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Cited by 227Adipokines, Inflammation, and Metabolic DiseasesRegulation of Appetite and ObesityLipid metabolism and disorders

Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy

Open access
Javor, Edward D., Cochran, Elaine K., Musso, Carla, Young, Janice Ryan, DePaoli, Alex M., Gorden, Phillip·2005·Diabetes
DOI 10.2337/diabetes.54.7.1994
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Abstract

Ectopic fat accumulation has been implicated as a contributing factor in the abnormal metabolic state of obesity. One human model of ectopic fat deposition is generalized lipodystrophy. Generalized lipodystrophy is a rare disorder characterized by a profound deficiency of adipose tissue with resultant loss of triglyceride storage capacity and reduced adipokines, including leptin. Subjects with generalized lipodystrophy and reduced leptin levels often have an increased appetite leading to hyperphagia. Excess fuel consumption, coupled with a lack of adipose tissue, contributes to the significant ectopic triglyceride accumulation in the muscle and liver seen in these subjects. This ectopic fat, along with the deficiency in leptin signaling and perhaps other adipokines, likely contributes to insulin resistance, diabetes, and hepatic steatosis. We report here the long-term effects of leptin replacement in a cohort of these subjects. Fifteen patients with generalized lipodystrophy were treated with twice-daily recombinant methionyl human leptin (r-metHuLeptin) for 12 months. We evaluated metabolic parameters at baseline and every 4 months. Antidiabetes medications were decreased or discontinued as necessary. Reductions were seen in serum fasting glucose (from 205 ± 19 to 126 ± 11 mg/dl; P < 0.001), HbA1c (from 9 ± 0.4 to 7.1 ± 0.5%; P < 0.001), triglycerides (from 1,380 ± 500 to 516 ± 236 mg/dl; P < 0.001), LDL (from 139 ± 16 to 85 ± 7 mg/dl; P < 0.01), and total cholesterol (from 284 ± 40 to 167 ± 21 mg/dl; P < 0.01). HDL was unchanged (from 31 ± 3 to 29 ± 2 mg/dl; P = 0.9). Liver volumes were significantly reduced (from 3,663 ± 326 to 2,190 ± 159 cm3; P < 0.001), representing loss of steatosis. Decreases were seen in total body weight (from 61.8 ± 3.6 to 57.4 ± 3.4 kg; P = 0.02) and resting energy expenditure (from 1,929 ± 86 to 1,611 ± 101 kcal/24 h; P < 0.001). R-metHuLeptin led to significant and sustained improvements in glycemia, dyslipidemia, and hepatic steatosis. Leptin represents the first novel, effective, long-term treatment for severe forms of lipodystrophy.

AI snapshot

Written from the paper’s full text.

TL;DR

In 15 patients with generalized lipodystrophy, 12 months of twice-daily recombinant methionyl human leptin produced sustained improvements in glycemia, dyslipidemia, and hepatic steatosis, with many able to reduce or discontinue antidiabetes medications. The authors conclude leptin replacement represents the first novel, effective, long-term treatment for severe forms of lipodystrophy.

Key findings

  • Glycemic control improved: fasting glucose fell from 205 ± 19 to 126 ± 11 mg/dl (P < 0.001) and HbA1c from 9 ± 0.4 to 7.1 ± 0.5% (P < 0.001). Insulin sensitivity more than doubled by the K constant (0.0074 to 0.015, P < 0.001).
  • Lipids improved: triglycerides decreased from 1,380 ± 500 to 516 ± 236 mg/dl (P < 0.001), LDL from 139 ± 16 to 85 ± 7 mg/dl (P < 0.01), and total cholesterol from 284 ± 40 to 167 ± 21 mg/dl (P < 0.01); HDL was unchanged (31 ± 3 to 29 ± 2 mg/dl, P = 0.9).
  • Liver volume decreased from 3,663 ± 326 to 2,190 ± 159 cm³ (P < 0.001), representing loss of steatosis. Weight fell from 61.8 ± 3.6 to 57.4 ± 3.4 kg (P = 0.02), BMI from 21.5 to 20 kg/m² (P < 0.001), and resting energy expenditure from 1,929 ± 86 to 1,611 ± 101 kcal/24 h (P < 0.001).
  • Antidiabetes therapy decreased: 9 of 15 patients were on insulin at baseline (mean dose 916 units daily); at 12 months, 3 of 15 remained on insulin (mean dose 322 units daily), and six patients discontinued insulin. Six of eight patients discontinued oral agents.

Methods

  • Open-label pilot study of 27 consecutive patients with congenital or acquired generalized lipodystrophy; 20 met inclusion criteria for r-metHuLeptin, and 15 completed at least 1 year of treatment and were analyzed. Inclusion required hypoleptinemia (male <4 ng/ml, female <5 ng/ml) and metabolic abnormalities such as hypertriglyceridemia, hyperinsulinemia, or diabetes.
  • r-metHuLeptin was self-administered twice daily subcutaneously, escalated over 2 months, then usual replacement doses of 0.06–0.08 mg/kg/day for females and 0.04 mg/kg/day for males. Patients were evaluated at the NIH Clinical Center at baseline and every 4 months for 1 year.
  • Results are means ± SE; one-way ANOVA for repeated measures was used, with log10 transformation for non-normally distributed parameters, plus paired t tests where applicable; P < 0.05 was considered significant.

Limitations

  • The authors state the study power is limited by its small size, its nonrandomized open-label nature, and the combination of r-metHuLeptin with conventional medications.
  • Five of the 20 patients who initiated therapy withdrew before 12 months; the authors note they cannot exclude the possibility that leptin therapy was associated with exacerbation of underlying renal disease in two patients with acquired generalized lipodystrophy.
  • Evident from the text: there was no control group, and the open-label design plus concomitant medication changes limit causal attribution of all observed improvements to leptin alone.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.2337/diabetes.54.7.1994

Cites

43 of 43 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 52 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    In 15 patients with generalized lipodystrophy treated with r-metHuLeptin for 12 months, HbA1c decreased from 9.0 to 7.1% (P < 0.001).

    “A1C (from 9.0 to 7.1%, P Ͻ 0.001)”
    Quote in the paperSubstantial claim
  • Findingown data

    In 15 patients with generalized lipodystrophy treated with r-metHuLeptin for 12 months, BMI decreased from 21.5 to 20 kg/m2 (P < 0.001).

    “BMI (from 21.5 to 20 kg/m 2 , P Ͻ 0.001)”
    Quote in the paperSubstantial claim
  • Findingown data

    The improvement in satiety was sustained throughout r-metHuLeptin therapy.

    “This improvement in satiety was sustained throughout r-metHuLeptin therapy”
    Quote in the paperSubstantial claim
  • Findingown data

    In 15 patients with generalized lipodystrophy treated with r-metHuLeptin for 12 months, mean triglycerides decreased from 1,380 to 516 mg/dl (P < 0.001).

    “R-metHuLeptin led to a 63% reduction in mean triglycerides (from 1,380 to 516 mg/dl, P Ͻ 0.001)”
    Quote in the paperSubstantial claim
  • Findingcitation

    Most female patients resumed and sustained normal menses following initiation of r-metHuLeptin.

    “Most female patients resumed and sustained normal menses following initiation of r-metHuLeptin”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [9] Oral EA, Ruiz E, Andewelt A, Sebring N, Wagner AJ, Depaoli AM, Gorden P: Effect of leptin replacement on pituitary hormone regulation in patients with severe lipodystrophy. J Clin Endocrinol Metab 87:3110–3117,2002 source

      Not checked in the free run.

    • cites [10] Musso C, Cochran E, Javor E, Young J, Depaoli AM, Gorden P: The long-term effect of recombinant methionyl human leptin therapy on hyperandrogenism and menstrual function in female and pituitary function in male and female hypoleptinemic lipodystrophic patients. Metabolism 54:255–263,2005 source

      Not checked in the free run.

  • Classified as probably not a substantial claim. 27
  • May combine two claims. 47
  • The quote only partly states this claim. 3

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Patients had mild to extreme hepatomegaly (mean liver volume 3,663 ml, range 1,754-6,736 ml).

    “Patients had mild to extreme hepatomegaly (mean 3,663 ml [range 1,754 -6,736])”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingcitation

    Female patients generally had hypogonadotropic amenorrhea.

    “Female patients generally had hypogonadotropic amenorrhea, as previously described (9,10).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [9] Oral EA, Ruiz E, Andewelt A, Sebring N, Wagner AJ, Depaoli AM, Gorden P: Effect of leptin replacement on pituitary hormone regulation in patients with severe lipodystrophy. J Clin Endocrinol Metab 87:3110–3117,2002 source

      Not checked in the free run.

    • cites [10] Musso C, Cochran E, Javor E, Young J, Depaoli AM, Gorden P: The long-term effect of recombinant methionyl human leptin therapy on hyperandrogenism and menstrual function in female and pituitary function in male and female hypoleptinemic lipodystrophic patients. Metabolism 54:255–263,2005 source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    All but one patient had hypertriglyceridemia >150 mg/dl (mean 1,380 mg/dl, range 95-7,420) despite fibrate therapy.

    “All but one patient had hypertriglyceridemia Ͼ150 mg/dl (mean 1,380 mg/dl [range 95-7,420 mg/dl]) despite therapy with fibrates.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    During r-metHuLeptin therapy, serum leptin levels increased and were sustained in a range to simulate normal.

    “During this period, serum leptin levels increased and were sustained in a range to simulate normal (Table 3).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Several patients developed binding antibodies that act to increase the half-life of r-metHuLeptin and cause elevations in serum levels.

    “Several patients developed binding antibodies, which act to increase the half-life of r-metHuLeptin and cause elevations in their serum levels.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    There were no consistent abnormalities in inflammatory markers such as C-reactive protein in these patients.

    “There were no consistent abnormalities in inflammatory markers such as C-reactive protein (Table 2).”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    In 15 patients with generalized lipodystrophy treated with r-metHuLeptin for 12 months, LDL decreased from 139 to 85 mg/dl (P = 0.01).

    “LDL levels decreased significantly (from 139 to 85 mg/dl, P ϭ 0.01)”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    There were no consistent abnormalities in thyroid function tests in these patients.

    “There were no consistent abnormalities in thyroid function tests (Table 2).”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    In 15 patients with generalized lipodystrophy treated with r-metHuLeptin for 12 months, fasting serum glucose decreased from 205 to 126 mg/dl (P < 0.001).

    “Leptin led to significant reductions in fasting glucose (from 205 to 126 mg/dl, P Ͻ 0.001)”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingnone given

    Patients generally had normal growth and secondary sexual development.

    “patients generally had normal growth and secondary sexual development.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingnone given

    Both male and female patients had a suppressed growth hormone axis with low IGF-1.

    “both male and female patients had a suppressed growth hormone axis with low IGF-1.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The reductions in weight, BMI, and REE were significant after 4 months, without further significant change from 4 to 12 months.

    “These reductions were significant after 4 months, without further significant change from 4 to 12 months.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingnone given

    At baseline, patients were on aggressive conventional treatment for diabetes and dyslipidemia.

    “At baseline, patients were on aggressive conventional treatment for diabetes and dyslipidemia.”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    Severe dyslipidemia in these patients was significantly improved with r-metHuLeptin.

    “The severe dyslipidemia in these patients was significantly improved.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Before r-metHuLeptin therapy, 9 of 15 patients were on insulin with a mean dose of 916 units daily.

    “Before r-metHuLeptin therapy, 9 of 15 patients were on insulin with a mean dose of 916 units daily (Table 4).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Compared with baseline, insulin levels peaked earlier and the overall amount of insulin secreted in response to glucose at 12 months was less.

    “Compared with baseline, insulin levels peaked earlier and the overall amount of insulin secreted in response to glucose at 12 months was less”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Thyroid and adrenal functions were normal at baseline and did not change with r-metHuLeptin therapy.

    “both thyroid and adrenal (data not shown) functions were normal at baseline and did not change with r-metHuLeptin therapy.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Total cholesterol and LDL cholesterol were moderately elevated at baseline and both were significantly reduced with r-metHuLeptin.

    “Both total cholesterol and LDL cholesterol were moderately elevated at baseline, and both were significantly reduced with r-metHuLeptin.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    HDL cholesterol levels were uniformly low in these patients and correlated with very high triglyceride levels.

    “HDL cholesterol levels were uniformly low in these patients, correlating with the very high triglyceride levels.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingreasoning

    IGF-1 levels significantly increased during r-metHuLeptin therapy despite no significant change in fasting growth hormone levels.

    “Despite no significant change in fasting growth hormone levels, IGF-1 levels significantly increased”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Changes in serum triglycerides, glucose, and A1C were all significant (P < 0.001).

    “Changes were all significant (P < 0.001).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Mean serum triglycerides, glucose, and A1C all progressively decreased during r-metHuLeptin therapy in 15 patients.

    “Mean serum triglycerides (A), glucose (B), and A1C (C) all progressively decreased during r-metHuLeptin therapy.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Adiponectin levels were low to undetectable in our patients at baseline and unchanged following r-metHuLeptin therapy.

    “Adiponectin levels, which are low in all forms of insulin resistance, were low to undetectable in our patients at baseline and unchanged following r-metHuLeptin therapy (data not shown).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The mean serum insulin response to dextrose at 12 months peaked and declined earlier than at baseline with a lower area under the curve; however, this was not statistically significant.

    “B: The mean serum insulin response to dextrose at 12 months peaked and declined earlier than at baseline with a lower area under the curve; however, this was not statistically significant.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingnone given

    R-metHuLeptin led to a reduction in appetite, weight, and REE.

    “R-metHuLeptin led to a reduction in appetite, weight, and REE.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    These changes were apparent after 4 months of treatment, plateaued, and then maintained from the 4th to the 12th month of therapy.

    “These changes were apparent after 4 months of treatment, plateaued, and then maintained from the 4th to the 12th month of therapy.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationown data

    The hepatomegaly in these patients was consistent with nonalcoholic fatty liver disease (NAFLD).

    “consistent with nonalcoholic fatty liver disease (NAFLD)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    R-metHuLeptin led to significant and sustained improvements in glycemia, dyslipidemia, and hepatic steatosis in patients with generalized lipodystrophy over 12 months.

    “R-metHuLeptin led to significant and sustained improvements in glycemia, dyslipidemia, and hepatic steatosis.”
    • Also stated in: § DISCUSSION · boosted
      “we have shown that r-metHuLeptin sustained its effectiveness in ameliorating hyperlipidemia, insulin resistance, and hepatomegaly throughout 12 months of therapy in 15 patients with generalized lipodystrophy.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Two patients did not have insulin tolerance testing at 8 or 12 months because of hypoglycemia during 4-month testing.

    “two patients did not have insulin tolerance testing at 8 or 12 months because of hypoglycemia (Ͻ40 mg/dl) during 4-month testing.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    This mechanism of insulin resistance is similar, albeit more severe, to that seen in obesity.

    “This mechanism of insulin resistance is similar, albeit more severe, to that seen in obesity.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    The study was nonrandomized and open-label.

    “Other limitations include the nonrandomized open-label nature of the study and the combination of r-metHuLeptin use with conventional medications.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Glucose tolerance tests demonstrated lower fasting insulin levels, a more rapid insulin peak, and a reduced amount of insulin required to maintain euglycemia, further supporting a decrease in insulin resistance.

    “Glucose tolerance tests demonstrated lower fasting insulin levels, a more rapid insulin peak, and a reduced amount of insulin required to maintain euglycemia, further supporting a decrease in insulin resistance.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Recombinant leptin administration could ameliorate dyslipidemia, insulin resistance, and diabetes in rodent models and preliminary short-term human studies.

    “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.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [5] Shimomura I, Hammer RE, Ikemoto S, Brown MS, Goldstein JL: Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy. Nature 401:73–76,1999 source

      Not checked in the free run.

    • cites [6] Oral EA, Simha V, Ruiz E, Andewelt A, Premkumar A, Snell P, Wagner AJ, DePaoli AM, Reitman ML, Taylor SI, Gorden P, Garg A: Leptin-replacement therapy for lipodystrophy. N Engl J Med 346:570–578,2002 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Patients with obesity are hyperleptinemic and leptin resistant, and leptin has a limited therapeutic effect.

    “These patients are hyperleptinemic and leptin resistant, and leptin has a limited therapeutic effect.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Heymsfield SB, Greenberg AS, Fujioka K, Dixon RM, Kushner R, Hunt T, Lubina JA, Patane J, Self B, Hunt P, McCamish M: Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. JAMA 282:1568–1575,1999 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In obesity, there is often moderate storage of ectopic fat and moderate insulin resistance.

    “Often, there is moderate storage of ectopic fat and moderate insulin resistance.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Heymsfield SB, Greenberg AS, Fujioka K, Dixon RM, Kushner R, Hunt T, Lubina JA, Patane J, Self B, Hunt P, McCamish M: Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. JAMA 282:1568–1575,1999 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Obesity is characterized by excess fat stored in normal adipocytes with normal endocrine function.

    “The first example is obesity (17), where the phenotype is excess fat stored in normal adipocytes with normal endocrine function.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Heymsfield SB, Greenberg AS, Fujioka K, Dixon RM, Kushner R, Hunt T, Lubina JA, Patane J, Self B, Hunt P, McCamish M: Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. JAMA 282:1568–1575,1999 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    r-metHuLeptin use was combined with conventional medications.

    “Other limitations include the nonrandomized open-label nature of the study and the combination of r-metHuLeptin use with conventional medications.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The metabolic phenotype of generalized lipodystrophy is characterized by extreme dyslipidemia, insulin resistance, and diabetes.

    “The metabolic phenotype is characterized by extreme dyslipidemia, insulin resistance, and diabetes (4).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [4] Lawrence RD: Lipodystrophy and hepatomegaly with diabetes, lipaemia, and other metabolic disturbances: a case throwing new light on the action of insulin. Lancet 1:724–731, 773–725,1946 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Informed consents were obtained from each patient or his/her legal guardian.

    “Informed consents were obtained from each patient or his/her legal guardian.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    r-metHuLeptin increases insulin-stimulated peripheral glucose uptake and increases insulin suppression of hepatic glucose output.

    “showing that r-metHuLeptin increases insulin-stimulated peripheral glucose uptake and increases insulin suppression of hepatic glucose output (11).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] 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 109:1345–1350,2002 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Congenital leptin deficiency is characterized by obesity, excessive adipose tissue, moderate storage of ectopic fat, and moderate insulin resistance.

    “The second example is congenital leptin deficiency (18 -20), which is characterized by obesity, excessive adipose tissue, moderate storage of ectopic fat, and moderate insulin resistance.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [18] Farooqi IS, Jebb SA, Langmack G, Lawrence E, Cheetham CH, Prentice AM, Hughes IA, McCamish MA, O’Rahilly S: Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med 341:879–884,1999 source

      Not checked in the free run.

    • cites [19] 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 U S A 101:4531–4536,2004 source

      Not checked in the free run.

    • cites [20] Gibson WT, Farooqi IS, Moreau M, DePaoli AM, Lawrence E, O’Rahilly S, Trussell RA: Congenital leptin deficiency due to homozygosity for the Delta133G mutation: report of another case and evaluation of response to four years of leptin therapy. J Clin Endocrinol Metab 89:4821–4826,2004 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Leptin had a progressive effect to diminish ectopic fat, which corresponded temporally with improvements in NAFLD and insulin resistance.

    “These data suggest that leptin had a progressive effect to diminish ectopic fat, which corresponded temporally with improvements in NAFLD and insulin resistance.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The protocol was approved by the institutional review board of the National Institute of Diabetes and Digestive and Kidney Diseases.

    “The protocol was approved by the institutional review board of the National Institute of Diabetes and Digestive and Kidney Diseases.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Ectopic triglycerides usually signify the presence of long-chain free fatty acids, which are cytotoxic and believed to interfere with normal insulin signaling leading to insulin resistance.

    “Ectopic triglycerides usually signify the presence of long-chain free fatty acids, which are cytotoxic (15,16) and believed to interfere with normal insulin signaling leading to insulin resistance.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [15] Listenberger LL, Han X, Lewis SE, Cases S, Farese RV Jr, Ory DS, Schaffer JE: Triglyceride accumulation protects against fatty acid-induced lipotoxicity. Proc Natl Acad Sci U S A 100:3077–3082,2003 source

      Not checked in the free run.

    • cites [16] Browning JD, Horton JD: Molecular mediators of hepatic steatosis and liver injury. J Clin Invest 114:147–152,2004 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Both leptin deficiency and leptin resistance represent states of decreased leptin signaling, potentially leading to mitochondrial dysfunction.

    “Both leptin deficiency and leptin resistance represent states of decreased leptin signaling, potentially leading to mitochondrial dysfunction.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Leptin is crucial in mitochondrial function.

  • May combine two claims.

    Interpretationreasoning

    These patients' hypertriglyceridemia and insulin resistance are more severe than what is seen in obesity or congenital leptin deficiency.

    “These patients' hypertriglyceridemia and insulin resistance are more severe than what is seen in obesity or congenital leptin deficiency.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Adiponectin is another adipokine that is associated with increased insulin sensitivity and fatty acid oxidation.

    “Adiponectin is another adipokine that is associated with increased insulin sensitivity and fatty acid oxidation (33).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33] Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori Y, Ide T, Murakami K, Tsuboyama-Kasaoka N, Ezaki O, Akanuma Y, Gavrilova O, Vinson C, Reitman ML, Kagechika H, Shudo K, Yoda M, Nakano Y, Tobe K, Nagai R, Kimura S, Tomita M, Froguel P, Kadowaki T: The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 7:941–946,2001 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In obesity and other insulin-resistant states, a predominant mechanism for ectopic fat accumulation appears to be mitochondrial dysfunction, leading to decreased fatty acid oxidation in tissues such as muscle and liver.

    “In obesity and other insulinresistant states, a predominant mechanism for ectopic fat accumulation appears to be mitochondrial dysfunction (27), leading to decreased fatty acid oxidation in tissues such as muscle and liver.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27] Petersen KF, Dufour S, Befroy D, Garcia R, Shulman GI: Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N Engl J Med 350:664–671,2004 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Zucker diabetic fatty rats transfected with leptin had a dramatic augmentation in PPARγ coactivator-1α expression in white adipose tissue with resultant delipidation.

    “Zucker diabetic fatty rats transfected with leptin had a dramatic augmentation in PPAR␥ coactivator-1␣ expression in white adipose tissue with resultant delipidation (31).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] 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 U S A 101:2058–2063,2004 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Obesity in congenital leptin deficiency is directly related to leptin deficiency, and the effect of leptin therapy is largely mediated by leptin's role in reducing energy intake.

    “Obesity in this case is directly related to leptin deficiency, and the effect here is largely mediated by leptin's role in reducing energy intake.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Leptin appears to enhance mitochondrial production and function, which likely accelerates the removal of ectopic fat.

    “Thus, leptin appears to enhance mitochondrial production and function, which likely accelerates the removal of ectopic fat.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Leptin is crucial in mitochondrial function.

  • May combine two claims.

    Premisecitation

    R-metHuLeptin therapy led to a decrease in serum androgen levels and normal cyclic menses in women of reproductive age.

    “R-metHuLeptin therapy led to a decrease in serum androgen levels and normal cyclic menses in women of reproductive age (9,10).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [9] Oral EA, Ruiz E, Andewelt A, Sebring N, Wagner AJ, Depaoli AM, Gorden P: Effect of leptin replacement on pituitary hormone regulation in patients with severe lipodystrophy. J Clin Endocrinol Metab 87:3110–3117,2002 source

      Not checked in the free run.

    • cites [10] Musso C, Cochran E, Javor E, Young J, Depaoli AM, Gorden P: The long-term effect of recombinant methionyl human leptin therapy on hyperandrogenism and menstrual function in female and pituitary function in male and female hypoleptinemic lipodystrophic patients. Metabolism 54:255–263,2005 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    The values at 8 and 12 months represent 13 patients, since 2 patients experienced severe hypoglycemia (<40 mg/dl) at 4 months.

    “The values at 8 and 12 months represent 13 patients, since 2 patients experienced severe hypoglycemia (<40 mg/dl) at 4 months.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    This decrease in energy consumption would potentially allow for mobilization of stored triglycerides.

    “This decrease in energy consumption would potentially allow for mobilization of stored triglycerides.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    This sustained effect is in contrast to the hyperleptinemic state of obesity, in which leptin has a limited effect.

    “This is in contrast to the hyperleptinemic state of obesity, in which leptin has a limited effect.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    When patients with lipodystrophy and reduced leptin were placed on r-metHuLeptin, they reported improved satiety and satiation, resulting in approximately 40% reduction of caloric intake.

    “When patients with lipodystrophy and reduced leptin were placed on r-metHuLeptin, they reported improved satiety and satiation, resulting in ϳ40% reduction of caloric intake (22).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [22] McDuffie JR, Riggs PA, Calis KA, Freedman RJ, Oral EA, DePaoli AM, Yanovski JA: Effects of exogenous leptin on satiety and satiation in patients with lipodystrophy and leptin insufficiency. J Clin Endocrinol Metab 89:4258–4263,2004 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Pair feeding may lead to some improvement in the metabolic profile compared with the ad lib state, but it does not correct the metabolic abnormalities to the same extent as leptin replacement.

    “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.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites (5,(23)(24)(25)

      Not checked in the free run.

    • cites [6] Oral EA, Simha V, Ruiz E, Andewelt A, Premkumar A, Snell P, Wagner AJ, DePaoli AM, Reitman ML, Taylor SI, Gorden P, Garg A: Leptin-replacement therapy for lipodystrophy. N Engl J Med 346:570–578,2002 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In congenital leptin deficiency, leptin replacement therapy is highly effective in controlling appetite, reducing food intake, and reducing overall fat mass.

    “Here, leptin replacement therapy is highly effective in controlling appetite, reducing food intake, and reducing overall fat mass.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [18] Farooqi IS, Jebb SA, Langmack G, Lawrence E, Cheetham CH, Prentice AM, Hughes IA, McCamish MA, O’Rahilly S: Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med 341:879–884,1999 source

      Not checked in the free run.

    • cites [19] 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 U S A 101:4531–4536,2004 source

      Not checked in the free run.

    • cites [20] Gibson WT, Farooqi IS, Moreau M, DePaoli AM, Lawrence E, O’Rahilly S, Trussell RA: Congenital leptin deficiency due to homozygosity for the Delta133G mutation: report of another case and evaluation of response to four years of leptin therapy. J Clin Endocrinol Metab 89:4821–4826,2004 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In one animal model, leptin alone produced a near-maximal effect, whereas a second model demonstrated a synergistic effect with adiponectin.

    “Likewise, in one animal model, leptin alone produced a near-maximal effect (35), whereas a second model demonstrated a synergistic effect with adiponectin (33).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [35] Colombo C, Cutson JJ, Yamauchi T, Vinson C, Kadowaki T, Gavrilova O, Reitman ML: Transplantation of adipose tissue lacking leptin is unable to reverse the metabolic abnormalities associated with lipoatrophy. Diabetes 51:2727–2733,2002 source

      Not checked in the free run.

    • cites [33] Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori Y, Ide T, Murakami K, Tsuboyama-Kasaoka N, Ezaki O, Akanuma Y, Gavrilova O, Vinson C, Reitman ML, Kagechika H, Shudo K, Yoda M, Nakano Y, Tobe K, Nagai R, Kimura S, Tomita M, Froguel P, Kadowaki T: The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 7:941–946,2001 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    R-MetHuLeptin therapy is associated with decreased energy intake, improvements in dyslipidemia, hepatic steatosis, and insulin resistance, as well as hypothalamic regulation of the gonadal axis.

    “R-MetHuLeptin therapy is associated with decreased energy intake, improvements in dyslipidemia, hepatic steatosis, and insulin resistance, as well as hypothalamic regulation of the gonadal axis (9,10).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [9] Oral EA, Ruiz E, Andewelt A, Sebring N, Wagner AJ, Depaoli AM, Gorden P: Effect of leptin replacement on pituitary hormone regulation in patients with severe lipodystrophy. J Clin Endocrinol Metab 87:3110–3117,2002 source

      Not checked in the free run.

    • cites [10] Musso C, Cochran E, Javor E, Young J, Depaoli AM, Gorden P: The long-term effect of recombinant methionyl human leptin therapy on hyperandrogenism and menstrual function in female and pituitary function in male and female hypoleptinemic lipodystrophic patients. Metabolism 54:255–263,2005 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In rodent models, leptin increased expression of AMP-activated protein kinase and PPARα, activating enzymes of fatty acid oxidation and inhibiting enzymes of lipogenesis.

    “In rodent models, leptin increased expression of AMP-activated protein kinase (28) and peroxisome proliferator-activated receptor (PPAR) ␣ (29), activating enzymes of fatty acid oxidation, including carnitine palmitoyl transferase-1 and acyl-CoA oxidase, and inhibiting enzymes of lipogenesis, including acyl-CoA carboxylase and stearoyl-CoA desaturase-1 (28,30).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [28] 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 415:339–343,2002 source

      Not checked in the free run.

    • cites [29] Lee Y, Yu X, Gonzales F, Mangelsdorf DJ, Wang MY, Richardson C, Witters LA, Unger RH: PPAR alpha is necessary for the lipopenic action of hyperleptinemia on white adipose and liver tissue. Proc Natl Acad Sci U S A 99:11848–11853,2002 source

      Not checked in the free run.

    • cites [30] 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 113:414–424,2004 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Leptin acts at the hypothalamus, inhibiting the synthesis and release of orexigenic peptides, including neuropeptide Y and agouti-related protein.

    “Leptin is known to act at the hypothalamus, inhibiting the synthesis and release of orexigenic peptides, including neuropeptide Y and agoutirelated protein (21).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Tritos NA, Elmquist JK, Mastaitis JW, Flier JS, Maratos-Flier E: Characterization of expression of hypothalamic appetite-regulating peptides in obese hyperleptinemic brown adipose tissue-deficient (uncoupling protein-promoter-driven diphtheria toxin A) mice. Endocrinology 139:4634–4641,1998 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Patient weight reduction has been shown to involve reductions of both fat mass and lean body mass with no change in bone mass.

    “Patient weight reduction has been shown to involve reductions of both fat mass and lean body mass with no change in bone mass (32).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] Moran SA, Patten N, Young JR, Cochran E, Sebring N, Reynolds J, Premkumar A, Depaoli AM, Skarulis MC, Oral EA, Gorden P: Changes in body composition in patients with severe lipodystrophy after leptin replacement therapy. Metabolism 53:513–519,2004 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    r-metHuLeptin therapy has a sustained effect to improve insulin resistance, dyslipidemia, and hepatic steatosis in a hypoleptinemic group of lipodystrophic patients.

    “We conclude that r-metHuLeptin therapy has a sustained effect to improve insulin resistance, dyslipidemia, and hepatic steatosis in a hypoleptinemic group of lipodystrophic patients.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Generalized lipodystrophy leads to severe metabolic abnormalities, including hypertriglyceridemia, NAFLD, insulin resistance, and diabetes.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Their shrunken adipocytes were filled with mitochondria, demonstrating conversion from fat-storing into fat-burning cells.

    “Their shrunken adipocytes were filled with mitochondria, demonstrating conversion from fat-storing into fat-burning cells.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] 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 U S A 101:2058–2063,2004 source

      Not checked in the free run.

65 of 65

  • The paper relies on this without support.

    Before this study, there were no substantial data demonstrating the long-term effectiveness of leptin replacement therapy.

    “Until now, however, there have been no substantial data demonstrating the long-term effectiveness of leptin replacement therapy.”

  • The paper relies on this without support.

    Generalized lipodystrophy leads to severe metabolic abnormalities, including hypertriglyceridemia, NAFLD, insulin resistance, and diabetes.

    “Generalized lipodystrophy leads to severe metabolic abnormalities, including hypertriglyceridemia, NAFLD, in- sulin resistance, and diabetes.”

  • The paper relies on this without support.

    The lack of subcutaneous and visceral adipose tissue results in the storage of triglycerides in ectopic locations such as muscle and liver.

    “The lack of subcutaneous and visceral adipose tissue results in the storage of triglycerides in ectopic locations such as muscle and liver.”

  • The paper relies on this without support.

    The degree of ectopic fat accumulation is further compounded by hyperphagia, which is characteristic of the hypoleptinemic state in rodents and humans.

    “The degree of ectopic fat accumulation is further compounded by hyperphagia, which is characteristic of the hypoleptinemic state in rodents and humans.”

  • The paper relies on this without support.

    Generalized lipodystrophy is characterized by absence of adipose tissue with hypoleptinemia, hyperphagia, and excessive ectopic fat accumulation.

    “The third example is generalized lipodystrophy, characterized by absence of adipose tissue with hypoleptinemia, hyperphagia, and excessive ectopic fat accumulation.”

  • The paper relies on this without support.

    Leptin is crucial in mitochondrial function.

    “Leptin is believed to be crucial in mitochondrial function.”

  • The paper relies on this without support.

    Hyperinsulinemia leads to increased androgen production from the ovaries, forming the basis of polycystic ovarian syndrome.

    “Hyperinsulinemia leads to increased androgen production from the ovaries, forming the basis of polycystic ovarian syndrome.”

  • The paper relies on this without support.

    Leptin is the first and only adipokine to be administered to humans for long-term therapeutic purposes.

    “Leptin is the first and only adipokine to be administered to humans for long-term therapeutic purposes.”
8 of 8

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • In humans with lipodystrophy, leptin therapy has demonstrated significant improvements in glycemia, dyslipidemia, and hepatic steatosis.

    “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 [89]

  • The finding of body fat loss with metreleptin has also been observed in studies assessing metreleptin in humans with severe lipodystrophy and other conditions associated with relative leptin deficiency.

    “This fi nding also has been observed in studies assessing the effect of metreleptin on metabolic parameters in humans with severe lipodystrophy and other conditions associated with relative leptin de fi ciency (39 -41).”

    From Leptin is an effective treatment for hypothalamic amenorrhea (2011) · cites this paper as [41]

Cites

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Related

Authors
Javor, E. D., Cochran, E. K., Musso, C., Young, J. R., DePaoli, A. M., & Gorden, P.
Affiliations
  • National Institutes of Health (US)
  • Amgen (United States) (US)
  • Clinical Endocrinology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
ORCID
Venue
Diabetes
Publisher
American Diabetes Association
Published
2005-07-01
Volume
54
Issue
7
Pages
1994-2002
ISSN
  • 0012-1797 (ISSN-L)
  • 1939-327X
DOI
10.2337/diabetes.54.7.1994
OpenAlex
W2100364658
Semantic Scholar
a77b0da702672573c3e91c424af70216bb94106e
Cited by
226
References
45
Citations by year
2025: 3 · 2024: 7 · 2023: 4 · 2022: 4 · 2021: 9 · 2020: 3 · 2019: 8 · 2018: 6 · 2017: 5 · 2016: 11 · 2015: 16 · 2014: 20 · 2013: 19 · 2012: 11
FWCI
13.15
Type
journal article
Language
en
Open access
Locations
  • Diabetes (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • NIH Clinical Center
Topics
  • Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
Keywords
generalized lipodystrophy, leptin replacement, recombinant human leptin, ectopic fat deposition, insulin resistance, hypertriglyceridemia, hepatic steatosis, liver volume, hyperphagia, adipose tissue deficiency, long-term metabolic outcomes, weight loss, lipid profile, HbA1c, LDL cholesterol, HDL cholesterol, triglycerides
MeSH terms
Adolescent, Adult, Blood Glucose, Child, Female, Glycated Hemoglobin, Humans, Lipodystrophy, Male, Triglycerides, Cohort Studies, Body Mass Index, Leptin

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

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