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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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In the citing paper
“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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Self-citationPathogenesis of nonalcoholic steatohepatitis
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“Discussion Leptin has potent antidiabetic and antisteatotic effects in human and rodent lipodystrophy (6, 9).”
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Chou, C. J., Haluzı́k, M., Gregory, C., Dietz, K. R., Vinson, C., Gavrilova, O., & Reitman, M. L. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m202449200 · Cited by 197
Self-citationAnti-obesity therapy: from rainbow pills to polyagonists
Müller, T. D., Clemmensen, C., Finan, B., DiMarchi, R. D., & Tschöp, M. H. (2018) · Pharmacological Reviews · doi:10.1124/pr.117.014803 · Cited by 199
“…et al., 1995; Pelleymounter et al., 1995), congenitally leptin-deficient humans (Montague et al., 1997; Farooqi et al., 1999, 2002; Licinio et al., 2004), and individuals with lipodystrophy (Shimomura et al., 1999; Oral et al., 2002; Petersen et al., 2002; Ebihara et al., 2007; Chong et al., 2010).”
BackgroundResistin- and Obesity-associated Metabolic Diseases
Lazar, M. A. (2007) · Hormone and Metabolic Research · doi:10.1055/s-2007-985897 · Cited by 201
“Leptin is an insulin-sensitizing hormone, and defi ciency due to leptin gene mutation [13] or reduced adipose mass causes insulin resistance [14, 15] .”
Diagnosis and treatment of lipodystrophy: a step-by-step approach
Araújo-Vilar, D., & Santini, F. (2019) · Journal of Endocrinological Investigation · doi:10.1007/s40618-018-0887-z · Cited by 194
Longevity, lipotoxicity and leptin: the adipocyte defense against feasting and famine
Unger, R. H. (2005) · Biochimie · doi:10.1016/j.biochi.2004.11.014 · Cited by 184
“The result is generalized lipotoxicity that can be ameliorated by leptin replacement therapy or transplantation of normal fat tissue [33–35].”
BackgroundSchreuder, T. C. M. A., Verwer, B. J., van Nieuwkerk, C. M., & Mulder, C. J. J. (2008) · World Journal of Gastroenterology · doi:10.3748/wjg.14.2474 · Cited by 197
Brain regulation of food intake and appetite: molecules and networks
Roberger, C. B. (2005) · Cited by 191
Adipose tissue and metabolic syndrome: too much, too little or neither
Grundy, S. M. (2015) · European Journal of Clinical Investigation · doi:10.1111/eci.12519 · Cited by 187
Lipid droplet proteins and metabolic diseases
Xu, S., Zhang, X., & Liu, P. (2017) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2017.07.019 · Cited by 192
Peripheral metabolic actions of leptin
Muoio, D. M., & Lynis Dohm, G. (2002) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1053/beem.2002.0223 · Cited by 183
Farooqi, I. S., Matarese, G., Lord, G. M., Keogh, J. M., Lawrence, E., Agwu, C., Sanna, V., Jebb, S. A., Perna, F., Fontana, S., et al. (2002) · Journal of Clinical Investigation · doi:10.1172/jci200215693 · Cited by 183
Self-citationWhat lipodystrophies teach us about the metabolic syndrome
Mann, J. P., & Savage, D. B. (2019) · Journal of Clinical Investigation · doi:10.1172/jci129190 · Cited by 185
“Lastly, as mentioned previously, leptin replacement therapy is highly effective in lipodystrophy (38, 189), but patients with obesity (who have high circulating leptin) do not appear to show a response to additional exogenous leptin unless they are already in a weight-reduced state (190).”
BackgroundDiker‐Cohen, T., Cochran, E. K., Görden, P., & Brown, R. J. (2015) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2014-4491 · Cited by 181
“Studies conducted at the National Institutes of Health (NIH) Clinical Center showed that metreleptin treatment reduced food intake (13) and substantially improved most metabolic abnormalities in lipodystrophy patients, studied as a cohort of all forms with no distinction between lipodystrophy subtypes (14, 15).”
BackgroundExpression of leptin receptors and response to leptin stimulation of human natural killer cell lines
Zhao, Y., Sun, R., You, L., Gao, C., & Tian, Z. (2003) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(02)02838-3 · Cited by 229
Lee, M.-W., Lee, M., & Oh, K. (2019) · Journal of Clinical Medicine · doi:10.3390/jcm8060854 · Cited by 192
Efficacy of leptin therapy in the different forms of human lipodystrophy
Chong, A. Y., Lupsa, B. C., Cochran, E. K., & Görden, P. (2009) · Diabetologia · doi:10.1007/s00125-009-1502-9 · Cited by 175
“injection as previously described [ 4 , 8, 10].”
BackgroundMethodInfluentialPoirier, H., Shapiro, J. S., Kim, R. J., & Lazar, M. A. (2006) · Diabetes · doi:10.2337/db06-0036 · Cited by 188
“Lipoatrophy-associated insulin resistance can be ameliorated by leptin in rodents (19,20) as well as humans (21,22).”
BackgroundEctopic fat and cardiometabolic and vascular risk
Lim, S. K., & Meigs, J. B. (2013) · International Journal of Cardiology · doi:10.1016/j.ijcard.2013.08.077 · Cited by 175
“Treatment with recombinant leptin decreased triglyceride levels, improved glucose homeostasis, and enhanced insulin-stimulated hepatic and peripheral glucose metabolism in patients with lipodystrophy [158,159].”
BackgroundBates, S. H., Kulkarni, R. N., Seifert, M., & Myers, M. G. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2005.02.001 · Cited by 173
Jan, V., Cervera, P., Maachi, M., Baudrimont, M., Kim, M. J., Vidal, H., Girard, P., Levan, P., Rozenbaum, W., Lombès, A., et al. (2004) · Antiviral Therapy · doi:10.1177/135965350400900412 · Cited by 169
“Serum adiponectin and leptin levels are decreased in human genetic syndromes with generalized lipoatrophy and insulin resistance: the metabolic disorders in these patients are markedly improved by leptin replacement therapy [37].”
BackgroundLeptin therapy, insulin sensitivity, and glucose homeostasis
Paz-Filho, G., Mastronardi, C. A., Wong, M., & Licinio, J. (2012) · Indian Journal of Endocrinology and Metabolism · doi:10.4103/2230-8210.105571 · Cited by 173
“[76] Human studies evaluated the insulin-sensitizing effects of leptin replacement in patients with lipodystrophy.[77-80] Humans with lipoatrophic disorders (exhibiting very low levels of leptin, increased insulin resistance and hyperinsulinemia) experienced a decrease in insulin resistance after treatment with r-metH…”
BackgroundLeptin Predicts a Worsening of the Features of the Metabolic Syndrome Independently of Obesity
Franks, P. W., Brage, S., Luan, J., Ekelund, U., Rahman, M., Farooqi, I. S., Halsall, I., O’Rahilly, S., & Wareham, N. J. (2005) · Obesity Research · doi:10.1038/oby.2005.178 · Cited by 173
Tan, C. Y., & Vidal‐Puig, A. (2008) · Biochemical Society Transactions · doi:10.1042/bst0360935 · Cited by 169
Pharmacological Treatment of the Overweight Patient
Bray, G. A., & Greenway, F. L. (2007) · Pharmacological Reviews · doi:10.1124/pr.59.2.2 · Cited by 169
“Liver volume was also reduced by an average of 28% and resting metabolic rate decreased significantly with therapy (Oral et al., 2002).”
BackgroundCongenital generalized lipodystrophy: significance of triglyceride biosynthetic pathways
Agarwal, A. K., & Garg, A. (2003) · Trends in Endocrinology and Metabolism · doi:10.1016/s1043-2760(03)00078-x · Cited by 166
Self-citationLee, J. H., Chan, J. L., Sourlas, E., Raptopoulos, V., & Mantzoros, C. S. (2006) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2005-1545 · Cited by 163
Leptin and the Control of Metabolism: Role for Stearoyl-CoA Desaturase-1 (SCD-1)
Cohen, P., & Friedman, J. M. (2004) · Journal of Nutrition · doi:10.1093/jn/134.9.2455s · Cited by 165
Ectopic fat accumulation and metabolic syndrome
Rasouli, N., Molavi, B., Elbein, S. C., & Kern, P. A. (2006) · Diabetes Obesity and Metabolism · doi:10.1111/j.1463-1326.2006.00590.x · Cited by 169
Leshan, R. L., Louis, G. W., Jo, Y., Rhodes, C. J., Münzberg, H., & Myers, M. G. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.0155-09.2009 · Cited by 162
“…of puberty, whereas the lack of leptin in rodents or humans with genetic leptin deficiency or lipodystrophy results in hypothalamic amenorrhea that is reversible with leptin replacement (Ahima et al., 1996, 1997; Chehab et al., 1996; Farooqi et al., 1999; Shimomura et al., 1999; Oral et al., 2002).”
Muscular diacylglycerol metabolism and insulin resistance
Timmers, S., Schrauwen, P., & den Bosch, J. D. V. (2008) · Physiology & Behavior · doi:10.1016/j.physbeh.2007.12.002 · Cited by 163
“In that respect, treatment of lipodystrophic mice and humans with the anorexogenic adipo-cyte-derived hormone leptin [36,37] resulted in a remarkable improvement in insulin-stimulated liver and muscle glucose metabolism together with lowering fat stores [38].”
BackgroundLeptin and the Regulation of Body Weigh
Friedman, J. M. (2011) · The Keio Journal of Medicine · doi:10.2302/kjm.60.1 · Cited by 169
The role of leptin in health and disease
Ramos-Lobo, A. M., & Donato, J. (2017) · Temperature · doi:10.1080/23328940.2017.1327003 · Cited by 172
Inflammation and adipose tissue macrophages in lipodystrophic mice
Herrero, L., Shapiro, H., Nayer, A., Lee, J., & Shoelson, S. E. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0905310107 · Cited by 163
“Preclinical studies with these mice formed the basis for ultimately using leptin to treat patients with lipodystrophy (20, 21), further suggesting that the pathophysiology and pharmacological responsiveness of these mice is relevant to related human conditions.”
BackgroundResultPolycystic ovary syndrome, adipose tissue and metabolic syndrome
Delitala, A. P., Capobianco, G., Delitala, G., Cherchi, P. L., & Dessole, S. (2017) · Archives of Gynecology and Obstetrics · doi:10.1007/s00404-017-4429-2 · Cited by 159
“Although leptin therapy has limited success in common obesity, it has impressive effects in patients with genetic leptin deficiency or lipodystrophy [89, 90].”
BackgroundSeipin: from human disease to molecular mechanism
Cartwright, B. R., & Goodman, J. M. (2012) · Journal of Lipid Research · doi:10.1194/jlr.r023754 · Cited by 160
Leptin's Physiologic Role: Does the Emperor of Energy Balance Have No Clothes?
Flier, J. S., & Maratos–Flier, E. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.05.013 · Cited by 160
“It is now approved for administration in extremely rare patients with genetic leptin deficiency or leptin deficiency secondary to rare forms of lipoatrophic diabetes (Oral et al., 2002).”
BackgroundJaganathan, R., Ravindran, R., & Dhanasekaran, S. (2017) · Canadian Journal of Diabetes · doi:10.1016/j.jcjd.2017.10.040 · Cited by 154
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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