Dissecting Leptin RolesIn the following paper there is an attempt to explicate the role of leptin in the various systems of the body most specifically the central nervous system (CNS), endocrine and immune system. The primal start of the paper would be its associated roles in eating disorders since most of the literatures abound in this topic. The mechanism of leptin is explicated in the regulation part of the paper. Immunity roles of leptin are current areas of study so I will include a small part on that. A general review/comment is given at the end of the discussionCauses of Eating DisordersBullimia nervosa and anorexia nervosa are psychological maladies classified under eating-disorders. Bullimia nervosa is an eating disorder characterized by binge eating followed by compensatory efforts to prevent weight gain by purging out the food either by induced vomiting, use of laxatives, fasting and excessive exercise. Anorexia nervosa, on the other hand is characterized by self-starvation due to fear of gaining weight even when he/she is already underweight.
Eating disorders also include chronic over-eating which result to obesity (1). Vanity-associated dieting aside from the anorexia nervosa is common in highly developed countries especially where it is a fad to be “thin”. Reduction in calorie intake, however is associated with metabolic and immune malfunction, inflammation and hormonal imbalances (3)The causes of the eating disorders are pointed to negative-family influences and socio-cultural factors, genetic and hormonal abnormalities (2). A small part of the paper dabbles on the pathophysiological importance of leptin and its potential role in treating eating disorders.Breakthrough Discovery Leptin is a 16 kilodalton hormone protein consisting of one hundred sixty-seven amino acids and is a member of the cytokine family through structure (5, 6). It was first discovered by Zhang and colleagues (7) by positional cloning of the ob gene and the by-product of this gene they termed as leptin, meaning thin. They found that the mice deficient in ob gene can have significant weight reduction by introducing leptin.
The hormone is expressed at the following sites: white fat cells, stomach, hypothalamic region, pituitary gland, striations in skeletal muscle , placenta and mammary organ.The role of leptin as a regulatory hormone in neuroendocrine processes especially in starvation (7, 8) rather than an anti-obesity molecule is now recognized rather than as an anti-obesity hormone. The pathophysiology of the leptin proceeds by the following manner: Adipose tissues produced leptin which then interacts with leptin receptors (LepRa–LepRf ).
LepRb isoform ‘intracellular signaling domains’ wields its effects in the hypothalamic nuclei, where it attaches to the ventral medial nucleus of the hypothalamus thus signaling ‘satiation’ (9, 10).Leptin in Eating DisordersSerum leptin concentrations are significantly reduced in anorexia nervosa and bulimia nervosa compared to control subjects (11, 12, 13). A strong correlation exists between the body mass index and serum and leptin concentrations. Overindulging in food could be one of the phenotype. Mutation in melanocortin-4 receptor gene could lead to this phenotype (14).Leptin RegulationExpression of OB-Rb, in the arcuate and ventromedial hypothalamic nuclei are important in ‘satiation’ signals and sexual behavior.
Receptors are expressed GnRH-secreting neurons thus accelerating its pulsality of the gonadotropin releasing-hormone in region of arcuate hypothalamus thus regulating the release of gonadotropins (15), suggesting possible metabolic control. GnRH secretion can also proceed by altering the secretion of neuropeptides (16) and/or by liberating nitric oxide from adrenaline-stimulating interneuron (17). Expression of leptin receptors in reproductive areas like the ovarian follicles, Leydig cells, granulosa and cumulus cells (18,19) suggests endocrine effects on gonads.Circadian rhythm is displayed by leptin with a morning peak and afternoon low-point. Its’ pattern is parallel to that of thyrotroph emission, prolactin, free f.a.’s, and 5-methoxy-N-acetyl tryptamine and inversely related to adenocorticopic hormone and cortisol.
Leptin is synchronous to that of luteinizing hormone and estradiol levels in females, particularly during the nighttime when leptin levels are high, suggesting that leptin may effect hormone regulation in the reproductory system (21). Leptin treatment has been demonstrated to be effective in correcting sterility in obese female mice and congenital leptin deficiency. Leptin-wanting children when treated with the hormone had undergone changes in puberty.
In anorexic patients, supplementation of leptin leads to weight gain accompanied by rise in FSH and LH levels.Leptin level decrease is associated with suppression of T4 and T3 concentrations and increase in reverse T3 leading to a state of hypothyroidism (22). It was also found that the administration of the hormone exogenously to starved rats can correct the thyroid concentration. Impairment of the thyroid regulation system can be associated with the congenital leptin deficiency. The mutation in the receptor gene results to hypothyroidism marked by leptin resistance.
Leptin administered to starved human volunteers increases free T4 levels and normalizes TSH pulsality (23). In anorexic patients, leptin serum levels , TSH and thyroid hormones equivocates that of normal subjects after weight revival (24).The role of leptin in the adrenal axis has not been fully elucidated yet. Glucocortinoid concentrations do not effect growth retardation in leptin-deficient patients or those having the congenital disease (25). In addition, it odes not effect satiety signals in cortisol secretion in human subjects. More studies have to be conducted regarding this area.Leptin and ImmunityLeptin’s role as a fat biomarker and energy indicator has been thoroughly studied.
Its’ role in the endocrine, reproduction and metabolism has been explicated above.There are also recent discoveries suggesting the role of leptin in immunology. It wields effects on hemopoiesis, angiogenesis, and immune responses. Leptin has been demostrated to increase during inflammation. Leptin in immunity proceeds by delayed apoptosis of mature neutrophils in vitro technique by blocking anti-leptin receptor mAb through a concentration gradient. The pathways involved PI3K- and MAPK-signaling cascade.
It prolonged the cleavage Bid-Bax cleavage, the mitochondrial release of cyt c and the mt-derived activator of caspase, and activates caspase 8 and 3 (26).Leptin receptor-deficient db/db and control db/+ was transplanted into bone marrow chimera and the cellularity and humoral response was similar to that of the wild type. The receptor was found to effect T cell development since there the cell number was decreased in thymic region. Leptin was found to be not needed in the thymus region and is unnecesaary for T lymphocyte development.
However, the leptin receptor deficiency may affect changes indirectly through the systemic environment (27).Thymus tissues, producer of T cells, is highly vulnerable to atrophy induced by pressure, infectivity, and ionizing radiation and delayed atrophy can lead to T cell paucity or prevent immune revitalization of the damaged cells. Thymus involution may be treated by leptin since it was found to combat bacterial endotoxin-induced atrophy in the thymus region using the LPS rodent model. Leptin protects the thymus from acute involution by encouraging expansion of CD4– or CD8– thymocytes and thwart edema of CD4+ or CD8+ thymocytes (28). This suggests the therapeutic value of leptin during stress conditions.Corollary to this is that the hormone may improve the human dendritic cells by downstream regulation of IL-10 production and impel naive T cell polarization in the direction of Th1 phenotype.
Spontaneous and UVB activated apoptosis can be prevented with leptin by starting of NF- B and parallel upstream regulation of bcl-2 and bcl-xL.(29)Other studies also suggest the importance of leptin in NK signaling in bone marrow, selective augmentation of thymopoiesis, B lymphocyte activity, attenuation of experimental arthritis and effective proinflammatory immune response in encephalomyelitis.Review of the RolesLeptin’s role in energy homeostasis and biomarkers are well studied and is applicable to “starvation” regulation in human body. Much of the literature that I have found potentiate on the impact of leptin in eating-disorder therapy. The neural machinations for the leptin hormone and its’ associated receptor is well studied. However, there are gray areas that still exist for the effect of the protein on the endocrine system. This is not to say that there are no studies regarding this area but the turnabouts of the studies relating to this area are disappointing.
Repetitive and more human subjects as well as cognitive endocrinal disorders should be carefully studied.Leptin therapy in psychological eating disorders has been demonstrated in the previous studies. Recent evidences also show that the therapeutic capacity of the hormone can extend to immunity. It has been found to be effective in combating inflammatory diseases and Th1 mediated immune responses.
Morever, I think that, what is most important in these studies is that they find the “leptin efficacy” within the conjunction of human health. Double placebo-designed experiments and not just clinical evidences should support the “regulatory” role of leptin in eating disorder patients and those with immune-associated problems. Works Cited (1) American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. American Psychiatric Press Inc; 1994.(2) Bulik CM, Sullivan PF, Wade TD, Kendler KS. Twin studies of eating disorders: a review. Int J Eat Disord.
Jan 2000;27(1):1-20.(3) Morgan JF. Eating disorders and reproduction. Aust N Z J Obstet Gynaecol.
May 1999;39(2):167-73(4) Mehler PS, Crews C, Weiner K. Bulimia: medical complications. J Womens Health (Larchmt). Jul-Aug 2004;13(6):668-75.
(5) Zhang, F., Basinski, M. B., Beals, J. M., Briggs, S. L., Churgay, L.
M., Clawson, D. K.
, DiMarchi, R. D., Furman, T.
C. & Hale, J. E., et al (1997) Crystal structure of the obese protein leptin- E100. Nature 387:206-209(6) Madej, T., Boguski, M.
S. & Bryant, S. H. (1995) Threading analysis suggests that the obese gene product may be a helical cytokine. FEBS Lett. 373:13-18(7) Tartaglia, L. A.
, Dembski, M., Weng, X., Deng, N., Culpepper, J. & Devos, R. (1995) Identification and cloning of a leptin receptor, OB-R.
Cell 83:1263-1271(8) Tartaglia, L. A. (1997) The leptin receptor. J. Biol.
Chem. 272:6093-6096.(9) Heretier, A., Charnay, Y. & Aubert, M. L. (1997) Regional distribution of mRNA encoding the long form of receptor in mouse brain. Neurosci.
Res. Commun. 21:113-118.(10) Huang, X. F., Lin, S. & Zhang, R. (1997) Upregulation of leptin receptor mRNA expression in obese mouse brain.
Neuroreport 8:1035-1038(11) Brewerton TD, Lesem MD, Kennedy A, Garvey WT. Reduced plasma leptin concentrations in bulimia nervosa. Psychoneuroendocrinology. Oct 2000;25(7):649-58.(12) Wolfe BE, Jimerson DC, Orlova C, Mantzoros CS. Effect of dieting on plasma leptin, soluble leptin receptor, adiponectin and resistin levels in healthy volunteers.
Clin Endocrinol (Oxf). Sep 2004;61(3):332-8.(13) Hebebrand, J.
, van der Heyden, J., Devos, R., Kopp, W., Herpertz, S., Remschmidt, H.
& Herzog, W. (1995) Plasma concentrations of obese protein in anorexia nervosa [letter]. Lancet 346:1624-1625(14) Branson, R., Potoczna, N., Kral, J. G., Lentes, K.
U., Hoehe, M. R. & Horber, F. F. (2003) : Binge eating as a major phenotype of melanocortin 4 receptor gene mutations. N.
Engl. J. Med. 348:1096-1103(15) Masuzaki, H., Ogawa, Y.
, Sagawa, N., Hosoda, K., Matsumoto, T., Mise, H., Nishimura, H.
, Yoshimasa, Y. & Tanaka, I., et al (1997) Nonadipose tissue production of leptin: leptin as a novel placenta-derived hormone in humans.
Nat. Med. 3:1029-1033(16) Terasawa, E.
(1998) Cellular mechanism of pulsatile LHRH release. Gen. Comp.
Endocrinol. 112:283-295.(17) Yu, W. H.
, Walczewska, A., Karanth, S. & McCann, S. M. (1997) Nitric oxide mediates leptin-induced luteinizing hormone-releasing hormone (LHRH) and LHRH and leptin-induced LH release from the pituitary gland. Endocrinology 138:5055-5058.
(18) Karlsson, C., Lindell, K., Svensson, E., Bergh, C.
, Lind, P., Billig, H., Carlsson, L. M. & Carlsson, B. (1997) Expression of functional leptin receptors in the human ovary. J.
Clin. Endocrinol. Metab.
82:4144-4148.(19) Caprio, M., Isidori, A. M., Carta, A.
R., Moretti, C., Dufau, M. L. & Fabbri, A.
(1999) Expression of functional leptin receptors in rodent Leydig cells. Endocrinology 140:4939-4947.(20) Mantzoros, C. S., Ozata, M., Negrao, A. B., Suchard, M.
A., Ziotopoulou, M., Caglayan, S., Elashoff, R.
N., Cogswell, R. J. & Negro, P., et al (2001) 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. 86:3284-3291.(21) Licinio, J., Negrao, A. B.
, Mantzoros, C., Kaklamani, V., Wong, M. L., Bongiorno, P. B., Negro, P. P.
, Mulla, A. & Veldhuis, J. D., et al (1998) Sex differences in circulating human leptin pulse amplitude: Clinical implications. J. Clin. Endocrinol.
Metab. 83:4140-4147(22) Flier, J. S., Harris, M. & Hollenberg, A.
N. (2000) Leptin, nutrition, and the thyroid; the why, the wherefore, and the wiring. J. Clin.
Invest. 105:859-661.(23) Chan, J., Heist, K., DePaoli, A. M., Veldhuis, J. D.
& Mantzoros, C. S. (2003) The role of falling leptin levels in the neuroendocrine and metabolic adaptation to short-term starvation in healthy men.
J. Clin. Invest. 111:1409-1421.(24) Gordon, C. M.
, Emans, S. J., DuRant, R. H., Mantzoros, C.
, Grace, E., Harper, G. P. & Majzoub, J. A. (2000) Endocrinologic and psychological effects of short-term dexamethasone in anorexia nervosa. Eat Weight Disord.
5:175-182(25) Farooqi, I. S., Jebb, S. A., Langmack, G.
, Lawrence, E., Cheetham, C. H., Prentice, A. M.
, Hughes, I. A., McCamish, M. A. & O’Rahilly, S. (1999) Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N. Engl.
J. Med. 341:879-884.
(26)Bruno, A., Conus, S., Schmid, I., and S. Hans-Uwe. (2005). Journ. of Imm.
174: 8090-8096.(27) Palmer, G., Aurrand-Lions, M., Contassot, E.
, Talabot-Ayer, D. ,Ducrest-Gay D., Vesin, C., Chobaz-Péclat, V.
, Buss, N., and C. Gabay. (2006). Indirect Effects of Leptin Receptor Deficiency on Lymphocyte Populations and Immune Response in db/db Mice. Journ.of Imm.
177: 2899-2907.(28) Gruver, A., Ventevogel, M., and G.
Sempowski. (2007). Journ. of Imm. 178: 85.9.(29) Mattioli, B.
, Straface, E., Quaranta, M. G.
, Giordani, L. and M. Viora.
(2005). Journ. of Imm174: 6820-6828.