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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]
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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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BackgroundAdipokines in the HIV/HAART-associated lipodystrophy syndrome
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“insulin sensitivity and glucose tolerance, and reduced hemoglobin A1c levels [69–71].”
BackgroundLeptin, diabetes, and the brain
Morton, G. J., & Meek, T. H. (2012) · Indian Journal of Endocrinology and Metabolism · doi:10.4103/2230-8210.105568 · Cited by 47
“[26] Consistent with this, transplantation of body fat from wild-type, but not leptin-defi cient, ob/ob mice improves glycemia in lipodystrophic mice,[27,28] while the diabetes phenotype of lipodystrophic mice[29,30] and humans[31,32] is ameliorated with leptin treatment.”
BackgroundResistin and Adiponectin—of Mice and Men
Stümvoll, M., & Häring, H. U. (2002) · Obesity Research · doi:10.1038/oby.2002.162 · Cited by 46
Kršek, M., Silha, J. V., Ježková, J., Hána, V., Marek, J., Weiss, V., Stepan, J. J., & Murphy, L. J. (2004) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2003.01987.x · Cited by 46
Tsiodras, S., & Mantzoros, C. S. (2006) · American Journal of Infectious Diseases · doi:10.3844/ajidsp.2006.141.152 · Cited by 46
“Leptin administration resulted in improvement of hyperglycemia, hyperinsulinemia, hypertriglyceridemia, as well as a significant decrease in fatty infiltration of the liver([48]).”
BackgroundInfluentialAbulizi, A., Perry, R. J., Camporez, J. P. G., Jurczak, M. J., Petersen, K. F., Aspichueta, P., & Shulman, G. I. (2017) · The FASEB Journal · doi:10.1096/fj.201700001r · Cited by 41
“resistance in patients with severe lipodystrophy (4, 6, 7), it is not effective in reversing these conditions in patients with partial lipodystrophy (8).”
BackgroundÖzen, S., Akıncı, B., & Oral, E. A. (2019) · Journal of Clinical Research in Pediatric Endocrinology · doi:10.4274/jcrpe.galenos.2019.2019.0124 · Cited by 44
Self-citationNovel strategy for the use of leptin for obesity therapy
Tam, C. S., Lecoultre, V., & Ravussin, É. (2011) · Expert Opinion on Biological Therapy · doi:10.1517/14712598.2011.619974 · Cited by 50
“Improvement in insulin suppression of glucose production in the liver and increase in insulin-stimulated peripheral glucose uptake in the muscle [20,53,61] Therefore, leptin acts via multiple mechanisms to decrease triglyceride and other lipid intermediates in lipodystrophy patients, reducing their accumulation in tis…”
BackgroundInfluentialLebastchi, J., Ajluni, N., Neidert, A., & Oral, E. A. (2015) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2015-2589 · Cited by 43
“Although metreleptin therapy has been shown to improve metabolic abnormalities in lipodystrophy (1), the effect on AGL patients with active autoimmune disease is unknown and remained controversial.”
BackgroundSelf-citationClinical and molecular aspects of Berardinelli–Seip Congenital Lipodystrophy (BSCL)
Gomes, K. B., Pardini, V. C., & Fernandes, A. P. (2009) · Clinica Chimica Acta · doi:10.1016/j.cca.2008.12.032 · Cited by 43
The association between leptin and left ventricular hypertrophy
Pladevall, M., Williams, K. L., Guyer, H., Sadurní, J. R., Falces, C., Ribes, A., Paré, C., Brotons, C., Gabriel, R., Serrano‐Ríos, M., et al. (2003) · Journal of Hypertension · doi:10.1097/00004872-200308000-00009 · Cited by 42
Leptin, nutrition and reproduction: new insights
POPOVIC, V. M., & Casanueva, F. F. (2002) · HORMONES · doi:10.14310/horm.2002.1169 · Cited by 43
Glitazones in lipodystrophy syndrome induced by highly active antiretroviral therapy
Calmy, A., Hirschel, B. J., Hans, D. B., Karsegard, V. L., & Meier, C. A. (2003) · AIDS · doi:10.1097/00002030-200303280-00022 · Cited by 43
Simha, V., Zerwekh, J. E., Sakhaee, K., & Garg, A. (2002) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2002-020792 · Cited by 42
Self-citationLeptin: a novel therapeutic role in lipodystrophy
Savage, D. B., & O’Rahilly, S. (2002) · Journal of Clinical Investigation · doi:10.1172/jci15326 · Cited by 48
Leptin therapy for partial lipodystrophy linked to a PPAR‐γ mutation
Guettier, J., Park, J. Y., Cochran, E. K., Poitou, C., Basdevant, A., Meier, M., Clément, K., Magré, J., & Görden, P. (2007) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2007.03095.x · Cited by 42
Sekizkardes, H., Cochran, E. K., Malandrino, N., Garg, A., & Brown, R. J. (2019) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2018-02787 · Cited by 42
Self-citationNew Frontiers for the Use of IP6 and Inositol Combination in Treating Diabetes Mellitus: A Review
Omoruyi, F. O., Stennett, D., Foster, S. R., & Dilworth, L. (2020) · Molecules · doi:10.3390/molecules25071720 · Cited by 43
Leptin decreases de novo lipogenesis in patients with lipodystrophy
Baykal, A. P., Parks, E. J., Shamburek, R. D., Syed‐Abdul, M. M., Chacko, S. K., Cochran, E. K., Startzell, M. S., Gharib, A. M., Ouwerkerk, R., Abd‐Elmoniem, K. Z., et al. (2020) · JCI Insight · doi:10.1172/jci.insight.137180 · Cited by 44
Leptin and Body Fat in Type 2 Diabetes and Monodrug Therapy
Sivitz, W. I., Wayson, S. M., Bayless, M., Larson, L. F., Sinkey, C. A., Bar, R. S., & Haynes, W. G. (2003) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2002-021193 · Cited by 42
Techniques: New pharmacological perspectives for the leptin receptor
Peelman, F., Couturier, C., Dam, J., Zabeau, L., Tavernier, J. H., & Jockers, R. (2006) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2006.02.009 · Cited by 44
Endothelial Function Varies According to Insulin Resistance Disease Type
Beckman, J. A., Goldfine, A. B., Dunaif, A. E., Gerhard‐Herman, M. D., & Creager, M. A. (2007) · Diabetes Care · doi:10.2337/dc06-2142 · Cited by 42
Yi, X., Cao, S., Chang, B., Zhao, D., Gao, H., Wan, Y., Jiaojiao, S., Wei, W., & Guan, Y. (2013) · Journal of Diabetes Research · doi:10.1155/2013/946432 · Cited by 43
“Leptin deficiency or dysfunction is one of the main causes for insulin resistance (IR) and lipid metabolism disorders [1, 2].”
BackgroundEfficacy and Safety of Metreleptin Therapy in Patients With Type 1 Diabetes: A Pilot Study
Vasandani, C., Clark, G. O., ADAMS-HUET, B. A., Quittner, C., & Garg, A. (2017) · Diabetes Care · doi:10.2337/dc16-1553 · Cited by 41
Self-citationHuang, W., Liu, X., Queen, N. J., & Cao, L. (2017) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2017.06.002 · Cited by 41
Papargyri, P., Zapanti, E. D., Salakos, N., Papargyris, L., Bargiota, Α., & Mastorakos, G. P. (2018) · Expert Review of Endocrinology & Metabolism · doi:10.1080/17446651.2018.1543585 · Cited by 42
Huang, W., Dedousis, N., & O'Doherty, R. M. (2007) · Journal of Applied Physiology · doi:10.1152/japplphysiol.01449.2006 · Cited by 43
“Interest in a therapeutic role for leptin has recently been rekindled due to its capacity to correct metabolic abnormalities in lipodystrophy, where there are low circulating leptin concentrations (19, 24, 27, 29) and in Rabson-Mendenhall syndrome (severe insulin resistance with insulin-receptor mutation) (9, 38).”
BackgroundMosbah, H., Vantyghem, M., Nobécourt, E., Andréelli, F., Archambeaud, F., Bismuth, É., Briet, C., Cartigny, M., Chevalier, B., Donadille, B., et al. (2022) · Diabetes Obesity and Metabolism · doi:10.1111/dom.14726 · Cited by 40
Role of leptin in regulating appetite, neuroendocrine function, and bone remodeling
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“In humans with lipodystrophic diabetes, administration of leptin improves insulin sensitivity and diabetes, whereas food restriction does not [Oral et al., 2002; Petersen et al., 2002].”
BackgroundNonalcoholic Fatty Liver Disease in Children
Mager, D. R., & Roberts, E. A. (2006) · Clinics in Liver Disease · doi:10.1016/j.cld.2005.10.007 · Cited by 39
“In generalized lipodystrophy syndromes, characterized by defective expression of leptin, leptin supplementation has improved hepatic steatosis [85].”
BackgroundAdipokine Profile and Urinary Albumin Excretion in Isolated Growth Hormone Deficiency
Oliveira, C. R. P., Salvatori, R., Meneguz‐Moreno, R. A., Aguiar-Oliveira, M. H., Pereira, R. M. C., Valença, E. H. A., Araújo, V. P., Farias, N. T., Silveira, D. C. R., Vieira, J. G. H., et al. (2009) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-1919 · Cited by 38
Pleotropic effects of leptin to reverse insulin resistance and diabetic ketoacidosis
Perry, R. J., Petersen, K. F., & Shulman, G. I. (2016) · Diabetologia · doi:10.1007/s00125-016-3909-4 · Cited by 39
“As discussed earlier, leptin replacement therapy has been shown to be efficacious at reversing hepatic and muscle insulin resistance, hyperglycaemia, hepatic steatosis and hyperphagia in patients with severe lipodystrophy [1, 19].”
Vigouroux, C., Guénantin, A.-C., Vatier, C., Capel, É., Dour, C. L., Afonso, P., Bidault, G., Béréziat, V., Lascols, O., Capeau, J., et al. (2018) · Nucleus · doi:10.1080/19491034.2018.1456217 · Cited by 42
Update on Therapeutic Options in Lipodystrophy
Akıncı, B., Meral, R., & Oral, E. A. (2018) · Current Diabetes Reports · doi:10.1007/s11892-018-1100-7 · Cited by 41
Self-citationZiegler, J., Böttcher, C., Letizia, M., Yerinde, C., Wu, H., Freise, I., Rodriguez‐Sillke, Y., Stoyanova, A. K., Kreis, M. E., Asbach, P., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-13559-7 · Cited by 39
Drug targeting of leptin resistance
Santoro, A. N., Raso, G. M., & Meli, R. (2015) · Life Sciences · doi:10.1016/j.lfs.2015.05.012 · Cited by 41
“[115,116].”
Shp2 as a therapeutic target for leptin resistance and obesity
Feng, G. (2006) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.10.1.135 · Cited by 39
“Leptin administration has also proven efficient in treating patients with lipodystrophy and some obese individuals with low plasma leptin levels [11,12].”
BackgroundHaluzı́k, M., Gavrilova, O., & LeRoith, D. (2003) · Endocrinology · doi:10.1210/en.2003-1015 · Cited by 39
Sepsis-Induced Adipokine Change with regard to Insulin Resistance
Hillenbrand, A., Weiß, M., Knippschild, U., Wolf, A. M., & Huber-Lang, M. S. (2012) · International Journal of Inflammation · doi:10.1155/2012/972368 · Cited by 39
“The influence of leptin on insulin resistance is still not fully understood, whereby studies in lipodystrophic patients and in patients with mutations of the insulin receptor have indicated that leptin therapy is associated with a marked improvement in the metabolic state of the patients with remarkable improvements i…”
BackgroundCook, K., Adamski, K. N., Gomes, D. A., Tuttle, E., Kalden, H., Cochran, E. K., & Brown, R. J. (2021) · Journal of the Endocrine Society · doi:10.1210/jendso/bvab019 · Cited by 40
“Single-arm open-label studies have indicated that metreleptin can reduce the severity of multiple metabolic abnormalities in patients with lipodystrophy, including hyperglycemia, hypertriglyceridemia, and hepatic steatosis [6, 8, 18-28].”
BackgroundSadashiv, Modi, A., Khokhar, M., Sharma, P., Joshi, R. P., Mishra, S. S., Bharshankar, R. N., Tiwari, S., Singh, P. K., Bhosale, V. V., et al. (2021) · Journal of Obesity & Metabolic Syndrome · doi:10.7570/jomes20131 · Cited by 39
“Accordingly, supplementation of leptin in generalized lipodystrophy (absence of adipose tissue) polish up insulin sensitivity and metabolic parameters.(10) Leptin expression(11) and its serum levels are directly associated with obesity extremity.”
BackgroundThe role of adiposity as a determinant of an inflammatory milieu
Calabrò, P., Limongelli, G., Pacileo, G., Salvo, G. D., Golino, P., & Calabrò, R. (2008) · Journal of Cardiovascular Medicine · doi:10.2459/jcm.0b013e3282eee9a8 · Cited by 39
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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