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Leptin-Replacement Therapy for Lipodystrophy
Open accessAbstract
BACKGROUND: The adipocyte hormone leptin is important in regulating energy homeostasis. Since severe lipodystrophy is associated with leptin deficiency, insulin resistance, hypertriglyceridemia, and hepatic steatosis, we assessed whether leptin replacement would ameliorate this condition. METHODS: Nine female patients (age range, 15 to 42 years; eight with diabetes mellitus) who had lipodystrophy and serum leptin levels of less than 4 ng per milliliter (0.32 nmol per milliliter) received recombinant methionyl human leptin (recombinant leptin). Recombinant leptin was administered subcutaneously twice a day for four months at escalating doses to achieve low, intermediate, and high physiologic replacement levels of leptin. RESULTS: During treatment with recombinant leptin, the serum leptin level increased from a mean (+/- SE) of 1.3 +/- 0.3 ng per milliliter to 11.1 +/- 2.5 ng per milliliter (0.1 +/- 0.02 to 0.9 +/- 0.2 nmol per milliliter). The absolute decrease in the glycosylated hemoglobin value was 1.9 percent (95 percent confidence interval, 1.1 to 2.7 percent; P=0.001) in the eight patients with diabetes. Four months of therapy decreased average triglyceride levels by 60 percent (95 percent confidence interval, 43 to 77 percent; P<0.001) and liver volume by an average of 28 percent (95 percent confidence interval, 20 to 36 percent; P=0.002) in all nine patients and led to the discontinuation of or a large reduction in antidiabetes therapy. Self-reported daily caloric intake and the measured resting metabolic rate also decreased significantly with therapy. Overall, recombinant leptin therapy was well tolerated. CONCLUSIONS: Leptin-replacement therapy improved glycemic control and decreased triglyceride levels in patients with lipodystrophy and leptin deficiency. Leptin deficiency contributes to the insulin resistance and other metabolic abnormalities associated with severe lipodystrophy.
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“Energy expenditure was assessed by indirect calorimetry in all patients before and after leptin treatment and was found to be slightly, but not significantly, lower in all patients after leptin treatment (1,660 ± 108 kcal/day before treatment versus 1,403 ± 62 kcal/day after treatment, P = 0.08).”
From Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy (2002) · cites this paper as [5]
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“At the time of the postleptin treatment study, all patients had their antidiabetic medication discontinued (5).”
From Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy (2002) · cites this paper as [5]
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“The improved glycemic control could be attributed to a marked increase in their insulin responsiveness, as reflected by an almost fourfold increase in the rate of glucose infusion required to maintain euglycemia during the clamp”
From Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy (2002) · cites this paper as [5]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Energy intake was monitored in patient NIH-6, and leptin treatment caused an approximately 50% reduction in energy intake, from 2,017 kcal/day before treatment to 962 kcal/day after 3 months of treatment.”
From Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy (2002) · cites this paper as [5]
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“More recently, Arioglu Oral et al. found that human recombinant leptin therapy reduced hyperglycemia and hypertriglyceridemia and increased the rate of glucose disappearance during an intravenous insulin tolerance test in nine lipodystrophic patients (5).”
From Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy (2002) · cites this paper as [5]
In the citing paper
“Marked effects of leptin in reducing food intake in lipodystrophic patients and others have also been noted (35).”
From Leptin at 14 y of age: an ongoing story (2009) · cites this paper as [35]
In the citing paper
“Previous studies had shown that leptin treatment can improve glucose homeostasis in patients with lipodystrophy (21) and in children treated with leptin on a long-term basis (8, 9).”
From Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults (2004) · cites this paper as [21]
In the citing paper
“Several lines of evidence from both humans and rodent models suggest that leptin deficiency contributes to insulin resistance and diabetes in this setting (139, 168, 169).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [139]
In the citing paper
“leptin therapy has been examined in several clinical trials in patients with lipodystrophy and these have demonstrated significant improvements in glycemia, dyslipidemia and hepatic steatosis (89, 90, 139, 142).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [139]
In the citing paper
“First in rodent models (5) and then in preliminary short-term studies in humans (6), it was shown that recombinant leptin administration could ameliorate dyslipidemia, insulin resistance, and diabetes.”
From Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy (2005) · cites this paper as [6]
In the citing paper
“Although pair feeding may lead to some improvement in the metabolic profile compared with the ad lib state, it does not correct the metabolic abnormalities to the same extent as leptin replacement.”
From Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy (2005) · cites this paper as [6]
In the citing paper
“Moreover, leptin dramatically improves insulin sensitivity in human lipodystrophy and in lipodystrophic mouse models which are characterized by low serum leptin levels and by severe insulin resistance (Oral et al., 2002; Petersen et al., 2002; Shimomura et al., 1999).”
From Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons (2009) · cites this paper as Oral et al., 2002
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BackgroundSommer, C., Gulseth, H. L., Jenum, A. K., Sletner, L., Thorsby, P. M., & Birkeland, K. I. (2016) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2016-2583 · Cited by 11
“Because leptin deficiency in patients with lipodystrophy (lacking adipose tissue and thereby leptin) is accompanied by insulin resistance and dysglycemia (4), it is likely that leptin resistance will influence glucose metabolism.”
BackgroundLightbourne, M., Wolska, A. T., Abel, B. S., Rother, K. I., Walter, M. F., Kushchayeva, Y. S., Auh, S., Shamburek, R. D., Remaley, A. T., Muniyappa, R., et al. (2020) · Journal of the Endocrine Society · doi:10.1210/jendso/bvaa191 · Cited by 11
“Other mechanisms that may be responsible for metreleptin-mediated reductions in triglycerides include decreased food intake [4, 5], decreased adipose tissue lipolysis [14, 25], increased fatty acid oxidation [26], and decreased de novo lipogenesis [27-29].”
BackgroundEtiology and Pathogenesis of Diabetes Mellitus in Children and Adolescents
Yau, M., Maclaren, N. K., & Sperling, M. A. (2021) · Europe PMC (PubMed Central) · Cited by 11
Impaired Muscle Mitochondrial Function in Familial Partial Lipodystrophy
Simha, V., Lanza, I. R., Dasari, S., Klaus, K. A., LeBrasseur, N. K., Vučković, I., LAURENTI, M. C., Cobelli, C., Port, J. D., & Nair, K. S. (2021) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgab725 · Cited by 11
Self-citationRoles of plasma leptin and resistin in novel subgroups of type 2 diabetes driven by cluster analysis
Peng, X., Huang, J., Zou, H., Peng, B., Xia, S.-S., Dong, K., Sun, N., Tao, J., & Yang, Y. (2022) · Lipids in Health and Disease · doi:10.1186/s12944-022-01623-z · Cited by 11
Short-term overfeeding increases resting energy expenditure in patients with HIV lipodystrophy
Kosmiski, L. A., Bessesen, D. H., STOTZ, S. A., Koeppe, J. R., & Horton, T. J. (2007) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/86.4.1009 · Cited by 11
“Persons with generalized lipodystrophy develop diabetes mellitus in their teenage years and can require thousands of units of insulin per day (24).”
Treatment of Obesity and Diabetes in Mice by Transplant of Gut Cells Engineered to Produce Leptin
Oosman, S. N., Lam, A., Harb, G., Unniappan, S., Lam, N. T., Webber, T. D., Bruch, D., Zhang, Q., Korbutt, G. S., & Kieffer, T. J. (2008) · Molecular Therapy · doi:10.1038/mt.2008.62 · Cited by 12
New and emerging agents in the management of lipodystrophy in HIV-infected patients
Bonnet, É. (2010) · HIV/AIDS - Research and Palliative Care · doi:10.2147/hiv.s13429 · Cited by 11
Akgün, S., Köken, T., & Kahraman, A. (2017) · Journal of Psychopharmacology · doi:10.1177/0269881117715608 · Cited by 11
“Leptin has been shown to be implicated in providing normal insulin sensitivity (Oral et al., 2002).”
BackgroundZiqubu, K., Mazibuko-Mbeje, S. E., & Dludla, P. V. (2024) · Biochimie · doi:10.1016/j.biochi.2024.11.007 · Cited by 11
Zouhar, P., Rakipovski, G., Bokhari, M. H., Busby, O., Paulsson, J. F., Conde‐Frieboes, K. W., Fels, J. J., Raun, K., Andersen, B., Cannon, B., et al. (2019) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00253.2019 · Cited by 10
Tall stature in children and adolescents
Urakami, T. (2021) · Minerva Pediatrics · doi:10.23736/s0026-4946.20.05971-x · Cited by 10
Casey, S., Lokan, J., Testro, A., Farquharson, S., Connelly, A., Proietto, J., & Angus, P. (2013) · American Journal of Transplantation · doi:10.1111/ajt.12436 · Cited by 10
“In a small number of patients, leptin has been shown to improve fatty liver disease, as evidenced by histological regression of hepatic steatosis (8,12).”
BackgroundIs there an estrogenic component in the metabolic syndrome?
Starcke, S., & Vollmer, G. (2006) · Genes & Nutrition · doi:10.1007/bf02829967 · Cited by 11
Leptin for type 1 diabetes: coming onto stage to be (or not?)
Oral, E. A. (2012) · Pediatric Diabetes · doi:10.1111/j.1399-5448.2011.00797.x · Cited by 10
“Leptin therapy leads to a reduction in food intake in non-obese humans such as women with hypothalamic amenorrhea (13) and in patients with lipodystrophy (14) as well as a few obese humans with mutations in the leptin gene (15).”
BackgroundSelf-citationCirculating serum chemerin levels are elevated in lipodystrophy
Miehle, K., Ebert, T., Kralisch, S., Hoffmann, A., Kratzsch, J., Schlögl, H., Stümvoll, M., & Faßhauer, M. (2015) · Clinical Endocrinology · doi:10.1111/cen.12976 · Cited by 10
Bruder-Nascimento, T. B., Kress, T. C., Pearson, M., Chen, W., Kennard, S., & de Chantemèle, E. J. B. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms221910596 · Cited by 10
Treatment Options for Lipodystrophy in Children
Mainieri, F., Tagi, V. M., & Chiarelli, F. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.879979 · Cited by 10
“As a confirmatory step, the discontinuation of metreleptin therapy caused the increase of fasting triglyceride and insulin levels in the first 48 hours, resolved by resuming therapy (2).”
BackgroundTakemori, K., Inoué, T., & Ito, H. (2013) · Lipids in Health and Disease · doi:10.1186/1476-511x-12-108 · Cited by 11
“Furthermore, in clinical trials, it was reported that leptin improved insulin resistance in lipoatrophic patients [20,21].”
Tsoukas, M. A., & Mantzoros, C. S. (2015) · Elsevier eBooks · doi:10.1016/b978-0-323-18907-1.00037-8 · Cited by 10
Role of modulator recognition factor 2 in adipogenesis and leptin expression in 3T3-L1 cells
Dong, J., Ishimori, N., Paigen, B. J., Tsutsui, H., & Fujii, S. (2007) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2007.12.002 · Cited by 10
Alterations of leptin and ghrelin serum concentrations in renal disease: simple epiphenomena?
Dötsch, J., Nüsken, K., Schroth, M. A., Rascher, W., & Meißner, U. (2005) · Pediatric Nephrology · doi:10.1007/s00467-005-1908-7 · Cited by 10
Satoh, M., Yoshizawa, A., Takesue, M., Saji, T., & Yokoya, S. (2006) · Endocrine Journal · doi:10.1507/endocrj.k06-014 · Cited by 10
Leptin and Appetite Control in Lipodystrophy
Ahima, R. S., & Osei, S. Y. (2004) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-1232 · Cited by 10
Zou, R. H., Nouraie, M. S., Karoleski, C. M., Zhang, Y., Sciurba, F. C., Forman, D. E., & Bon, J. M. (2023) · Respiratory Research · doi:10.1186/s12931-023-02521-3 · Cited by 9
“emergence of leptin replacement therapy, which has primarily been utilized for the treatment of lipodystrophy, [49] future studies targeting this adipokine pathway in individuals with reduced muscle loss may be an important area of research.”
BackgroundMetabolic Improvements With Tirzepatide in Lipodystrophy: A Novel Option?
Meral, R., Güler, M. Ç., Kaba, D., Prativadi, J., Frontera, E. D., Foss‐Freitas, M. C., Nachawi, N., Broome, D. T., Lightbourne, M., Brown, R. J., et al. (2025) · Diabetes Care · doi:10.2337/dc24-2408 · Cited by 9
Self-citationAhima, R. S., & Flier, J. S. (2025) · Annual Review of Physiology · doi:10.1146/annurev-physiol-042324-100259 · Cited by 10
Steroid receptor coactivator-1 modulates the function of Pomc neurons and energy homeostasis
Yang, Y., van der Klaauw, A. A., Zhu, L.-L., Cacciottolo, T. M., He, Y., Stadler, L. K. J., Wang, C., Xu, P., Saito, K., Hinton Jr, A., et al. (2019) · Yearbook of pediatric endocrinology · doi:10.1530/ey.16.11.3 · Cited by 9
Lipodistrofias primarias: presentación clínica y diagnóstico
Cortés, V., & Santos, J. L. (2019) · Revista médica de Chile · doi:10.4067/s0034-98872019001101449 · Cited by 9
Syndromes of Extreme Insulin Resistance
Grunberger, G., & Alfonso, B. (2009) · Springer eBooks · doi:10.1007/978-0-387-09841-8_17 · Cited by 9
Spice Up Your Life: Adipose Tissue and Inflammation
Agarwal, A. K. (2014) · Journal of Lipids · doi:10.1155/2014/182575 · Cited by 9
“Likewise, subjects with lipodystrophy who lack leptin have also been successfully treatedwith leptin replacement therapy [13].”
BackgroundEffect of Depot Medroxyprogesterone Acetate on Glucose Tolerance in Generalized Lipodystrophy
Yauger, B. J., Görden, P., Park, J., Cochran, E. K., & Stratton, P. (2008) · Obstetrics and Gynecology · doi:10.1097/aog.0b013e3181662d17 · Cited by 9
Leptin and Its Emerging Role in Children and Adolescents
Kelesidis, I., & Mantzoros, C. S. (2006) · Clinical Pediatric Endocrinology · doi:10.1297/cpe.15.1 · Cited by 8
Leptin: a cardiovascular perspective
Schutte, A. E., & Schutte, R. (2012) · Journal of Endocrinology Metabolism and Diabetes of South Africa · doi:10.1080/22201009.2012.10872280 · Cited by 9
Nakao, K. (2019) · Proceedings of the Japan Academy Series B · doi:10.2183/pjab.95.037 · Cited by 9
Hereditary syndromes with signs of premature aging
Golounina, O. O., Fadeev, V. V., & Belaya, Z. E. (2020) · Osteoporosis and Bone Diseases · doi:10.14341/osteo12331 · Cited by 9
The genetic elucidation of monogenic obesity in the Arab world: a systematic review
AbouHashem, N., Al‐Shafai, K. N., & Al-Shafai, M. N. (2022) · Journal of Pediatric Endocrinology and Metabolism · doi:10.1515/jpem-2021-0710 · Cited by 8
“In addition to the new knowledge attained, the discovery of genes and variants that predispose for obesity facilitates clinical diagnosis and management of this disease, as well as the development of pharmacological therapy for certain forms [3, 8].”
BackgroundNormal Adipose Tissue Biology: Adipocytokines and Inflammation
Kim, J., & Bajaj, M. (2014) · Elsevier eBooks · doi:10.1016/b978-0-12-386456-7.02006-2 · Cited by 9
Fat Metabolism and Diabetes: 2003 American Diabetes Association Postgraduate Course
Bloomgarden, Z. T. (2003) · Diabetes Care · doi:10.2337/diacare.26.7.2198 · Cited by 9
Energy balance in congenital generalized lipodystrophy type I
Taleban, S., Carew, H., Dichek, H. L., Deeb, S. S., Hollenback, D., Weigle, D. S., Cummings, D. E., & Brunzell, J. D. (2008) · Metabolism · doi:10.1016/j.metabol.2008.04.008 · Cited by 9
“Studies by Petersen et al [13] and Oral et al [30], who measured basal metabolic rate before and after leptin therapy, reported no change and a mean decrease from 1920 to 1580 kcal/d, respectively [13,30].”
MethodNon-Alcoholic Fatty Liver Disease
Tan, H., & Chang, J. P. (2010) · Proceedings of Singapore Healthcare · doi:10.1177/201010581001900106 · Cited by 9
Metadata
- Authors
- Oral, E. A., Simha, V., Ruiz, E., Andewelt, A., Premkumar, A., Snell, P., Wagner, A. J., DePaoli, A. M., Reitman, M. L., Taylor, S. I., Gorden, P., & Garg, A.
- Affiliations
- National Institutes of Health (US)
- The University of Texas Southwestern Medical Center (US)
- National Institute of Diabetes and Digestive and Kidney Diseases (US)
- Amgen (United States) (US)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2002-02-21
- Volume
- 346
- Issue
- 8
- Pages
- 570-578
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2084310603
- Cited by
- 1,247
- References
- 44
- Citations by year
- 2026: 18 · 2025: 37 · 2024: 38 · 2023: 41 · 2022: 41 · 2021: 46 · 2020: 31 · 2019: 44 · 2018: 31 · 2017: 55 · 2016: 46 · 2015: 50 · 2014: 57 · 2013: 56 · 2012: 50
- FWCI
- 24.91
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R01-DK-54387, R01DK054387)
- National Center for Research Resources (M01RR000633, M01 RR00633)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Keywords
- leptin replacement therapy, lipodystrophy, leptin deficiency, recombinant human leptin, insulin resistance, hypertriglyceridemia, hepatic steatosis, glycemic control, diabetes mellitus, liver volume, resting metabolic rate, energy intake
- MeSH terms
- Adolescent, Adult, Basal Metabolism, Blood Glucose, Energy Intake, Diabetes Mellitus, Female, Glycated Hemoglobin, Humans, Injections, Subcutaneous, Insulin Resistance, Lipodystrophy, Liver, Liver Function Tests, Prospective Studies, Triglycerides, Leptin, Diabetes Complications
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