Molecular Psychiatry (1997) 2, 267–269 1997 Stockton Press All rights reserved 1359–4184/97 $12.00 EDITORIAL Leptin in anorexia nervosa and amenorrhea In this issue of Molecular Psychiatry we publish two low leptin levels are a predictor of amenorrhea in low- articles by Hebebrand et al1 and Ko¨ pp et al2 on leptin, weight women. The authors show that in their popu- the product of the OB gene, which is synthesized by lation menstruation ceased to occur when leptin levels white fat cells, and acts in various organs, including were under the range of 1.85 mgL−1. In those subjects, the brain. Low leptin levels cause increases in food leptin levels were a better predictor of amenorrhea than intake and weight gain, and high leptin levels cause a BMI, fat mass, and percent body fat. The conclusion decrease in food intake, and increases in motor from the study is that a critical level of leptin is needed activity, energy metabolism, and body temperature, to maintain menstrual function. resulting in weight loss. The leptin receptor gene that Interestingly, studies conducted in the laboratory of has been cloned encodes five or more leptin receptor Jeffrey Flier have shown that the endocrine alterations isoforms, including a form predicted to be soluble, sev- that occur during starvation, such as increased adreno- eral short forms with small intracellular domains, and corticotropic hormone (ACTH) and cortisol levels, one long form with substantial homology to the sig- which are among the biological hallmarks of anorexia naling domain of the type I cytokine receptor family nervosa, can be reversed in food-deprived animals by that utilizes the JAK/STAT pathway for signal trans- the administration of exogenous leptin.7 Based on duction.3–5 The discoveries of leptin and leptin recep- those data, we have tested the hypothesis that in tors have created a new area of investigation in endo- humans endogenous leptin levels are inversely related crinology and metabolism. to pituitary-adrenal function, measuring leptin, ACTH, Eating disorders, particularly anorexia nervosa, are and cortisol levels every 7 min for 24 h, in healthy psychiatric disorders of high morbidity and mortality individuals (Figure 1).8 Total circulating leptin levels that are characterized by alterations in food intake and have a pattern indicative of highly pulsatile release, neuroendocrine function: anorexia nervosa is the only with 32.0 ± 1.5 pulses per 24 h, and pulse duration of psychiatric disorder that requires a specific endocrine 32.8 ± 1.6 min. Because leptin pulses are of short dur- defect, amenorrhea, for diagnosis. Hebebrand’s group ation, pulsatility of human leptin levels can only be has shown that as one would expect, leptin levels are low in patients with anorexia nervosa.1 However, as those individuals gain weight, leptin levels peak at values well in excess of those observed in controls matched for body mass index (BMI). This might help explain why it is so difficult for patients with anorexia nervosa to consistently gain and keep weight. The good news is that after long-term weight restoration, leptin levels return to normal. The findings of a research study are best validated by independent replication, which has been achieved in this case. Mantzoros et al6 have studied leptin levels longitudinally in plasma and cerebrospinal fluid (CSF) in a separate group of patients with anorexia nervosa. They found an increased CSF to plasma ratio for the patients com- pared with controls, and also found that CSF and plasma leptin levels normalized when patients started to gain weight, but before they reached normal body weight. The conclusion from these studies is that inap- propriately high leptin levels before full weight resto- ration contribute to the resistance to weight gain and/or incomplete weight recovery in anorexia nervosa. Figure 1 Simultaneous fluctuations in leptin, ACTH and In a separate study,2 Ko¨pp and colleagues show that cortisol levels in one healthy young man, studied for 24 h with sampling every 7 min for 207 simultaneous measure- ments of leptin (green), ACTH (blue) and cortisol (red). Each Correspondence: J Licinio, MD, Unit on Clinical Research, Clini- measurement is expressed as variability, defined as % of indi- cal Neuroendocrinology Branch, Intramural Research Program, vidual 24-h averages, using the formula: variability at time = National Institute of Mental Health, NIH, Bldg 10, Rm 2D46, t (hormone level at time t per 24-h individual average level) Bethesda, MD 20892-1284, USA. E-mail: licinioKnih.gov × 100.7 Note the inverse relationship between the rhythms of Received 24 April 1997; revised and accepted 12 May 1997 leptin and ACTH/cortisol. Editorial 268 assessed by rapid sampling. Rapid fluctuations in affected by diabetes, sterility, and somatotropic plasma levels of leptin are inversely related to those of defects. These results suggest that NPY is a central ACTH and cortisol. This cannot be accounted for on effector of leptin deficiency.20 Additionally, two other the basis of glucocorticoid suppression of leptin, and new hormones have been shown to modulate food may therefore be due to the acute effects of leptin on intake: urocortin, that binds with high affinity to the 21 corticotropin-releasing hormone (CRH) production. CRF2 receptors, suppresses food intake, and melanin- Leptin treatment of mice substantially blunts the concentrating hormone (MCH), which is localized in stress-induced rise in ACTH and corticosterone; more- the zona incerta and in the lateral hypothalamus, over, leptin acutely inhibits hypoglycemia-induced stimulates food intake after intracerebroventricular CRH secretion by perifused rat hypothalami.9 CRH not injection.22 The interactions among the central cir- only regulates hypothalamic-pituitary-function, but cuitries that mediate the effects of leptin, NPY, urocor- also influences the levels of behavioral arousal.10–13 tin, CRH, MCH, and classical neurotransmitters that Therefore, leptin-mediated alterations in the secretion modulate food intake and reward, such as serotonin, or actions of CHR14 might represent a mechanism by norepinephrine, and dopamine, represent a new fron- which a highly pulsatile peripheral signal of tier of investigation, integrating genetics, endocrin- nutritional status, such as leptin, could modulate endo- ology, metabolism, molecular biology, neuroscience, crine function and behavior.8 A key function of the behavioral science, and psychiatry.23 The hypothesis CNS is therefore regulated by a peripheral pulsatile that alterations in those circuitries contribute to the signal. pathophysiology of eating disorders should certainly Leptin affects the functioning of the hypothalamo- be tested. pituitary-gonadal axis. A recent study has shown that leptin, at very low concentrations, stimulated LHRH J Licinio, MD release from hypothalamic explants and LH release Editor from anterior pituitary in vitro and in vivo. These data indicate that leptin plays an important role in con- References trolling gonadotropin secretion by stimulatory actions in the hypothalamus and pituitary.15 Leptin has also 1 Hebebrand J, Blum WF, Barth N, Coners H, Englaro P, Juul A, 16 Ziegler A, Warnke A, Rascher W, Remschmidt H. Leptin synthesis been shown to act in the ovary. in patients with anorexia nervosa is reduced in the acute stage and Leptin administration affects reproduction: infertile elevated upon short-term weight restoration. Mol Psychiatry 1997; homozygous female OB/OB mice can be treated by 2: 330–334. repeated administration of only recombinant human 2Ko¨pp W, Blum W, von Prittwitz S, Ziegler A, Lu¨ bbert H, Emons G, Herzog W, Herpertz S, Deter H-C, Remschmidt H, Hebebrand J. leptin, which corrects their sterility, and results in ovu- Low leptin levels predict amenorrhea in underweight and eating 17 lation, pregnancy and parturition. Moreover, normal disordered females. Mol Psychiatry 1997; 2: 335–340. prepubertal female mice injected with leptin reproduce 3 Flier JS. Leptin expression and action: new experimental para- up to 9 days earlier than controls and show earlier digms. Proc Natl Acad Sci USA 1997; 94: 4242–4245. maturation of the reproductive tract.18 These results 4 Chen H, Charlat O, Tartaglia LA, Woolf EA, Weng X, Ellis SJ, Lakey ND, Culpepper J, Moore KJ, Breitbart RE, Duyk GM, Tepper RI, suggest that leptin acts as a signal triggering puberty, Morgenstern JP. Evidence that the diabetes gene encodes the leptin and support the hypothesis that fat accumulation receptor: identification of a mutation in the leptin receptor gene in enhances maturation of the reproductive tract. Ko¨pp’s db/db mice. Cell 1996; 84: 491–495. data in this issue of Molecular Psychiatry2 advance this 5 Lee GH, Proenca R, Montez JM, Carroll KM, Darvishzadeh JG, Lee JI, Friedman JM. Abnormal splicing of the leptin receptor in dia- concept and lead to the conclusion that adequate levels betic mice. Nature 1996; 379: 632–635. of leptin are required not only for the maturation of 6 Mantzoros C, Flier JS, Lesem MD, Brewerton TD, Jimerson DC. Cer- reproductive function, but also for the maintenance of ebrospinal fluid leptin in anorexia nervosa. Correlation with normal menstrual function in humans, possibly nutritional status and potential role in resistance to weight gain. J because of its actions at the level of the hypothalamus, Clin Endocrinol Metab 1997; 82: (in press). 15 15 16 7 Ahima RS, Prabakaran D, Mantzoros C, Qu D, Lowell B, Maratos- pituitary, and ovary. Flier E, Flier JS. Role of leptin in the neuroendocrine response to Leptin is a part of a complex molecular network that fasting. Nature 1996; 382: 250–252. controls food intake. Food intake is regulated by per- 8 Licinio J, Mantzoros C, Negra˜ o AB, Cizza G, Wong M-L, Bongiorno ipheral metabolic signals, including gastrointestinal PB, Chrousos GP, Karp B, Allen C, Flier JS, Gold PW. Human leptin levels are pulsatile and inversely related to pituitary-adrenal func- hormones, as well as by the central nervous system, tion.