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Cited by 505Regulation of Appetite and ObesityAdipokines, Inflammation, and Metabolic DiseasesHypothalamic control of reproductive hormones

Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults

Open access
Licinio, Julio, Caglayan, Sinan, Ozata, Metin, Yildiz, Bulent O., de Miranda, Patricia B., O'Kirwan, Fiona, Whitby, Robert, Liang, Liyin +8 more·2004·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0308767101PMC PMC384781
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Abstract

Genetic mutations in the leptin pathway can be a cause of human obesity. It is still unknown whether leptin can be effective in the treatment of fully established morbid obesity and its endocrine and metabolic consequences in adults. To test the hypothesis that leptin has a key role in metabolic and endocrine regulation in adults, we examined the effects of human leptin replacement in the only three adults identified to date who have genetically based leptin deficiency. We treated these three morbidly obese homozygous leptin-deficient adult patients with recombinant human leptin at low, physiological replacement doses in the range of 0.01–0.04 mg/kg for 18 months. Patients were hypogonadal, and one of them also had type 2 diabetes mellitus. We chose the doses of recombinant methionyl human leptin that would achieve normal leptin concentrations and administered them daily in the evening to model the normal circadian variation in endogenous leptin. The mean body mass index dropped from 51.2 ± 2.5 (mean ± SEM) at baseline to 26.9 ± 2.1 kg/m 2 after 18 months of treatment, mainly because of loss of fat mass. We document here that leptin replacement therapy in leptin-deficient adults with established morbid obesity results in profound weight loss, increased physical activity, changes in endocrine function and metabolism, including resolution of type 2 diabetes mellitus and hypogonadism, and beneficial effects on ingestive and noningestive behavior. These results highlight the role of the leptin pathway in adults with key effects on the regulation of body weight, gonadal function, and behavior.

AI snapshot

Written from the paper’s full text.

TL;DR

In three adults with genetically based leptin deficiency and long-established morbid obesity, 18 months of recombinant human leptin replacement at low physiological doses produced profound weight loss and resolved type 2 diabetes mellitus and hypogonadism. The results support a key role for the leptin pathway in adult body-weight, endocrine, and behavioral regulation.

Key findings

  • Mean BMI fell from 51.2 ± 2.5 kg/m² at baseline to 36.5 ± 2.3 at 6 months, 28.9 ± 3.2 at 12 months, and 26.9 ± 2.1 at 18 months. Individual 18-month weight losses were 76.2, 47.5, and 60.0 kg, corresponding to 53.8%, 43.5%, and 44.5% of body weight.
  • Weight loss was preferentially fat loss: at 18 months, patient A had 11% of initial fat mass and 77% of lean body mass; patient B had 28% and 82%; patient C had 40% and 72%. Mean daily caloric intake dropped 49%, from 2,330 ± 322 kcal/day at baseline to 1,180 ± 52 kcal/day at week 2, while daytime activity counts increased progressively.
  • The patient with type 2 diabetes had fasting/postprandial glucose decreases after 2 months and normal hemoglobin A1c at the time of report; the other two maintained normal fasting glucose but had insulin and C-peptide values decreased to less than half of original values. Hypogonadism resolved clinically, with regular ovulatory menstrual cycles in the two women and pubertal changes in the 27-year-old man.
  • Twenty-four-hour mean leptin, LH, testosterone, and cortisol increased significantly after 6 months of treatment; behavioral change from “very docile and infantile” to “assertive and adult-like” was observed within 2 weeks, before weight loss occurred.

Methods

  • Prospective study of the only three adult leptin-naive homozygous leptin-deficient patients identified at the time, from a consanguineous Turkish pedigree with a Cys-to-Thr mutation in codon 105. Patients had a 3-month baseline at the UCLA General Clinical Research Center, then received subcutaneous recombinant methionyl human leptin once daily in the evening at 0.01–0.04 mg/kg for 18 months, with doses titrated downward during weight loss.
  • Diet and activity were ad libitum except during 24-h blood collections and preceding 48-h acclimatization; measures included daily weights, food records, Actiwatch activity monitoring, DEXA body composition, lipid and glucose parameters, IGF/IGFBP, ghrelin, adiponectin, and Hamilton anxiety/depression scales.
  • In one male patient, blood was sampled every 7 min over 24 h at baseline and 6 months, generating 1,656 endocrine data points from eight time series of 207 points each; analyses included paired comparisons from month 0 to month 18 for the mean of the three patients and approximate entropy/pulse analysis of hormone rhythms.

Limitations

  • The paper states that it cannot fully ascertain whether changes in glucose homeostasis were a direct effect of leptin, mediated solely by weight loss, associated with increased adiponectin, or a combined effect of these and other factors.
  • The paper states that planned positron-emission tomography scans could not be performed because patients did not fit into the equipment, and that the behavioral change was a subjective but universal observation by treatment staff.
  • Evident from the text: the study had only three genetically related patients sharing the same mutation, no control group, and an open-label design; the authors note that phenotypes and treatment responses were not uniform, implicating nonshared gene alleles and environment.

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

Integrity signals

Registry

Crossref · 10.1073/pnas.0308767101

Cites

37 of 37 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 26 cited sources checked · 0 supported · 0 flagged

  • Findingcitation
    § Results

    Patients B and C had at baseline regular menstrual periods characterized by a luteal phase defect with low midluteal phase progesterone levels.

    “Patients B and C had at baseline regular menstrual periods characterized by a luteal phase defect with low midluteal phase progesterone levels (10).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Ozata, M., Ozdemir, I. C. & Licinio, J. (1999) J. Clin. Endocrinol. Metab. 84, 3686–3695. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • Findingown data
    § Results

    All these changes in body composition are statistically significant.

    “All these changes are statistically significant.”
    Quote in the paperSubstantial claim
  • Findingown data
    § Results

    For LH and testosterone, there were no changes in the number of pulses after leptin replacement.

    “For LH and T there were no changes in the number of pulses (29 pulses per 24 h for LH before treatment and 28 pulses per 24 h for T before treatment vs. 29 and 30 after treatment, respectively), which had the same concentration-independent features before or after leptin replacement.”
    Quote in the paperNot a substantial claim
  • Findingown data
    § Results

    Twenty-four-hour average concentrations of leptin, LH, testosterone, and cortisol significantly increased (P < 0.0001) from baseline to 6 months after leptin replacement.

    “Twenty-four-hour average concentrations of leptin, LH, T, and cortisol significantly increased (P < 0.0001) from a baseline of 0.77 ± 0.01 ng/ml, 0.75 ± 0.04 milliunits/ml, 2.61 ± 0.06 ng/ml, and 4.04 ± 0.22 μg/dl, to 12.67 ± 0.83 ng/ml, 2.75 ± 0.07 milliunits/ml, 7.50 ± 0.07 ng/ml, and 5.97 ± 0.30 μg/dl, respectively, 6 months after leptin replacement”
    Quote in the paperSubstantial claim
  • Findingown data
    § Discussion

    After reaching a nadir at months 4-6 after onset of leptin administration, the patients gradually started to increase their food intake toward baseline levels.

    “After reaching a nadir at months 4–6 after onset of leptin administration, the patients gradually started to increase their food intake toward baseline levels.”
    Quote in the paperSubstantial claim
  • May combine two claims. 42
  • The quote only partly states this claim. 2
  • Classified as probably not a substantial claim. 16

  • May combine two claims.

    Findingown data
    § Discussion

    At baseline, the patients were not eating as voraciously as they reportedly had during childhood; their pattern of food intake was stable at the 1,800-3,000 kcal/d range.

    “At baseline, our patients were not eating as voraciously as they reportedly had during their childhood. Their pattern of food intake was stable at the 1,800–3,000 kcal/d range.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Results

    All IGF-related parameters were within the normal range before initiation of therapy except postprandial IGFBP-1, which was below the lower limit of normal.

    “All of the IGF-related parameters were within the normal range before initiation of therapy except the postprandial IGFBP-1, which was below the lower limit of normal.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Results

    By 18 months of therapy, IGFBP-1 and IGFBP-2 levels were dramatically increased (by 7-fold and 2-fold, respectively, significant at the 10^-4 level) and were at or above the upper limit of normal.

    “By 18 months of therapy, IGFBP-1 and IGFBP-2 levels were dramatically increased (by 7-fold and 2-fold, respectively, significant at the 10–4 level) and were at or above the upper limit of normal.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Results

    As patients lost weight, fasting adiponectin levels increased and exhibited significant negative correlations with fasting C-peptide (r = -0.53; P < 0.04) and with the insulin sensitivity index derived by HOMA (r = -0.52; P < 0.04).

    “As patients lost weight, fasting adiponectin levels increased, exhibiting significant negative correlations with the levels of fasting C-peptide (r =–0.53; P < 0.04; see Fig. 5, which is published as supporting information on the PNAS web site) and also with the insulin sensitivity index derived by using the Homeostatic Model Assessment model (r =–0.52; P < 0.04).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Results

    Patients lost fat preferentially; a proportionately smaller decrease in fat-free body mass also occurred, and the loss of fat-free mass was substantially smaller than that of fat.

    “As shown in Table 1, patients lost fat preferentially. A proportionately smaller decrease in fat-free body mass also occurred. The loss of fat-free mass was substantially smaller than that of fat.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Results

    In patients A and B, fasting glucose remained normal but insulin and C-peptide values decreased significantly to less than half of their original values.

    “The other two patients maintained normal fasting glucose levels but their insulin and C-peptide values decreased significantly to less than half of their original values.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Results

    After 6 months of leptin treatment, patient A reported improvement in muscle strength, sense of well-being, and energy.

    “After 6 months of treatment he reported improvement in muscle strength, sense of well-being, and energy.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Results

    During leptin replacement, patient A developed increased facial hair, facial acne, pubic and axillary hair, growth of penis and testicles, and normal ejaculatory patterns.

    “Additionally, during the course of leptin replacement, we documented increased facial hair, onset of facial acne, development of pubic and axillary hair, growth of penis and testicles, and normal ejaculatory patterns.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Results

    After leptin replacement, patients B and C had regular menstrual periods associated with serial midluteal phase progesterone measurements >10 ng/ml, indicative of ovulation.

    “After leptin replacement both patients had regular menstrual periods that were associated with serial midluteal phase progesterone measurements >10 ng/ml, which are indicative of ovulation.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data
    § Discussion

    In parallel with the decrease in body weight, the level of physical activity increased.

    “In parallel, their level of physical activity increased.”
    Quote in the paperSubstantial claim

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

    Findingown data
    § Results

    At baseline, male patient A was 27 years old with a body mass index of 51.4 kg/m2.

    “At baseline, male patient A was 27 years old, and his body mass index (BMI) was 51.4 kg/m2.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Results

    At baseline, patients A and B had normal glucose and insulin levels and normal glucose tolerance after a 2-h, 75-g oral glucose tolerance test; patient C had a clinical diagnosis of type 2 diabetes mellitus.

    “As shown in Table 2, at baseline, patients A and B had normal glucose and insulin levels. They also had normal glucose tolerance after a 2-h, 75-g standard oral glucose tolerance test; patient C had a clinical diagnosis of type 2 diabetes mellitus.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Abstract

    Mean body mass index dropped from 51.2 ± 2.5 at baseline to 26.9 ± 2.1 kg/m2 after 18 months of leptin treatment, mainly because of loss of fat mass.

    “The mean body mass index dropped from 51.2 ± 2.5 (mean ± SEM) at baseline to 26.9 ± 2.1 kg/m2 after 18 months of treatment, mainly because of loss of fat mass.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Results

    At 18 months after treatment, patient A had 11% of his initial fat mass and 77% of his lean body mass; patient B had 28% and 82%; patient C had 40% and 72%.

    “At 18 months after treatment, patient A had 11% of his initial fat mass and 77% of his lean body mass. Those figures were 28% and 82% for patient B and 40% and 72% for patient C, respectively.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Results

    During leptin treatment, there were increases in HDL cholesterol (34-78%), although most of the increase occurred between 8 and 18 months.

    “On the other hand, there were increases in HDL cholesterol (34–78%) although most of the increase occurred between 8 and 18 months.”
    Quote in the paperNot a substantial claim

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

    Findingown data
    § Results

    At baseline, female patients B and C were 35 and 40 years old with body mass indexes of 46.7 and 55.4 kg/m2, respectively.

    “Female patients B and C were 35 and 40 years old with a BMI of 46.7 and 55.4 kg/m2, respectively.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Results

    Mean BMI dropped from 51.2 ± 2.5 kg/m2 at baseline to 36.5 ± 2.3 kg/m2 after 6 months, 28.9 ± 3.2 kg/m2 after 12 months, and 26.9 ± 2.1 kg/m2 after 18 months of leptin treatment.

    “The mean BMI dropped from 51.2 ± 2.5 kg/m2 (mean ± SEM) at baseline to 36.5 ± 2.3 kg/m2 after 6 months; BMI was 28.9 ± 3.2 kg/m2 after 12 months of treatment (Fig. 2a) and 26.9 ± 2.1 after 18 months of treatment.”
    Quote in the paperSubstantial claim

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

    Findingown data
    § Results

    One of the two female patients had a mild skin reaction at the injection site for 1 week, which resolved spontaneously.

    “Leptin injections were very well tolerated; one of the two female patients had a mild skin reaction at the site of injection for 1 week, which resolved spontaneously.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Results

    Weight losses of patients A, B, and C after 18 months of leptin treatment were 76.2, 47.5, and 60.0 kg, corresponding to 53.8%, 43.5%, and 44.5% of their body weight, respectively.

    “The weight losses of patients A, B, and C after 18 months of treatment were 76.2, 47.5, and 60.0 kg, respectively, corresponding to 53.8%, 43.5%, and 44.5% of their body weight, respectively.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Results

    Six months of leptin replacement resulted in higher 24-h mean concentrations of cortisol, associated with fewer pulses of greater height, including a greater morning rise.

    “In addition, 6 months of leptin replacement resulted in higher 24-h mean concentrations of cortisol (from 4.04 ± 0.22 to 5.97 ± 0.30 μg/dl), which were associated with fewer pulses (25 vs. 19) of greater height (from 4.85 to 6.25 ± 1.11 μg/dl), including a greater morning rise (Fig. 4).”
    Quote in the paperNot a substantial claim

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

    Findingown data
    § Results

    Levels of apolipoprotein A1 changed minimally over the course of leptin treatment.

    “Interestingly, levels of apolipoprotein A1, the main HDL protein component, changed minimally over the course of treatment.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Results

    During leptin treatment, triglyceride levels dropped 49-66%, with smaller relative reductions in LDL cholesterol (21-65%) and apolipoprotein B (18-40%).

    “During the course of leptin treatment, triglyceride levels dropped 49–66%, with smaller relative reductions in LDL cholesterol (21– 65%) and apolipoprotein B (18–40%).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Results

    The ApEn of LH and testosterone increased from baseline to after leptin replacement.

    “The ApEn of LH and T increased from a baseline of 0.532 and 0.632 to 0.641 and 0.799, respectively, after leptin replacement.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Results

    In patient C, in the context of no other treatment, fasting and postprandial glucose values decreased after 2 months of leptin treatment, and hemoglobin A1c levels are in the normal range at the present time.

    “In the context of no other treatment, her fasting and postprandial glucose values decreased after 2 months of treatment, and her hemoglobin A1c levels, a measure of diabetes control, are in the normal range at the present time.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Results

    After leptin replacement, daily caloric intake decreased, reaching a nadir at 4-6 months; thereafter, it increased progressively.

    “After leptin replacement, daily caloric intake decreased, reaching a nadir at 4–6 months; thereafter, it increased progressively (Fig. 2b).”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data
    § Results

    Weight loss was observed within 1 week after the initiation of leptin treatment.

    “Weight loss was observed within 1 week after the initiation of treatment.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Abstract

    The three leptin-deficient adult patients were hypogonadal at baseline, and one of them had type 2 diabetes mellitus.

    “Patients were hypogonadal, and one of them also had type 2 diabetes mellitus.”
    • Also stated in: § Abstract · plain
      “They were hypogonadal, and one of them had type 2 diabetes mellitus.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Abstract

    The three leptin-deficient adults had morbid obesity fully established for two to four decades and had been at a stable but very high weight for more than 10 years.

    “Morbid obesity had been fully established for two to four decades in those patients, and they had been at a stable (but very high) weight for >10 years.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation
    § Abstract

    Leptin, the product of the ob gene, plays a central role in the regulation of food intake and energy expenditure.

    “Leptin, the product of the ob gene, plays a central role in the regulation of food intake and energy expenditure (4).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [4] Zhang, Y., Proenca, R., Maffei, M., Barone, M., Leopold, L. & Friedman, J. M. (1994) Nature 372, 425–432. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation
    § Abstract

    Nutritional intake modulates the insulin-like growth factors (IGFs) and their binding proteins (IGFBPs).

    “Because nutritional intake is well known to modulate the insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) (18), we measured IGFs and IGFBPs through the course of leptin replacement.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Le Roith, D. (1997) N. Engl. J. Med. 336, 633–640. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

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

    Study design and conductreasoning
    § Methods

    The study included a 3-month baseline period designed to avoid confounding factors of international travel, time-zone differences, and potential changes in food choice.

    “The study started with a 3-month baseline period at the General Clinical Research Center. This extended baseline period was designed to avoid the confounding factors of international travel, time-zone differences, and potential changes in food choice.”
    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 conductnone given
    § Methods

    The study took place under protocols approved by the Food and Drug Administration, the University of California at Los Angeles Institutional Review Boards, and the Central Ethical Committee of the Turkish Ministry of Health.

    “where the study took place under protocols approved by the Food and Drug Administration and by the University of California at Los Angeles Institutional Review Boards and the Central Ethical Committee of the Turkish Ministry of Health.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given
    § Methods

    The DEXA scanner was calibrated by using a soft-tissue phantom before each measurement.

    “The DEXA scanner was calibrated by using a soft-tissue phantom before each measurement.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given
    § Methods

    The patient was acclimated to the room where blood was collected for 48 h before sample collection.

    “The patient was acclimated to the room where blood was collected for 48 h before sample collection.”
    Quote in the paperNot a substantial claim

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

    Premisecitation
    § Discussion

    It is thought that adiponectin can decrease the insulin resistance of obesity.

    “It is thought that adiponectin can decrease the insulin resistance of obesity (28–30).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [28] Hotta, K., Funahashi, T., Bodkin, N. L., Ortmeyer, H. K., Arita, Y., Hansen, B. C. & Matsuzawa, Y. (2001) Diabetes 50, 1126–1133. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [29] Weyer, C., Funahashi, T., Tanaka, S., Hotta, K., Matsuzawa, Y., Pratley, R. E. & Tataranni, P. A. (2001) J. Clin. Endocrinol. Metab. 86, 1930–1935. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [30] Yamauchi, T., Kamon, J., Waki, H., Terauchi, Y., Kubota, N., Hara, K., Mori, Y., Ide, T., Murakami, K., Tsuboyama-Kasaoka, N., et al. (2001) Nat. Med. 7, 941–946. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

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

    Premisecitation
    § Discussion

    Previous studies had shown that leptin treatment can improve glucose homeostasis in patients with lipodystrophy and in children treated with leptin on a long-term basis.

    “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).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [21] 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., et al. (2002) N. Engl. J. Med. 346, 570–578. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [8] Farooqi, I. S., Jebb, S. A., Langmack, G., Lawrence, E., Cheetham, C. H., Prentice, A. M., Hughes, I. A., McCamish, M. A. & O'Rahilly, S. (1999) N. Engl. J. Med. 341, 879–884. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [9] 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) J. Clin. Invest. 110, 1093–1103. [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Discussion

    Compared with severely obese individuals, the IGFBP-1 levels in untreated leptin-deficient patients are not unusual; fasting IGFBP-1 levels in untreated leptin-deficient patients are higher than in other obese individuals with lower BMI.

    “Compared with those of severely obese individuals, however, these IGFBP-1 levels are not unusual; in fact, the fasting IGFBP-1 levels in untreated leptin-deficient patients are higher than in other obese individuals with lower BMI (31).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] Frystyk, J., Skjaerbaek, C., Vestbo, E., Fisker, S. & Orskov, H. (1999) Diabetes Metab. Rev. 15, 314–322. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data
    § Discussion

    In the absence of leptin, cortisol dynamics is characterized by a higher number of smaller peaks, with smaller morning rise, increased relative variability, and increased pattern irregularity.

    “In the absence of leptin, cortisol dynamics is characterized by a higher number of smaller peaks, with smaller morning rise, increased relative variability, and increased pattern irregularity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning
    § Discussion

    Puberty was delayed in this case because of the lack of leptin, and leptin administration led to maturation of the male reproductive axis.

    “It can be concluded that puberty was delayed in this case because of the lack of leptin, and that leptin administration led to maturation of the male reproductive axis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning
    § Discussion

    It is reasonable to presume that the initial weight loss was due to reduced food intake, but that over the course of the study period continued weight loss was achieved by progressively increased levels of physical activity above baseline levels, in the context of food intake that increased from its nadir but did not substantially exceed baseline.

    “It is therefore reasonable to presume that the initial weight loss was due to reduced food intake, but that over the course of the study period continued weight loss was achieved by progressively increased levels of physical activity above baseline levels, in the context of food intake that increased from its nadir but did not substantially exceed baseline.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data
    § Discussion

    Once-a-day leptin administration in the evening mimics the nocturnal rise of leptin, resulting in a pattern that has similarities with the endogenous situation.

    “First, we show that once-a-day leptin administration in the evening mimics the nocturnal rise of leptin, resulting in a pattern that has similarities with the endogenous situation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data
    § Discussion

    The profound phenotypic changes observed at baseline in our patients were due to the direct effects of leptin without unexpected abnormalities in these other peptides that are related to fat mass and food intake.

    “These data indicate that the profound phenotypic changes observed at baseline in our patients were due to the direct effects of leptin without unexpected abnormalities in these other peptides that are related to fat mass and food intake.”
    Quote in the paperSubstantial claim

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

    Premisecitation
    § Discussion

    In those children, leptin replacement reversed the effects of leptin deficiency, leading to puberty at an appropriate age.

    “In those children, leptin replacement reversed the effects of leptin deficiency, leading to puberty at an appropriate age (8, 9).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [8] Farooqi, I. S., Jebb, S. A., Langmack, G., Lawrence, E., Cheetham, C. H., Prentice, A. M., Hughes, I. A., McCamish, M. A. & O'Rahilly, S. (1999) N. Engl. J. Med. 341, 879–884. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [9] 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) J. Clin. Invest. 110, 1093–1103. [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

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

    Premisecitation
    § Discussion

    The obese are known to have increased insulin resistance and decreased adiponectin levels, which increase with weight loss.

    “The obese are known to have increased insulin resistance and decreased adiponectin levels (12), which increase with weight loss (27).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [12] Arita, Y., Kihara, S., Ouchi, N., Takahashi, M., Maeda, K., Miyagawa, J., Hotta, K., Shimomura, I., Nakamura, T., Miyaoka, K., et al. (1999) Biochem. Biophys. Res. Commun. 257, 79–83. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [27] Yang, W. S., Lee, W. J., Funahashi, T., Tanaka, S., Matsuzawa, Y., Chao, C. L., Chen, C. L., Tai, T. Y. & Chuang, L. M. (2001) J. Clin. Endocrinol. Metab. 86, 3815–3819. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Discussion

    In the presence of a leptin gene mutation, leptin treatment of obesity in adults was extraordinarily successful; in the absence of such a mutation, the same intervention was not markedly effective.

    “While in the presence of a leptin gene mutation, leptin treatment of obesity in adults was extraordinarily successful; in the absence of such a mutation, the same intervention was not markedly effective (35).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [35] Heymsfield, S. B., Greenberg, A. S., Fujioka, K., Dixon, R. M., Kushner, R., Hunt, T., Lubina, J. A., Patane, J., Self, B., Hunt, P. & McCamish, M. (1999) J. Am. Med. Assoc. 282, 1568–1575. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data
    § Discussion

    Leptin replacement therapy in leptin-deficient adults with established morbid obesity results in profound weight loss, changes in behavior, energy intake, increased physical activity, and resolution of type 2 diabetes mellitus and hypogonadism.

    “We show here that leptin replacement therapy in leptin-deficient adults with established morbid obesity results in profound weight loss, changes in behavior, energy intake, increased physical activity, and resolution of type 2 diabetes mellitus and hypogonadism.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given
    § Discussion

    It had been our original intention to conduct positron-emission tomography scans at baseline and longitudinally during treatment; however, patients did not fit into the equipment because of their morbid obesity.

    “It had been our original intention to conduct positron-emission tomography scans at baseline and longitudinally during treatment; however, patients did not fit into the equipment because of their morbid obesity.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data
    § Discussion

    Pulse heights were significantly higher in the postleptin series, which explains the effects of treatment leading to increased mean 24-h values.

    “Pulse heights were significantly higher in the postleptin series, which explains the effects of treatment leading to increased mean 24-h values.”
    Quote in the paperSubstantial claim

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

    Premisecitation
    § Discussion

    IGF-I treatment leads to marked suppression of leptin levels in both rodents and humans.

    “IGF-I treatment leads to marked suppression of leptin levels in both rodents and humans (33, 34).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [33] Boni-Schnetzler, M., Hauri, C. & Zapf, J. (1999) Diabetologia 42, 160–166. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [34] Dagogo-Jack, S., Franklin, S. C., Vijayan, A., Liu, J., Askari, H. & Miller, S. B. (1998) Int. J. Obes. 22, 1110–1115. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data
    § Discussion

    Leptin treatment per se did not reverse the reduced HDL cholesterol abnormality, and substantial increases were observed only after 18 months, consistent with evidence that increases in HDL with weight reduction are generally not observed during the active stages of weight loss.

    “Leptin treatment per se did not reverse this abnormality, and substantial increases were observed only after 18 months, consistent with evidence that increases in HDL with weight reduction are generally not observed during the active stages of weight loss.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data
    § Discussion

    Obesity in the absence of leptin is associated with a different phenotype than that of obesity associated with hyperleptinemia. In the former, there is hypogonadism but not pronounced cardiovascular and metabolic morbidity. The latter is characterized by metabolic and cardiovascular sequelae in the context of normal reproductive function.

    “First, it appears that obesity in the absence of leptin is associated with a different phenotype than that of obesity associated with hyperleptinemia. In the former, there is hypogonadism but not pronounced cardiovascular and metabolic morbidity. The latter is characterized by metabolic and cardiovascular sequelae in the context of normal reproductive function.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning
    § Discussion

    Leptin administration to an adult hypogonadic male had a profound effect on the dynamics of sex hormone concentrations while concurrently causing the onset of puberty at age 27.

    “These results indicate that leptin administration to an adult hypogonadic male had a profound effect on the dynamics of sex hormone concentrations while concurrently causing the onset of puberty at age 27.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data
    § Discussion

    Leptin replacement is effective after morbid obesity is fully established at a stable level for several decades; it can reverse obesity and resolve its complications, such as diabetes mellitus; and it can induce puberty even a decade or longer after the normal age for pubertal development.

    “What such previous work had not elucidated, and which is documented here, is that leptin replacement is effective after morbid obesity is fully established at a stable level for several decades; that it can not only reverse obesity but also resolve its complications, such as diabetes mellitus; and that it can induce puberty even a decade or longer after the normal age for pubertal development.”
    Quote in the paperSubstantial claim
53 of 53

  • The paper relies on this without support.

    It is still unknown whether leptin can be effective in the treatment of fully established morbid obesity and its endocrine and metabolic consequences in adults.

    “It is still unknown whether leptin can be effective in the treatment of fully established morbid obesity and its endocrine and metabolic consequences in adults.”
    “It is still unknown whether the leptin pathway is relevant to the treatment of established morbid obesity and its endocrine and metabolic consequences in adults.”

  • The paper relies on this without support.

    The three adult patients studied are the only three adults identified to date who have genetically based leptin deficiency.

    “we examined the effects of human leptin replacement in the only three adults identified to date who have genetically based leptin deficiency.”
    “the only three adult leptin-naive individuals identified in the world so far.”
2 of 2

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?

  • Leptin treatment of patients with hypogonadotropic hypogonadism and a homozygous mutation in LEP resulted in the induction of menstrual cycles, development of secondary sexual characteristics, and pulsatile gonadotropin secretion.

    “Leptin treatment of patients with hypogonadotropic hypogonadism and a homozygous mutation in LEP resulted in the induction of menstrual cycles, development of secondary sexual characteristics, and pulsatile gonadotropin secretion.101,102”

    From Pubertal development and regulation (2016) · cites this paper as [101]

  • 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.”

    From Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy (2005) · cites this paper as [19]

  • Adiponectin levels in the ob/ob mouse and patients with congenital leptin deficiency were increased following leptin replacement.

    “However, levels in the ob/ob mouse (34) and patients with congenital leptin deficiency (19) were increased following leptin replacement.”

    From Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy (2005) · cites this paper as [19]

  • 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.”

    From Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy (2005) · cites this paper as [19]

  • In congenital leptin deficiency, metabolic abnormalities of dyslipidemia, glucose intolerance, and steatosis, which are only mildly abnormal, are corrected by leptin therapy.

    “Metabolic abnormalities of dyslipidemia, glucose intolerance, and steatosis, which are only mildly abnormal, are also corrected by leptin therapy.”

    From Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy (2005) · cites this paper as [19]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

  • Patient A's six-month body-composition masses do not add to body weight

    Minor

    At six months, Table 1 lists 33.1 kg of fat mass and 63.6 kg of fat-free mass for patient A. Their sum is 96.7 kg, not the listed body weight of 99.7 kg.

    Reported 99.7 · recomputed 96.7

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Barrios, V., Buno, M., Pozo, J., Munoz, M. T. & Argente, J. (2000) Horm. Res. 53, 221–227.11150883

Cited by

Sorted by citations

Related

Authors
Licinio, J., Caglayan, S., Ozata, M., Yildiz, B. O., de Miranda, P. B., O'Kirwan, F., Whitby, R., Liang, L., Cohen, P., Bhasin, S., Krauss, R. M., Veldhuis, J. D., Wagner, A. J., DePaoli, A. M., McCann, S. M., & Wong, M.-L.
Affiliations
  • Center for Pharmacogenomics, Neuropsychiatric Institute, Department of Psychiatry and Biobehavioral Sciences, Department of Medicine, Division of Endocrinology, Diabetes, and Hypertension, General Clinical Research Center, and Department of Pediatrics, Division of Pediatric Endocrinology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095-1761; Department of Endocrinology and Metabolism, Gulhane Haydarpasa Training Hospital, Acibadem-Istanbul 34660, Turkey; Division of...
  • University of California, Los Angeles (US)
  • Amgen (United States) (US)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2004-03-09
Volume
101
Issue
13
Pages
4531-4536
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.0308767101
PMC
PMC384781
OpenAlex
W2053321990
Semantic Scholar
8db10cd08f69da15eb9aaa7c80ea9579ca2898ba
Cited by
505
References
37
Citations by year
2026: 4 · 2025: 12 · 2024: 12 · 2023: 14 · 2022: 13 · 2021: 14 · 2020: 17 · 2019: 17 · 2018: 24 · 2017: 24 · 2016: 18 · 2015: 29 · 2014: 29 · 2013: 30 · 2012: 31
FWCI
10.87
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Amgen
  • National Alliance for Research on Schizophrenia and Depression
  • National Institutes of Health (RR-00585, DK-063491)
  • National Institute on Aging (R01AG020954, AG-23133, R01AG023133, AG20954)
  • National Heart, Lung, and Blood Institute (K30HL004526, K30 HL04526, U19HL069757, U01HL069757, HL 069757)
  • National Institute of Mental Health (R21MH062777, MH-062777)
  • National Human Genome Research Institute (R03HG002500, HG002500)
  • National Cancer Institute (CA92131, CA 100938, P50CA092131, R01CA100938)
  • National Institute of General Medical Sciences (U01GM061394, GM61394)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK 60717, DK063491, R01DK063240, DK-063240, R01DK058851, DK-58851, R01DK060717, P30DK063491)
  • National Center for Research Resources (RR-017611, K12RR017611, RR-00585, RR000865, RR-16996, K24RR017365, M01RR000865, K24RR016996, M01RR000585, RR017365)
Topics
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
  • Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
  • Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
Keywords
leptin replacement therapy, leptin deficiency, morbid obesity, type 2 diabetes, hypogonadism, recombinant human leptin, weight loss, fat loss, physical activity, hormonal regulation, metabolic regulation, ingestive behavior
MeSH terms
Adult, Behavior, Body Composition, Circadian Rhythm, Diabetes Mellitus, Type 2, Female, Humans, Hypogonadism, Phenotype, Weight Loss, 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 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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