Novel Insights from Clinical Practice
Rapid Improvement of Hepatic Steatosis after Initiation of Leptin Substitution in a Leptin-Deficient Girlvon Schnurbein J.a, b · Heni M.c · Moss A.a, b · Nagel S.A.a, b · Machann J.d, e · Muehleder H.f · Debatin K.M.b · Farooqi S.g · Wabitsch M.a, b
aDivision of Pediatric Endocrinology and Diabetes at bDepartment of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, cDivision of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Department of Internal Medicine and dSection on Experimental Radiology, Department of Diagnostic Radiology, Eberhard Karls University Tübingen, and eInstitute for Diabetes Research and Metabolic Diseases - Metabolic Imaging, Helmholtz Center Munich, University of Tübingen, Paul Langerhans Institute, Tübingen, Germany; fChildren's Hospital Wels, Wels, Austria; gUniversity of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK
Do you have an account?
- Rent for 48h to view
- Buy Cloud Access for unlimited viewing via different devices
- Synchronizing in the ReadCube Cloud
- Printing and saving restrictions apply
Rental: USD 8.50
Cloud: USD 20.00
Article / Publication Details
Background: Leptin deficiency is associated with severe obesity and metabolic disturbances. Increased liver fat content has been reported in only one case beforehand, even though hepatic steatosis is a typical comorbidity of common obesity. It is also frequent in patients with lipodystrophy where it resolves under leptin therapy. Subject and Methods: In 2010, we reported a leptin-deficient patient with a novel homozygous mutation in the leptin gene and severe hepatic steatosis. We have now studied serum changes and changes in liver fat content during the substitution with recombinant methionyl human leptin. Results: After 23 weeks of leptin substitution, elevated transaminases, total cholesterol and low-density lipoprotein levels normalized. After 62 weeks, homeostasis model assessment of insulin resistance improved from 10.7 to 6.0 and body fat mass dropped from 50.2 to 37.8%. Liver fat content was drastically reduced from 49.7 to 9.4%. The first changes in liver fat content were detectable after 3 days of therapy. Conclusion: Our patient showed a remarkable reduction of liver fat content during the treatment with recombinant methionyl human leptin. These changes occurred rapidly after initiation of the substitution, which implies that leptin has a direct effect on hepatic lipid metabolism in humans as it is seen in rodents.
© 2013 S. Karger AG, Basel
- Farooqi IS, Matarese G, Lord GM, Keogh JM, Lawrence E, Agwu C, Sanna V, Jebb SA, Perna F, Fontana S, Lechler RI, DePaoli AM, O'Rahilly S: 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.
- Javor ED, Ghany MG, Cochran EK, Oral EA, DePaoli AM, Premkumar A, Kleiner DE, Gorden P: Leptin reverses nonalcoholic steatohepatitis in patients with severe lipodystrophy. Hepatology 2005;41:753-760.
- Pelleymounter MA, Cullen MJ, Baker MB, Hecht R, Winters D, Boone T, Collins F: Effects of the obese gene product on body weight regulation in ob/ob mice. Science 1995;269:540-543.
- Shimomura I, Bashmakov Y, Horton JD: Increased levels of nuclear SREBP-1c associated with fatty livers in two mouse models of diabetes mellitus. J Biol Chem 1999;274:30028-30032.
- Kakuma T, Lee Y, Higa M, Wang Z, Pan W, Shimomura I, Unger RH: Leptin, troglitazone, and the expression of sterol regulatory element binding proteins in liver and pancreatic islets. Proc Natl Acad Sci USA 2000;97:8536-8541.
- Brix AE, Elgavish A, Nagy TR, Gower BA, Rhead WJ, Wood PA: Evaluation of liver fatty acid oxidation in the leptin-deficient obese mouse. Mol Genet Metab 2002;75:219-226.
- Lu H, Sun J, Sun L, Shu X, Xu Y, Xie D: Polymorphism of human leptin receptor gene is associated with type 2 diabetic patients complicated with non-alcoholic fatty liver disease in china. J Gastroenterol Hepatol 2009;24:228-232.
- Nobili V, Manco M, Ciampalini P, Diciommo V, Devito R, Piemonte F, Comparcola D, Guidi R, Marcellini M: Leptin, free leptin index, insulin resistance and liver fibrosis in children with non-alcoholic fatty liver disease. Eur J Endocrinol 2006;155:735-743.
- Chitturi S, Farrell G, Frost L, Kriketos A, Lin R, Fung C, Liddle C, Samarasinghe D, George J: Serum leptin in NASH correlates with hepatic steatosis but not fibrosis: a manifestation of lipotoxicity? Hepatology 2002;36:403-409.
- Stefan N, Kantartzis K, Machann J, Schick F, Thamer C, Rittig K, Balletshofer B, Machicao F, Fritsche A, Haring HU: Identification and characterization of metabolically benign obesity in humans. Arch Intern Med 2008;168:1609-1616.
- Huang-Doran I, Sleigh A, Rochford JJ, O'Rahilly S, Savage DB: Lipodystrophy: metabolic insights from a rare disorder. J Endocrinol 2010;207:245-255.
- Stefan N, Hennige AM, Staiger H, Machann J, Schick F, Krober SM, Machicao F, Fritsche A, Haring HU: Alpha-2-Heremans-Schmid glycoprotein/fetuin-A is associated with insulin resistance and fat accumulation in the liver in humans. Diabetes Care 2006;29:853-857.
- Paz-Filho GJ, Ayala A, Esposito K, Erol HK, Delibasi T, Hurwitz BE, Wong ML, Licinio J: Effects of leptin on lipid metabolism. Horm Metab Res 2008;40:572-574.
- Muzzin P, Eisensmith RC, Copeland KC, Woo SL: Correction of obesity and diabetes in genetically obese mice by leptin gene therapy. Proc Natl Acad Sci USA 1996;93:14804-14808.
- Licinio J, Caglayan S, Ozata M, Yildiz BO, de Miranda PB, O'Kirwan F, Whitby R, Liang L, Cohen P, Bhasin S, Krauss RM, Veldhuis JD, Wagner AJ, DePaoli AM, McCann SM, Wong ML: Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults. Proc Natl Acad Sci USA 2004;101:4531-4536.
- Javor ED, Cochran EK, Musso C, Young JR, Depaoli AM, Gorden P: Long-term efficacy of leptin replacement in patients with generalized lipodystrophy. Diabetes 2005;54:1994-2002.
- Oral EA, Javor ED, Ding L, Uzel G, Cochran EK, Young JR, DePaoli AM, Holland SM, Gorden P: Leptin replacement therapy modulates circulating lymphocyte subsets and cytokine responsiveness in severe lipodystrophy. J Clin Endocrinol Metab 2006;91:621-628.
- Beltrand J, Beregszaszi M, Chevenne D, Sebag G, De Kerdanet M, Huet F, Polak M, Tubiana-Rufi N, Lacombe D, De Paoli AM, Levy-Marchal C: Metabolic correction induced by leptin replacement treatment in young children with Berardinelli-Seip congenital lipoatrophy. Pediatrics 2007;120:e291-e296.
- Ebihara K, Kusakabe T, Hirata M, Masuzaki H, Miyanaga F, Kobayashi N, Tanaka T, Chusho H, Miyazawa T, Hayashi T, Hosoda K, Ogawa Y, DePaoli AM, Fukushima M, Nakao K: Efficacy and safety of leptin-replacement therapy and possible mechanisms of leptin actions in patients with generalized lipodystrophy. J Clin Endocrinol Metab 2007;92:532-541.
- Petersen KF, Oral EA, Dufour S, Befroy D, Ariyan C, Yu C, Cline GW, DePaoli AM, Taylor SI, Gorden P, Shulman GI: Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy. J Clin Invest 2002;109:1345-1350.
- Ozata M, Ozdemir IC, Licinio J: Human leptin deficiency caused by a missense mutation: multiple endocrine defects, decreased sympathetic tone, and immune system dysfunction indicate new targets for leptin action, greater central than peripheral resistance to the effects of leptin, and spontaneous correction of leptin-mediated defects. J Clin Endocrinol Metab 1999;84:3686-3695.
- Gibson WT, Farooqi IS, Moreau M, DePaoli AM, Lawrence E, O'Rahilly S, Trussell RA: Congenital leptin deficiency due to homozygosity for the δ133g mutation: report of another case and evaluation of response to four years of leptin therapy. J Clin Endocrinol Metab 2004;89:4821-4826.
- Paz-Filho GJ, Babikian T, Asarnow R, Esposito K, Erol HK, Wong ML, Licinio J: Leptin replacement improves cognitive development. PLoS One 2008;3:e3098.
- Mazen I, El-Gammal M, Abdel-Hamid M, Amr K: A novel homozygous missense mutation of the leptin gene (N103k) in an obese Egyptian patient. Mol Genet Metab 2009;97:305-308.
- Fatima W, Shahid A, Imran M, Manzoor J, Hasnain S, Rana S, Mahmood S: Leptin deficiency and leptin gene mutations in obese children from Pakistan. Int J Pediatr Obes 2011;6:419-427.
- Saeed S, Butt TA, Anwer M, Arslan M, Froguel P: High prevalence of leptin and melanocortin-4 receptor gene mutations in children with severe obesity from Pakistani consanguineous families. Mol Genet Metab 2012;106:121-126.
- Fischer-Posovszky P, von Schnurbein J, Moepps B, Lahr G, Strauss G, Barth TF, Kassubek J, Muhleder H, Moller P, Debatin KM, Gierschik P, Wabitsch M: A new missense mutation in the leptin gene causes mild obesity and hypogonadism without affecting T-cell responsiveness. J Clin Endocrinol Metab 2010;95:2836-2840.
- Von Schnurbein J, Moss A, Nagel SA, Muehleder H, Debatin KM, Farooqi IS, Wabitsch M: Leptin substitution results in the induction of menstrual cycles in an adolescent with leptin deficiency and hypogonadotropic hypogonadism. Horm Res Paediatr 2012;77:127-133.
- Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC: Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985;28:412-419.
- Machann J, Thamer C, Schnoedt B, Haap M, Haring HU, Claussen CD, Stumvoll M, Fritsche A, Schick F: Standardized assessment of whole-body adipose tissue topography by MRI. J Magn Reson Imaging 2005;21:455-462.
- Machann J, Stefan N, Schick F: 1H-MR spectroscopy of skeletal muscle, liver and bone marrow. Eur J Radiol 2008;67:275-284.
- Machann J, Thamer C, Schnoedt B, Stefan N, Haring HU, Claussen CD, Fritsche A, Schick F: Hepatic lipid accumulation in healthy subjects: a comparative study using spectral fat-selective MRI and volume-localized 1H-MR spectroscopy. Magn Reson Med 2006;55:913-917.
- Szczepaniak LS, Nurenberg P, Leonard D, Browning JD, Reingold JS, Grundy S, Hobbs HH, Dobbins RL: Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am J Physiol Endocrinol Metab 2005;288:E462-E468.
- Montague CT, Farooqi IS, Whitehead JP, Soos MA, Rau H, Wareham NJ, Sewter CP, Digby JE, Mohammed SN, Hurst JA, Cheetham CH, Earley AR, Barnett AH, Prins JB, O'Rahilly S: Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 1997;387:903-908.
- Farooqi IS, Wangensteen T, Collins S, Kimber W, Matarese G, Keogh JM, Lank E, Bottomley B, Lopez-Fernandez J, Ferraz-Amaro I, Dattani MT, Ercan O, Myhre AG, Retterstol L, Stanhope R, Edge JA, McKenzie S, Lessan N, Ghodsi M, De Rosa V, Perna F, Fontana S, Barroso I, Undlien DE, O'Rahilly S: Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor. N Engl J Med 2007;356:237-247.
- Clement K, Vaisse C, Lahlou N, Cabrol S, Pelloux V, Cassuto D, Gourmelen M, Dina C, Chambaz J, Lacorte JM, Basdevant A, Bougneres P, Lebouc Y, Froguel P, Guy-Grand B: A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 1998;392:398-401.
- Anstee QM, Goldin RD: Mouse models in non-alcoholic fatty liver disease and steatohepatitis research. Int J Exp Pathol 2006;87:1-16.
- 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.
- Simha V, Szczepaniak LS, Wagner AJ, DePaoli AM, Garg A: Effect of leptin replacement on intrahepatic and intramyocellular lipid content in patients with generalized lipodystrophy. Diabetes Care 2003;26:30-35.
- Lee Y, Yu X, Gonzales F, Mangelsdorf DJ, Wang MY, Richardson C, Witters LA, Unger RH: PPAR-α is necessary for the lipopenic action of hyperleptinemia on white adipose and liver tissue. Proc Natl Acad Sci USA 2002;99:11848-11853.
- Asilmaz E, Cohen P, Miyazaki M, Dobrzyn P, Ueki K, Fayzikhodjaeva G, Soukas AA, Kahn CR, Ntambi JM, Socci ND, Friedman JM: Site and mechanism of leptin action in a rodent form of congenital lipodystrophy. J Clin Invest 2004;113:414-424.
- Minokoshi Y, Kim YB, Peroni OD, Fryer LG, Muller C, Carling D, Kahn BB: Leptin stimulates fatty-acid oxidation by activating amp-activated protein kinase. Nature 2002;415:339-343.
- Orci L, Cook WS, Ravazzola M, Wang MY, Park BH, Montesano R, Unger RH: Rapid transformation of white adipocytes into fat-oxidizing machines. Proc Natl Acad Sci USA 2004;101:2058-2063.
Soukas A, Cohen P, Socci ND, Friedman JM: Leptin-specific patterns of gene expression in white adipose tissue. Genes Dev 2000;14:963-980.
- Farooqi IS, O'Rahilly S: Leptin: a pivotal regulator of human energy homeostasis. Am J Clin Nutr 2009;89:980S-984S.
Article / Publication Details
Copyright / Drug Dosage / DisclaimerCopyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.