG, Hill RA. Leptin: a review of its peripheral actions and interactions. Int J Obes Relat Metab Disord. 2002;26:1407–1433. [PubMed]
17. Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med. 1996;334:292–295. [PubMed]
18. Yannakoulia M, Yiannakouris N, Blüher S, Matalas AL, Klimis-Zacas D, Mantzoros CS. Body fat mass and macronutrient intake in relation to circulating soluble leptin receptor, free leptin index, adiponectin, and resistin concentrations in healthy humans. J Clin Endocrinol Metab. 2003;88:1730–1736. [PubMed]
19. Mantzoros CS, Flier JS. Editorial: leptin as a therapeutic agent--trials and tribulations. J Clin Endocrinol Metab. 2000;85:4000–4002. [PubMed]
20. Mantzoros CS. Role of leptin in reproduction. Ann N Y Acad Sci. 2000;900:174–183. [PubMed]
21. Kelesidis T, Kelesidis I, Chou S, Mantzoros CS. Narrative review: the role of leptin in human physiology: emerging clinical applications. Ann Intern Med. 2010;152:93–100. [PMC free article] [PubMed]
22. Mullington JM, Chan JL, Van Dongen HP, Szuba MP, Samaras J, Price NJ, et al. Sleep loss reduces diurnal rhythm amplitude of leptin in healthy men. J Neuroendocrinol. 2003;15:851–854. [PubMed]
23. Scheer FA, Hilton MF, Mantzoros CS, Shea SA. Adverse metabolic and cardiovascular consequences of circadian misalignment. Proc Natl Acad Sci U S A. 2009;106:4453–4458. [PubMed]
24. Mantzoros CS, Liolios AD, Tritos NA, Kaklamani VG, Doulgerakis DE, Griveas I, et al. Circulating insulin concentrations, smoking, and alcohol intake are important independent predictors of leptin in young healthy men. Obes Res. 1998;6:179–186. [PubMed]
25. Chen H, Charlat O, Tartaglia LA, Woolf EA, Weng X, Ellis SJ, et al. Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell. 1996;84:491–495. [PubMed]
26. Clément K, Vaisse C, Lahlou N, Cabrol S, Pelloux V, Cassuto D, et al. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature. 1998;392:398–401. [PubMed]
27. Mantzoros CS, Moschos SJ. Leptin: in search of role(s) in human physiology and pathophysiology. Clin Endocrinol (Oxf) 1998;49:551–567. [PubMed]
28. Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R, et al. Identification and expression cloning of a leptin receptor, OB-R. Cell. 1995;83:1263–1271. [PubMed]
29. Fei H, Okano HJ, Li C, Lee GH, Zhao C, Darnell R, et al. Anatomic localization of alternatively spliced leptin receptors (Ob-R) in mouse brain and other tissues. Proc Natl Acad Sci U S A. 1997;94:7001–7005. [PubMed]
30. Baumann H, Morella KK, White DW, Dembski M, Bailon PS, Kim H, et al. The full-length leptin receptor has signaling capabilities of interleukin 6-type cytokine receptors. Proc Natl Acad Sci U S A. 1996;93:8374–8378. [PubMed]
31. Maffei M, Fei H, Lee GH, Dani C, Leroy P, Zhang Y, et al. Increased expression in adipocytes of ob RNA in mice with lesions of the hypothalamus and with mutations at the db locus. Proc Natl Acad Sci U S A. 1995;92:6957–6960. [PubMed]
32. Papathanassoglou E, El-Haschimi K, Li XC, Matarese G, Strom T, Mantzoros C. Leptin receptor expression and signaling in lymphocytes: kinetics during lymphocyte activation, role in lymphocyte survival, and response to high fat diet in mice. J Immunol. 2006;176:7745–7752. [PubMed]
33. Moon HS, Chamberland JP, Diakopoulos KN, Fiorenza CG, Ziemke F, Schneider B, 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;34:132–138. [PMC free article] [PubMed]
34. Moon HS, Matarese G, Brennan AM, Chamberland JP, Liu X, Fiorenza CG, et al. Efficacy of metreleptin in obese patients with type 2 diabetes: cellular and molecular pathways underlying leptin tolerance. Diabetes. 2011;60:1647–1656. [PMC free article] [PubMed]
35. Cioffi JA, Shafer AW, Zupancic TJ, Smith-Gbur J, Mikhail A, Platika D, et al. Novel B219/OB receptor isoforms: possible role of leptin in hematopoiesis and reproduction. Nat Med. 1996;2:585–589. [PubMed]
36. Lee GH, Proenca R, Montez JM, Carroll KM, Darvishzadeh JG, Lee JI, et al. Abnormal splicing of the leptin receptor in diabetic mice. Nature. 1996;379:632–635. [PubMed]
37. Peelman F, Couturier C, Dam J, Zabeau L, Tavernier J, Jockers R. Techniques: new pharmacological perspectives for the leptin receptor. Trends Pharmacol Sci. 2006;27:218–225. [PubMed]
38. Sun Q, Cornelis MC, Kraft P, Qi L, van Dam RM, Girman CJ, et al. Genome-wide association study identifies polymorphisms in LEPR as determinants of plasma soluble leptin receptor levels. Hum Mol Genet. 2010;19:1846–1855. [PMC free article] [PubMed]
39. Sinha MK, Ohannesian JP, Heiman ML, Kriauciunas A, Stephens TW, Magosin S, et al. Nocturnal rise of leptin in lean, obese, and non-insulin-dependent diabetes mellitus subjects. J Clin Invest. 1996;97:1344–1347. [PMC free article] [PubMed]
40. Shea SA, Hilton MF, Orlova C, Ayers RT, Mantzoros CS. Independent circadian and sleep/wake regulation of adipokines and glucose in humans. J Clin Endocrinol Metab. 2005;90:2537–2544. [PMC free article] [PubMed]
41. Rosenbaum M, Nicolson M, Hirsch J, Heymsfield SB, Gallagher D, Chu F, et al. Effects of gender, body composition, and menopause on plasma concentrations of leptin. J Clin Endocrinol Metab. 1996;81:3424–3427. [PubMed]
42. Saad MF, Damani S, Gingerich RL, Riad-Gabriel MG, Khan A, Boyadjian R, et al. Sexual dimorphism in plasma leptin concentration. J Clin Endocrinol Metab. 1997;82:579–584. [PubMed]
43. Roemmich JN, Clark PA, Berr SS, Mai V, Mantzoros CS, Flier JS, et al. Gender differences in leptin levels during puberty are related to the subcutaneous fat depot and sex steroids. Am J Physiol. 1998;275(3 Pt 1):E543–E551. [PubMed]
44. Lin KC. Increase of leptin levels following exogenous administration of estrogen in women with normal menstruation. Kaohsiung J Med Sci. 2000;16:13–19. [PubMed]
45. Shimizu H, Shimomura Y, Nakanishi Y, Futawatari T, Ohtani K, Sato N, et al. Estrogen increases in vivo leptin production in rats and human subjects. J Endocrinol. 1997;154:285–292. [PubMed]
46. Asimakopoulos B, Milousis A, Gioka T, Kabouromiti G, Gianisslis G, Troussa A, et al. Serum pattern of circulating adipokines throughout the physiological menstrual cycle. Endocr J. 2009;56:425–433. [PubMed]
47. Montague CT, Prins JB, Sanders L, Digby JE, O'Rahilly S. Depot- and sex-specific differences in human leptin mRNA expression: implications for the control of regional fat distribution. Diabetes. 1997;46:342–347. [PubMed]
48. Farooqi IS, Jebb SA, Langmack G, Lawrence E, Cheetham CH, Prentice AM, et al. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med. 1999;341:879–884. [PubMed]
49. Farooqi IS, Matarese G, Lord GM, Keogh JM, Lawrence E, Agwu C, et al. Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. J Clin Invest. 2002;110:1093–1103. [PMC free article] [PubMed]
50. Paz-Filho G, Delibasi T, Erol HK, Wong ML, Licinio J. Congenital leptin deficiency and thyroid function. Thyroid Res. 2009;2:11. [PMC free article] [PubMed]
51. Rosenbaum M, Goldsmith R, Bloomfield D, Magnano A, Weimer L, Heymsfield S, et al. Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight. J Clin Invest. 2005;115:3579–3586. [PMC free article] [PubMed]
52. Chan JL, Mietus JE, Raciti PM, Goldberger AL, Mantzoros CS. Short-term fasting-induced autonomic activation and changes in catecholamine levels are not mediated by changes in leptin levels in healthy humans. Clin Endocrinol (Oxf) 2007;66:49–57. [PubMed]
53. Mantzoros C, Flier JS, Lesem MD, Brewerton TD, Jimerson DC. Cerebrospinal fluid leptin in anorexia nervosa: correlation with nutritional status and potential role in resistance to weight gain. J Clin Endocrinol Metab. 1997;82:1845–1851. [PubMed]
54. Welt CK, Chan JL, Bullen J, Murphy R, Smith P, DePaoli AM, et al. Recombinant human leptin in women with hypothalamic amenorrhea. N Engl J Med. 2004;351:987–997. [PubMed]
55. Strobel A, Issad T, Camoin L, Ozata M, Strosberg AD. A leptin missense mutation associated with hypogonadism and morbid obesity. Nat Genet. 1998;18:213–215. [PubMed]
56. Licinio J, Caglayan S, Ozata M, Yildiz BO, de Miranda PB, O'Kirwan F, et al. Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults. Proc Natl Acad Sci U S A. 2004;101:4531–4536. [PubMed]
57. Mantzoros CS, Flier JS, Rogol AD. A longitudinal assessment of hormonal and physical alterations during normal puberty in boys. V. Rising leptin levels may signal the onset of puberty. J Clin Endocrinol Metab. 1997;82:1066–1070. [PubMed]
58. Ahima RS, Dushay J, Flier SN, Prabakaran D, Flier JS. Leptin accelerates the onset of puberty in normal female mice. J Clin Invest. 1997;99:391–395. [PMC free article] [PubMed]
59. Chen R, Mick GJ, Xu R, Zheng D, Fan Y, Lin X, et al. Effect of central antileptin antibody on the onset of female rat puberty. Int J Pediatr Endocrinol. 2009;2009:194807. [PMC free article] [PubMed]
60. Chehab FF, Lim ME, Lu R. Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin. Nat Genet. 1996;12:318–320. [PubMed]
61. Yu WH, Kimura M, Walczewska A, Karanth S, McCann SM. Role of leptin in hypothalamic-pituitary function. Proc Natl Acad Sci U S A. 1997;94:1023–1028. [PubMed]
62. Chan JL, Wong SL, Mantzoros CS. Pharmacokinetics of subcutaneous recombinant methionyl human leptin administration in healthy subjects in the fed and fasting states: regulation by gender and adiposity. Clin Pharmacokinet. 2008;47:753–764. [PMC free article] [PubMed]
63. Quennell JH, Mulligan AC, Tups A, Liu X, Phipps SJ, Kemp CJ, et al. Leptin indirectly regulates gonadotropin-releasing hormone neuronal function. Endocrinology. 2009;150:2805–2812. [PubMed]
64. Hill JW, Elmquist JK, Elias CF. Hypothalamic pathways linking energy balance and reproduction. Am J Physiol Endocrinol Metab. 2008;294:E827–E832. [PubMed]
65. Dardeno TA, Chou SH, Moon HS, Chamberland JP, Fiorenza CG, Mantzoros CS. Leptin in human physiology and therapeutics. Front Neuroendocrinol. 2010;31:377–393. [PMC free article] [PubMed]
66. Lehman MN, Coolen LM, Goodman RL. Minireview: kisspeptin/neurokinin B/dynorphin (KNDy) cells of the arcuate nucleus: a central node in the control of gonadotropin-releasing hormone secretion. Endocrinology. 2010;151:3479–3489. [PubMed]
67. Smith JT, Acohido BV, Clifton DK, Steiner RA. KiSS-1 neurones are direct targets for leptin in the ob/ob mouse. J Neuroendocrinol. 2006;18:298–303. [PubMed]
68. Kotani M, Detheux M, Vandenbogaerde A, Communi D, Vanderwinden JM, Le Poul E, et al. The metastasis suppressor gene KiSS-1 encodes kisspeptins, the natural ligands of the orphan G protein-coupled receptor GPR54. J Biol Chem. 2001;276:34631–34636. [PubMed]
69. Matsuzaki T, Iwasa T, Kinouchi R, Yoshida S, Murakami M, Gereltsetseg G, et al. Fasting reduces the kiss1 mRNA levels in the caudal hypothalamus of gonadally intact adult female rats. Endocr J. 2011;58:1003–1012. [PubMed]
70. Castellano JM, Bentsen AH, Sánchez-Garrido MA, Ruiz-Pino F, Romero M, Garcia-Galiano D, et al. Early metabolic programming of puberty onset: impact of changes in postnatal feeding and rearing conditions on the timing of puberty and development of the hypothalamic kisspeptin system. Endocrinology. 2011;152:3396–3408. [PubMed]
71. Irwig MS, Fraley GS, Smith JT, Acohido BV, Popa SM, Cunningham MJ, et al. Kisspeptin activation of gonadotropin releasing hormone neurons and regulation of KiSS-1 mRNA in the male rat. Neuroendocrinology. 2004;80:264–272. [PubMed]
72. Gottsch ML, Cunningham MJ, Smith JT, Popa SM, Acohido BV, Crowley WF, et al. A role for kisspeptins in the regulation of gonadotropin secretion in the mouse. Endocrinology. 2004;145:4073–4077. [PubMed]
73. Thompson EL, Patterson M, Murphy KG, Smith KL, Dhillo WS, Todd JF, et al. Central and peripheral administration of kisspeptin-10 stimulates the hypothalamic-pituitary-gonadal axis. J Neuroendocrinol. 2004;16:850–858. [PubMed]
74. Louis GW, Greenwald-Yarnell M, Phillips R, Coolen LM, Lehman MN, Myers MG., Jr Molecular mapping of the neural pathways linking leptin to the neuroendocrine reproductive axis. Endocrinology. 2011;152:2302–2310. [PubMed]
75. Donato J, Jr, Cravo RM, Frazão R, Gautron L, Scott MM, Lachey J, et al. Leptin's effect on puberty in mice is relayed by the ventral premammillary nucleus and does not require signaling in Kiss1 neurons. J Clin Invest. 2011;121:355–368. [PMC free article] [PubMed]
76. Mantzoros CS, Ozata M, Negrao AB, Suchard MA, Ziotopoulou M, Caglayan S, et al. Synchronicity of frequently sampled thyrotropin (TSH) and leptin concentrations in healthy adults and leptin-deficient subjects: evidence for possible partial TSH regulation by leptin in humans. J Clin Endocrinol Metab. 2001;86:3284–3291. [PubMed]
77. van der Kroon PH, Boldewijn H, Langeveld-Soeter N. Congenital hypothyroidism in latent obese (ob/ob) mice. Int J Obes. 1982;6:83–90. [PubMed]
78. Légrádi G, Emerson CH, Ahima RS, Flier JS, Lechan RM. Leptin prevents fasting-induced suppression of prothyrotropin-releasing hormone messenger ribonucleic acid in neurons of the hypothalamic paraventricular nucleus. Endocrinology. 1997;138:2569–2576. [PubMed]
79. Kim MS, Small CJ, Stanley SA, Morgan DG, Seal LJ, Kong WM, et al. The central melanocortin system affects the hypothalamo-pituitary thyroid axis and may mediate the effect of leptin. J Clin Invest. 2000;105:1005–1011. [PMC free article] [PubMed]
80. Sanchez VC, Goldstein J, Stuart RC, Hovanesian V, Huo L, Munzberg H, et al. Regulation of hypothalamic prohormone convertases 1 and 2 and effects on processing of prothyrotropin-releasing hormone. J Clin Invest. 2004;114:357–369. [PMC free article] [PubMed]
81. Mantzoros CS, Magkos F, Brinkoetter M, Sienkiewicz E, Dardeno TA, Kim SY, et al. Leptin in human physiology and pathophysiology. Am J Physiol Endocrinol Metab. 2011;301:E567–E584. [PubMed]
82. Shetty GK, Matarese G, Magkos F, Moon HS, Liu X, Brennan AM, et al. Leptin administration to overweight and obese subjects for 6 months increases free leptin concentrations but does not alter circulating hormones of the thyroid and IGF axes during weight loss induced by a mild hypocaloric diet. Eur J Endocrinol. 2011;165:249–254. [PMC free article] [PubMed]
83. Farooqi IS, Wangensteen T, Collins S, Kimber W, Matarese G, Keogh JM, et al. Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor. N Engl J Med. 2007;356:237–247. [PMC free article] [PubMed]
84. Chan JL, Williams CJ, Raciti P, Blakeman J, Kelesidis T, Kelesidis I, et al. Leptin does not mediate short-term fasting-induced changes in growth hormone pulsatility but increases IGF-I in leptin deficiency states. J Clin Endocrinol Metab. 2008;93:2819–2827. [PubMed]
85. Pralong FP, Roduit R, Waeber G, Castillo E, Mosimann F, Thorens B, et al. Leptin inhibits directly glucocorticoid secretion by normal human and rat adrenal gland. Endocrinology. 1998;139:4264–4268. [PubMed]
86. Heiman ML, Ahima RS, Craft LS, Schoner B, Stephens TW, Flier JS. Leptin inhibition of the hypothalamic-pituitary-adrenal axis in response to stress. Endocrinology. 1997;138:3859–3863. [PubMed]
87. Sienkiewicz E, Magkos F, Aronis KN, Brinkoetter M, Chamberland JP, Chou S, et al. Long-term metreleptin treatment increases bone mineral density and content at the lumbar spine of lean hypoleptinemic women. Metabolism. 2011;60:1211–1221. [PubMed]
88. Blüher S, Shah S, Mantzoros CS. Leptin deficiency: clinical implications and opportunities for therapeutic interventions. J Investig Med. 2009;57:784–788. [PubMed]
89. Montague CT, Farooqi IS, Whitehead JP, Soos MA, Rau H, Wareham NJ, et al. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature. 1997;387:903–908. [PubMed]
90. 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;366:74–85. [PubMed]
91. Miller KK, Parulekar MS, Schoenfeld E, Anderson E, Hubbard J, Klibanski A, et al. Decreased leptin levels in normal weight women with hypothalamic amenorrhea: the effects of body composition and nutritional intake. J Clin Endocrinol Metab. 1998;83:2309–2312. [PubMed]
92. Chou SH, Chamberland JP, Liu X, Matarese G, Gao C, Stefanakis R, et al. Leptin is an effective treatment for hypothalamic amenorrhea. Proc Natl Acad Sci U S A. 2011;108:6585–6590. [PubMed]
93. Arimura C, Nozaki T, Takakura S, Kawai K, Takii M, Sudo N, et al. Predictors of menstrual resumption by patients with anorexia nervosa. Eat Weight Disord. 2010;15:e226–e233. [PubMed]
94. Fiorenza CG, Chou SH, Mantzoros CS. Lipodystrophy: pathophysiology and advances in treatment. Nat Rev Endocrinol. 2011;7:137–150. [PMC free article] [PubMed]
95. Pardini VC, Victória IM, Rocha SM, Andrade DG, Rocha AM, Pieroni FB, et al. Leptin levels, beta-cell function, and insulin sensitivity in families with congenital and acquired generalized lipoatropic diabetes. J Clin Endocrinol Metab. 1998;83:503–508. [PubMed]
96. Nagy GS, Tsiodras S, Martin LD, Avihingsanon A, Gavrila A, Hsu WC, et al. Human immunodeficiency virus type 1-related lipoatrophy and lipohypertrophy are associated with serum concentrations of leptin. Clin Infect Dis. 2003;36:795–802. [PubMed]
97. Musso C, Cochran E, Javor E, Young J, Depaoli AM, Gorden P. The long-term effect of recombinant methionyl human leptin therapy on hyperandrogenism and menstrual function in female and pituitary function in male and female hypoleptinemic lipodystrophic patients. Metabolism. 2005;54:255–263. [PubMed]
98. Oral EA, Simha V, Ruiz E, Andewelt A, Premkumar A, Snell P, et al. Leptin-replacement therapy for lipodystrophy. N Engl J Med. 2002;346:570–578. [PubMed]
99. Chong AY, Lupsa BC, Cochran EK, Gorden P. Efficacy of leptin therapy in the different forms of human lipodystrophy. Diabetologia. 2010;53:27–35. [PubMed]
100. Mantzoros CS. W(h)ither metreleptin for lipodystrophy and the metabolic syndrome? Endocr Pract. 2010:1–18. [PubMed]
101. Mantzoros CS. Whither recombinant human leptin treatment for HIV-associated lipoatrophy and the metabolic syndrome? J Clin Endocrinol Metab. 2009;94:1089–1091. [PubMed]
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