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Cited by 575Regulation of Appetite and ObesityAdipokines, Inflammation, and Metabolic DiseasesHypothalamic control of reproductive hormones

Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight

Open access
Rosenbaum, M.·2005·Journal of Clinical Investigation
DOI 10.1172/jci25977PMC PMC1297250
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Abstract

Maintenance of a reduced body weight is accompanied by decreased energy expenditure that is due largely to increased skeletal muscle work efficiency. In addition, decreased sympathetic nervous system tone and circulating concentrations of leptin, thyroxine, and triiodothyronine act coordinately to favor weight regain. These "weight-reduced" phenotypes are similar to those of leptin-deficient humans and rodents. We examined metabolic, autonomic, and neuroendocrine phenotypes in 10 inpatient subjects (5 males, 5 females [3 never-obese, 7 obese]) under 3 sets of experimental conditions: (a) maintaining usual weight by ingesting a liquid formula diet; (b) maintaining a 10% reduced weight by ingesting a liquid formula diet; and (c) receiving twice-daily subcutaneous doses of leptin sufficient to restore 8 am circulating leptin concentrations to pre-weight-loss levels and remaining on the same liquid formula diet required to maintain a 10% reduced weight. During leptin administration, energy expenditure, skeletal muscle work efficiency, sympathetic nervous system tone, and circulating concentrations of thyroxine and triiodothyronine returned to pre-weight-loss levels. These responses suggest that the weight-reduced state may be regarded as a condition of relative leptin insufficiency. Prevention of weight regain might be achievable by strategies relevant to reversing this leptin-insufficient state.

AI snapshot

Written from the paper’s full text.

TL;DR

In 10 inpatient subjects, maintenance of a 10% reduced body weight produced coordinated declines in energy expenditure, skeletal muscle efficiency, sympathetic tone, and thyroid hormones. Low-dose leptin, titrated to restore 8 am leptin concentrations to pre-weight-loss levels, reversed many of these weight-reduced adaptations, suggesting the state is one of relative leptin insufficiency.

Key findings

  • At Wt−10%, 24-hour energy expenditure (TEE) and nonresting energy expenditure (NREE) fell out of proportion to body-composition changes; skeletal muscle gross mechanical efficiency at 10 W was approximately 23% higher than at Wtinitial, and glucose oxidation at 10 W fell by approximately 12%.
  • Leptin administration at Wt−10%lep restored TEE, NREE, skeletal muscle work efficiency, fuel utilization, sympathetic nervous system activity, urinary epinephrine, and circulating T4/T3 to pre-weight-loss levels; it did not significantly alter TSH, 24-hour urinary norepinephrine, parasympathetic activity, or intrinsic heart rate.
  • Mean total daily leptin dose was 0.068 ± 0.01 mg/kg (range 0.019–0.121 mg/kg/d) divided q12 hours; 8 am plasma leptin at Wt−10%lep was not significantly different from Wtinitial.
  • During leptin administration on an isocaloric diet, body weight and fat mass declined further; fat mass accounted for 67.2% ± 8.5% of weight lost during leptin, versus 71% ± 6.7% during the initial 800-kcal/d weight loss. No significant gender or initial somatotype effects were noted, except lean subjects lost 10% of weight faster (mean 6 weeks) than obese subjects (mean 9 weeks).

Methods

  • Ten subjects (5 male, 5 female; 3 never-obese, 7 obese; mean ± SEM age 32.2 ± 2.9 years) were studied as inpatients at three weight plateaus: usual weight (Wtinitial), 10% reduced weight (Wt−10%), and 10% reduced weight during 5 weeks of twice-daily subcutaneous recombinant human leptin (A-100; Amgen) titrated to restore 8 am leptin to Wtinitial levels (Wt−10%lep).
  • Measurements included body composition by DXA; energy expenditure by weight-maintenance caloric titration, indirect calorimetry, and calculated NREE; skeletal muscle work efficiency by graded bicycle ergometry; autonomic function by heart-rate analysis during pharmacological blockade and 24-hour urinary catecholamines; and neuroendocrine measures by ELISA/RIA.
  • Intragroup comparisons used repeated-measures ANOVA; between-group comparisons used ANOVA; significance was prospectively defined as P < 0.05.

Limitations

  • Stated in the paper: twice-daily exogenous leptin does not mimic normal leptin pulsatility, and effects of weight reduction or exogenous leptin on leptin pulsatility in humans had not been reported; therefore 8 am leptin concentrations may not reflect total daily leptin or pulsatility.
  • Stated in the paper: organ-specific autonomic measures do not necessarily reflect systemic autonomic nervous system tone; longer studies are needed to determine whether chronic leptin-axis reactivation helps maintain reduced body weight.
  • Evident from the text: the study had only 10 subjects, some energy-expenditure and thyroid data from 4 subjects had been reported previously, and the leptin phase lasted 5 weeks, limiting generalizability and long-term inference.

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

Integrity signals

Registry

Crossref · 10.1172/jci25977

Cites

95 of 95 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 95 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    No significant effects of weight loss or leptin administration on resting energy expenditure (REE) or the thermic effect of feeding (TEF) beyond those predicted by changes in body composition were noted.

    “No significant effects of weight loss or leptin administration on resting energy expenditure (REE) or the thermic effect of feeding (TEF) beyond those predicted by changes in body composition were noted.”
    Quote in the paperNot a substantial claim
  • Findingown data

    At Wt-10%, circulating concentrations of T3 and T4 were reduced compared with Wt initial.

    “At Wt -10% , circulating concentrations of T3 and T4 were reduced compared with Wt initial .”
    Quote in the paperSubstantial claim
  • Findingown data

    The relationships among TEE, NREE, and body composition were restored at Wt-10%lep to levels present at Wt initial.

    “The relationships among TEE, NREE, and body composition were restored at Wt -10%lep to levels present at Wt initial (Figure 4).”
    Quote in the paperSubstantial claim
  • Findingcitation

    Extrapolating from RQ data, at Wt-10% there was an approximate 12% decrease compared with Wt initial in the percentage of calories derived from the oxidation of glucose during bicycling to generate 10 W of power.

    “Extrapolating from RQ data (31), at Wt -10% there was an approximate 12% decrease -compared with Wt initial -in the percentage of calories derived from the oxidation of glucose during bicycling to generate 10 W of power.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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  • Findingown data

    Administration of leptin to subjects ingesting the same number of calories required to maintain their weight at Wt-10% resulted in further reduction in body weight.

    “Administration of leptin to subjects ingesting the same number of calories required to maintain their weight at Wt -10% resulted in further reduction in body weight.”
    Quote in the paperSubstantial claim
  • May combine two claims. 32
  • Classified as probably not a substantial claim. 22
  • The quote only partly states this claim. 1

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    Findingcitation

    At Wt-10%, skeletal muscle work efficiency was increased and RQ was decreased at low levels of work (10 W) compared with subjects at Wt initial.

    “At Wt -10% , skeletal muscle work efficiency was increased and RQ was decreased at low levels of work (pedaling a bicycle ergometer to generate 10 W of power) compared with sub- jects at Wt initial , similar to our previous observations (3).”
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    Findingown data

    Lean subjects consistently required less time (mean 6 weeks) to lose 10% of their weight than obese subjects (mean 9 weeks).

    “No significant effects of gender or initial somatotype were noted on any results, except that lean subjects consistently required less time (mean 6 weeks) to lose 10% of their weight than obese subjects (mean 9 weeks).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    At Wt-10%lep, circulating T4 and T3 concentrations were, respectively, similar to and higher than those at Wt initial.

    “At Wt -10%lep , circulating T4 and T3 concentrations were, respectively, similar to and higher than those at Wt initial .”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    At Wt-10%, the gross mechanical efficiency (GME) of skeletal muscle while bicycling to generate 10 W of power was approximately 23% higher than at Wt initial and was fully reversed during leptin administration at Wt-10%lep.

    “At Wt -10% , the gross mechanical efficiency (GME) of skeletal muscle while bicycling to generate 10 W of power was approximately 23% higher than at Wt initial and was fully reversed during leptin administration at Wt -10%lep .”
    Quote in the paperSubstantial claim

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

    Findingown data

    No significant effects of gender or initial somatotype were noted on any results.

    “No significant effects of gender or initial somatotype were noted on any results, except that lean subjects consistently required less time (mean 6 weeks) to lose 10% of their weight than obese subjects (mean 9 weeks).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Loss of fat mass accounted for 67.2% ± 8.5% of the weight lost during leptin administration, similar to 71% ± 6.7% of weight lost as fat observed during weight loss on an 800-kcal/d diet from Wt initial to Wt-10%.

    “Loss of fat mass accounted for 67.2% ± 8.5% of the weight lost during leptin administration, similar to 71% ± 6.7% of weight lost as fat observed during weight loss on an 800-kcal/d diet from Wt initial to Wt -10% (Figure 3).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    When subjects who had lost 10% of initial body weight received subcutaneous leptin, plasma leptin concentrations at 8 am were significantly higher than those at Wt-10% and not significantly different from those at Wt initial.

    “When subjects who had lost 10% (Wt -10% ) of their initial body weight (Wt initial ) received subcutaneous leptin (Wt -10%lep ), plasma leptin concentrations at 8 am were significantly higher than those values observed at Wt -10% and not significantly different from those observed at Wt initial (Figure 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Maintenance of a 10% reduced body weight was associated with decreased SNS activity (measured by heart rate analysis and by urinary catecholamine excretion) and increased PNS activity (measured by heart rate analysis).

    “Maintenance of a 10% reduced body weight was associated with decreased SNS activity (measured by heart rate analysis and by urinary catecholamine excretion) and increased PNS activity (measured by heart rate analysis).”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Findingown data

    Mean total daily leptin doses relative to body mass at Wt-10% were 0.068 ± 0.01 mg/kg (range 0.019-0.121 mg/kg/d) divided q12 hours.

    “In the present study, mean ± SEM total daily leptin doses relative to body mass at Wt -10% were 0.068 ± 0.01 mg/kg (range 0.019-0.121mg/kg/d) divided q12 hours (8 am and 8 pm)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Administration of leptin to weight-reduced subjects reversed the decline in SNS activity and 24-hour urinary epinephrine excretion but did not significantly alter the decline in 24-hour urinary norepinephrine excretion or the increase in PNS activity.

    “Administration of leptin to weight-reduced subjects reversed the decline in SNS activity and 24-hour urinary epinephrine excretion but did not significantly alter the decline in 24-hour urinary norepinephrine excretion or the increase in PNS activity (Figure 6).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Administration of leptin to leptin-deficient rodents in doses that restore circulating leptin concentrations to their physiological range increases energy expenditure, decreases energy intake, increases SNS output, and normalizes hypothalamic-pituitary-adrenal, thyroid, and gonadal function.

    “Administration of leptin to leptindeficient rodents in doses that restore circulating leptin concentrations to their physiological range increases energy expenditure, decreases energy intake, increases SNS output (18,19), and normalizes hypothalamic-pituitary-adrenal, thyroid, and gonadal function (20)(21)(22)(23).”
    Quote in the paperSubstantial claim0 of 3 sources checked
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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Twice-daily administration of exogenous leptin does not mimic the normal pulsatility of leptin secretion.

    “It should be noted that twice-daily administration of exogenous leptin does not mimic the normal pulsatility of leptin secretion (27)(28)(29)(30)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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    Premisecitation

    No such effects were detected when leptin was administered in similar doses to eumenorrheic women without reduced fat mass.

    “no such effects were detected when leptin was administered in similar doses to eumenorrheic women without reduced fat mass.”
    Quote in the paperSubstantial claim0 of 1 sources checked
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    Premisecitation

    Leptin administration (0.08 mg/kg/d) to women with secondary hypothalamic amenorrhea due to reduced fat mass reversed the decline in hypothalamic-pituitary-gonadal axis function and raised circulating concentrations of triiodothyronine (T3) and thyroxine (T4).

    “Similarly, Welt et al. (26) reported that leptin administration (0.08 mg/kg/d) to women with secondary hypothalamic amenorrhea due to reduced fat mass reversed the decline in hypothalamic-pituitary-gonadal axis function and raised circulating concentrations of triiodothyronine (T3) and thyroxine (T4); no such effects were detected when leptin was administered in similar doses to eumenorrheic women”
    Quote in the paperSubstantial claim0 of 1 sources checked
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    Premisecitation

    Leptin administration to leptin-deficient humans decreases energy intake and increases activity of the hypothalamic-pituitary-thyroid axis.

    “Leptin administration to leptin-deficient humans decreases energy intake and increases activity of the hypothalamic-pituitary-thyroid axis (15,24).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
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    Premisecitation

    In weight-reduced subjects, sympathetic nervous system tone and circulating concentrations of leptin and bioactive thyroid hormones are reduced, while parasympathetic nervous system tone is increased.

    “In such subjects, sympathetic nervous system (SNS) tone and circulating concentrations of leptin and bioactive thyroid hormones are reduced, while parasympathetic nervous system (PNS) tone is increased (2)(3)(4)(5)(6)(7)(8)(9).”
    Quote in the paperSubstantial claim0 of 1 sources checked
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    Premisecitation

    The metabolic phenotypes of weight-reduced humans, leptin-deficient humans, and leptin-deficient rodents are similar but not identical.

    “The metabolic phenotypes of weight-reduced humans, leptindeficient humans, and leptin-deficient rodents are similar but not identical (13)(14)(15).”
    Quote in the paperSubstantial claim0 of 1 sources checked
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  • May combine two claims.

    Interpretationreasoning

    These in vivo responses of weight-reduced humans to leptin are concordant with in vitro and in vivo studies of leptin effects on skeletal muscle, autonomic nervous system activity, and neuroendocrine axes and demonstrate that leptin administration to weight-reduced subjects reverses many of the metabolic phenotypes that characterize the weight-reduced state.

    “These in vivo responses of weight-reduced humans to leptin are concordant with in vitro and in vivo studies of leptin effects on skeletal muscle, autonomic nervous system activity, and neuroendocrine axes and demonstrate that leptin administration to weight-reduced subjects reverses many of the metabolic phenotypes that characterize the weight-reduced state.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Both systemic and intracerebroventricular leptin administration increase insulin-mediated glucose uptake in rat skeletal muscle.

    “Both systemic and intracerebroventricular leptin administration increase insulin-mediated glucose uptake in rat skeletal muscle (36)(37)(38), and leptin increases both glucose and fatty acid oxidation in rodent skeletal muscle in vitro (34,36,(39)(40)(41)(42).”
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    Premisecitation

    Physiological responses to concentrations of leptin below and above the threshold are very asymmetrical: decreased concentrations of leptin trigger full-strength counterregulation to what is perceived as a threat to survival; concentrations of leptin above the threshold are not responded to vigorously, or at all.

    “Physiological responses to concentrations of leptin below and above this threshold are very asymmetrical: decreased concentrations of leptin trigger full-strength counterregulation to what is “perceived” as a threat to survival; concentrations of leptin above the threshold -signaling “sufficient” or excess fat stores -are not responded to vigorously, or at all (74).”
    Quote in the paperSubstantial claim0 of 1 sources checked
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  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationreasoning

    Leptin could affect skeletal muscle function via direct interaction with muscle cells and/or by engaging hypothalamic/brain stem pathways regulating autonomic and neuroendocrine function.

    “Leptin could affect skeletal muscle function via direct interaction with muscle cells and/or by engaging hypothalamic/brain stem pathways regulating autonomic and neuroendocrine function.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    These organ-specific measures of autonomic activity do not necessarily reflect systemic autonomic nervous system tone.

    “These organ-specific measures of autonomic activity do not necessarily reflect systemic autonomic nervous system tone.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Skeletal muscle expresses the short and long isoforms of the leptin receptor.

    “Skeletal muscle expresses the short and long isoforms of the leptin receptor (34), and incubation of skeletal muscle from lean mice with leptin stimulates oxygen consumption (35).”
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    Premisecitation

    Incubation of skeletal muscle from lean mice with leptin stimulates oxygen consumption.

    “Skeletal muscle expresses the short and long isoforms of the leptin receptor (34), and incubation of skeletal muscle from lean mice with leptin stimulates oxygen consumption (35).”
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    Premisecitation

    Similar doses of leptin decrease hunger and increase satiety in individuals who are hypoleptinemic by virtue of lipodystrophy.

    “Similar doses of leptin decrease hunger and increase satiety in individuals who are hypoleptinemic by virtue of lipodystrophy (70).”
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    Premisecitation

    Leptin increases both glucose and fatty acid oxidation in rodent skeletal muscle in vitro.

    “Both systemic and intracerebroventricular leptin administration increase insulin-mediated glucose uptake in rat skeletal muscle (36)(37)(38), and leptin increases both glucose and fatty acid oxidation in rodent skeletal muscle in vitro (34,36,(39)(40)(41)(42).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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    Interpretationown data

    These data suggest that changes in SNS, but not PNS, activity following weight loss are due to decreased circulating leptin concentrations.

    “These data suggest that that changes in SNS, but not PNS, activity following weight loss are due to decreased circulating leptin concentrations.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    These inferences are supported by direct effects of leptin on epinephrine release from porcine adrenal medullary cells and the increases in circulating concentrations of epinephrine and norepinephrine, renal sympathetic nerve activity, heart rate, arterial pressure, and sympathoexcitation of brown adipose tissue following systemic leptin infusion, or injection of leptin into the dorsomedial hypoth

    “These inferences are supported by direct effects of leptin on epinephrine release from porcine adrenal medullary cells (50) and the increases in circulating concentrations of epinephrine and norepinephrine, renal sympathetic nerve activity, heart rate, arterial pressure, and sympathoexcitation of brown adipose tissue (51-54) following systemic leptin infusion, or”
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    Premisecitation

    TSH bioactivity is decreased in low-TRH states, analogous to the low-TRH state of weight-reduced humans.

    “Increased TRH secretion increases TSH bioactivity in vitro and in vitro by apparent effects on sialation of TSH (63), and TSH bioactivity is decreased in low-TRH states (analogous to the low-TRH state of weight-reduced humans) (64)(65)(66)(67).”
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    Premisecitation

    In rats, the thyroid gland expresses the long isoform of the leptin receptor, and administration of leptin to euthyroid, leptin-sufficient animals increases circulating concentrations of T3 and T4, thyroid gland weight, and volume of the thyroid follicle epithelium without affecting circulating concentrations of TSH.

    “In rats, the thyroid gland expresses the long isoform of the leptin receptor, and administration of leptin to euthyroid, leptin-sufficient animals increases circulating concentrations of T3 and T4, thyroid gland weight, and volume of the thyroid follicle epithelium without affecting circulating concentrations of TSH (61,62).”
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    Interpretationown data

    Leptin-stimulated TRH release alone would not account for the observation that 5 weeks of leptin administration to weight-reduced subjects raised circulating concentrations of T3 and T4 but not TSH, nor the observation that 1-6 months of leptin administration to humans with congenital leptin deficiency raised circulating concentrations of bioactive thyroid hormones but not TSH.

    “Leptin-stimulated TRH release alone would not account for our observation that 5 weeks of leptin administration to weightreduced subjects raised circulating concentrations of T3 and T4 but not TSH, nor the observation of Farooqi et al. (15) that 1-6 months of leptin administration to humans with congenital leptin deficiency raised circulating concentrations of bioactive thyroid hormones but not”
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  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    This asymmetry permits the deposition of additional fat stores in environmental circumstances when this is possible, conveying survival advantage in most instances.

    “This asymmetry permits the deposition of additional fat stores in environmental circumstances when this is possible, conveying survival advantage in most instances.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Leptin-mediated SNS effects probably reflect both the peripheral stimulatory effects of leptin on adrenal epinephrine release and centrally mediated increases in sympathetic outflow.

    “Leptin-mediated SNS effects probably reflect both the peripheral stimulatory effects of leptin on adrenal epinephrine release and centrally mediated increases in sympathetic outflow.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Leptin deficiency is associated with decreased SNS tone as measured by blood pressure changes during a cold pressor test in humans and a leptin-reversible decline in brown adipose tissue thermogenesis in mice.

    “Leptin deficiency is associated with decreased SNS tone as measured by blood pressure changes during a cold pressor test in humans (46) and a leptin-reversible decline in brown adipose tissue thermogenesis in mice (47).”
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  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Pharmacologic and other strategies designed to maintain lost body weight may be more effective than those designed to induce weight loss.

    “Pharmacologic and other strategies designed to maintain lost body weight may, for these reasons, be more effective than those designed to induce weight loss (74).”
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  • Probably not a substantial claim: may not pass S3 (load-bearing). The quote only partly states this claim.

    Study design and conductown data

    The intraassay coefficients of variation for the catecholamine assays are less than 5%.

    “The intraassay coefficients of variation for these assays are less than 5%.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    SNS activity measured by pharmacological blockade reflects the action of catecholamines (predominantly norepinephrine) released at nerve endings and from the adrenal gland (predominantly epinephrine), as well as the sensitivity, number, and relative proportion of cardiac α and β-adrenoreceptors.

    “SNS activity measured by pharmacological blockade reflects the action of catecholamines (predominantly norepinephrine) released at nerve endings and from the adrenal gland (predominantly epinephrine), as well as the sensitivity, number, and relative proportion of cardiac αand β-adrenoreceptors (84).”
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    Premisecitation

    Regressions relating energy expenditure to body composition have a non-zero intercept.

    “To correct for the non-zero intercept of regressions relating energy expenditure to body composition (83), residual values of REE, TEE, and NREE were calculated for subjects at Wt-10% and Wt-10%lep as the difference between measured energy expenditures and values predicted from the regression equations relating energy expenditure to fat mass and fat-free mass at Wtinitial (83).”
    Quote in the paperSubstantial claim0 of 1 sources checked
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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    The interassay coefficients of variation for assays of dopamine, epinephrine, and norepinephrine are, respectively, 6.2%, 5.7%, and 7.1%.

    “The interassay coefficients of variation for assays of dopamine, epinephrine, and norepinephrine are, respectively, 6.2%, 5.7%, and 7.1%.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    In this model, the experiments described here are examples of restoration of circulating leptin concentrations to points above each subject's threshold with resultant reversal of leptin-insufficient/weight-reduced phenotypes.

    “In this model, the experiments described here are examples of restoration of circulating leptin concentrations to points above each subject's threshold with resultant reversal of leptin-insufficient/weight-reduced phenotypes.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: The threshold for determination of leptin sufficiency is determined by anatomic and functional characteristics of the hypothalamus and other parts of the brain that are, in turn, determined by genetic and developmental factors.

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

    Study design and conductnone given

    All women were in the follicular phase of their menstrual cycle at the start of testing.

    “All women were in the follicular phase of their menstrual cycle at the start of testing.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    In larger study groups, the order of testing and duration of time spent at reduced weight had no significant effect on any of these parameters.

    “In larger study groups, we have not found a significant effect of the order of testing or of duration of time spent at reduced weight on any of these parameters (2).”
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    Study design and conductown data

    Circulating leptin concentrations at 8 am were adjusted to be similar to those measured at 8 am at Wtinitial in subjects receiving leptin.

    “Circulating leptin concentrations at 8 am were measured weekly in subjects receiving leptin, and dosages were adjusted until circulating leptin concentrations were similar to those measured at 8 am at Wtinitial.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    The intra- and interassay coefficients of variation for leptin, TSH, T4, and T3 assays are less than 5%.

    “The intra-and interassay coefficients of variation for each of these assays are less than 5%.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductreasoning

    To prevent changes in physical fitness as a result of the 6-7 months in-patient stay, and to insure that subjects did not substantially vary their in-patient physical activity levels during the study, each subject's aerobic fitness was measured by bicycle ergometry upon admission and was then maintained at that level throughout the study.

    “To prevent changes in physical fitness as a result of the 6-7 months in-patient stay, and to insure that subjects did not substantially vary their in-patient physical activity levels during the study, either of which might affect skeletal muscle metabolism/performance, each subject's aerobic fitness was measured by bicycle ergometry upon admission and was then maintained at that level throughout”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Chemical energy content is 9.4 kcal/g wet weight of fat mass and 0.91 kcal/g wet weight of fat-free mass excluding bone.

    “Chemical energy content was assigned as 9.4 kcal/g wet weight of fat mass and 0.91 kcal/g wet weight of fat-free mass excluding bone (82).”
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  • The authors state this as an assumption.

    The threshold for determination of leptin sufficiency is determined by anatomic and functional characteristics of the hypothalamus and other parts of the brain that are, in turn, determined by genetic and developmental factors.

    “The threshold for determination of leptin sufficiency in this context is determined by anatomic and functional characteristics of the hypothalamus and other parts of the brain that are, in turn, determined by genetic and developmental factors.”
1 of 1

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?

  • To date there is limited evidence that leptin mediates thermogenesis via the SNS in humans.

    “In addition, leptin, released by white adipocytes, regulates energy balance by effects on the hypothalamus that lead to inhibition of food intake and increased thermogenesis via activation of the SNS, though to date there is limited evidence that leptin mediates thermogenesis via the SNS in humans 66–70.”

    From Cellular bioenergetics as a target for obesity therapy (2010) · cites this paper as [70]

  • Leptin, released by white adipocytes, regulates energy balance by effects on the hypothalamus that lead to inhibition of food intake and increased thermogenesis via activation of the SNS.

    “In addition, leptin, released by white adipocytes, regulates energy balance by effects on the hypothalamus that lead to inhibition of food intake and increased thermogenesis via activation of the SNS, though to date there is limited evidence that leptin mediates thermogenesis via the SNS in humans 66–70.”

    From Cellular bioenergetics as a target for obesity therapy (2010) · cites this paper as [70]

  • In weight-reduced humans, leptin administration at doses maintaining pre-weight-loss plasma levels blocks the reduction of sympathetic nervous system activity and metabolic rate.

    “In humans subjected to weight loss due to energy restriction, administration of leptin at doses that maintain pre-weight loss plasma levels blocks the reduction of sympathetic nervous system (SNS) activity and metabolic rate characteristic of the weight-reduced state (151).”

    From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [151]

Self-check

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

Each contradiction between two passages listed here was confirmed by an independent check.

  • Gross mechanical efficiency is defined in opposite directions

    Minor

    The Methods define gross mechanical efficiency as work generated divided by energy expended above rest. The Figure 4 caption describes energy expended above rest divided by work generated, its reciprocal.

1 of 1

Cites

Flagged first, then by citations

3 of the 98 references couldn’t be matched to a known paper.

Research works printed but not linked: 2

  1. Keesey, R.E. 1980. A set-point analysis of the regu- lation of body weight. In Obesity. A.J. Stunkard, editor. W.B. Saunders. Philadelphia, Pennsylvania, USA. 144-165.
  2. Miles, L. 1977. Chapter 4. In Handbook of radioimmu- noassay. G. Abraham, editor. Marcel Dekker. New York, New York, USA. 679-680.

Cited by

Sorted by citations

Related

Authors
Rosenbaum, M.
Affiliations
Columbia University Irving Medical Center (US)
Corresponding author
Rosenbaum, M.
ORCID
Rosenbaum, M.
Venue
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Published
2005-12-01
Volume
115
Issue
12
Pages
3579-3586
ISSN
0021-9738 (ISSN-L)
DOI
10.1172/jci25977
PMC
PMC1297250
OpenAlex
W2109742508
Semantic Scholar
126ea46d72a14873cc23d560a0eb4e0c3b639c19
Cited by
575
References
98
Citations by year
2026: 12 · 2025: 18 · 2024: 14 · 2023: 21 · 2022: 14 · 2021: 22 · 2020: 14 · 2019: 27 · 2018: 26 · 2017: 30 · 2016: 34 · 2015: 38 · 2014: 45 · 2013: 32 · 2012: 33
FWCI
9.17
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Investigation (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Amgen
  • National Institutes of Health (DK26687, RR-00645)
  • National Institute of Diabetes and Digestive and Kidney Diseases (P30 DK-26687, R01DK064773, DK64773, P30DK026687)
  • National Center for Research Resources (RR 00645, M01RR000645)
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, weight maintenance, weight loss, weight regain, energy expenditure, sympathetic tone, thyroxine, triiodothyronine, neuroendocrine adaptation, leptin deficiency, obesity, liquid formula diet
MeSH terms
Adult, Body Composition, Body Weight, Energy Intake, Calorimetry, Diet, Reducing, Energy Metabolism, Female, Humans, Male, Neurosecretory Systems, Obesity, Phenotype, Thyroxine, Time Factors, Triiodothyronine, Weight Loss, Body Mass Index, Muscle, Skeletal, 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.

What counts as a claim ›How we measure confidence ›How we check this ›

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