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Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight
Open accessAbstract
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.
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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.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight > Body composition.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“At Wt -10% , circulating concentrations of T3 and T4 were reduced compared with Wt initial .”
§ Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight > Skeletal muscle.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The relationships among TEE, NREE, and body composition were restored at Wt -10%lep to levels present at Wt initial (Figure 4).”
§ Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight > Body composition.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“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.”
§ Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight > Skeletal muscle.
What the sources say
- Not checked yetcites [31]
Strength:hedged· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight > Body composition.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“At all study periods, the respiratory quotient (RQ) at rest was not significantly different from the diet formula quotient (by bomb calorimetry) of 0.85.”
§ Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight > Body composition.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“At Wt -10% and Wt -10%lep , circulating thyroid-stimulating hormone (TSH) concentrations were significantly reduced compared with Wt initial values; no significant effects of leptin administration on circulating TSH concentrations were noted (Figure 5).”
§ Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight > Skeletal muscle.
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“At Wt -10% , 24-hour energy expenditure (TEE) and nonresting energy expenditure (NREE; energy expended in physical activity above resting) were decreased out of proportion to changes in body composition from Wt initial .”
§ Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight > Body composition.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
- It may state two separate claims as one. 32
- Probably not a substantial claim. 22
- The quote only partly states this claim. 1
In the paper
“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).”
§ Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight > Skeletal muscle.
What the sources say
- Not checked yetcites [3]
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight > Results
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“At Wt -10%lep , circulating T4 and T3 concentrations were, respectively, similar to and higher than those at Wt initial .”
§ Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight > Skeletal muscle.
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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 .”
§ Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight > Skeletal muscle.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight > Results
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight > Body composition.
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight > Results
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight > Autonomic function.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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)”
§ Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight > Results
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight > Autonomic function.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight > Introduction
What the sources say
- Not checked yetcites [18]
- Not checked yetcites [19]
- Not checked yetcites (20)(21)(22)(23)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“It should be noted that twice-daily administration of exogenous leptin does not mimic the normal pulsatility of leptin secretion (27)(28)(29)(30)”
§ Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight > Results
What the sources say
- Not checked yetcites (27)(28)(29)(30)
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“no such effects were detected when leptin was administered in similar doses to eumenorrheic women without reduced fat mass.”
§ Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight > Introduction
What the sources say
- Not checked yetcites [26]
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
In the paper
“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”
§ Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight > Introduction
What the sources say
- Not checked yetcites [26]
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Leptin administration to leptin-deficient humans decreases energy intake and increases activity of the hypothalamic-pituitary-thyroid axis (15,24).”
§ Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight > Introduction
What the sources say
- Not checked yetcites [15]
- Not checked yetcites [24]
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“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).”
§ Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight > Introduction
What the sources say
- Not checked yetcites (2)(3)(4)(5)(6)(7)(8)(9)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“The metabolic phenotypes of weight-reduced humans, leptindeficient humans, and leptin-deficient rodents are similar but not identical (13)(14)(15).”
§ Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight > Introduction
What the sources say
- Not checked yetcites (13)(14)(15)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“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).”
§ Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight > Discussion
What the sources say
- Not checked yetcites (36)(37)(38)
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“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).”
§ Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight > Discussion
What the sources say
- Not checked yetcites [74]
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✗ Based: failsProbably not a substantial claim. The paper may give no reason why it holds. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These organ-specific measures of autonomic activity do not necessarily reflect systemic autonomic nervous system tone.”
§ Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight > Discussion
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✗ Based: failsProbably not a substantial claim. The paper may give no reason why it holds.
In the paper
“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).”
§ Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight > Discussion
What the sources say
- Not checked yetcites [34]
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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).”
§ Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight > Discussion
What the sources say
- Not checked yetcites [35]
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Similar doses of leptin decrease hunger and increase satiety in individuals who are hypoleptinemic by virtue of lipodystrophy (70).”
§ Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight > Discussion
What the sources say
- Not checked yetcites [70]
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“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).”
§ Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight > Discussion
What the sources say
- Not checked yetcites (34,36,(39)(40)(41)(42)
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These data suggest that that changes in SNS, but not PNS, activity following weight loss are due to decreased circulating leptin concentrations.”
§ Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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”
§ Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight > Discussion
What the sources say
- Not checked yetcites [50]
- Not checked yetcites [51]
- Not checked yetcites [52]
- Not checked yetcites [53]
- Not checked yetcites [54]
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“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).”
§ Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight > Discussion
What the sources say
- Not checked yetcites (64)(65)(66)(67)
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight > Discussion
What the sources say
- Not checked yetcites [61]
- Not checked yetcites [62]
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“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”
§ Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight > Discussion
What the sources say
- Not checked yetcites [15]
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This asymmetry permits the deposition of additional fat stores in environmental circumstances when this is possible, conveying survival advantage in most instances.”
§ Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight > Discussion
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✗ Checkable: fails✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Leptin-mediated SNS effects probably reflect both the peripheral stimulatory effects of leptin on adrenal epinephrine release and centrally mediated increases in sympathetic outflow.”
§ Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight > Discussion
What the sources say
- Not checked yetcites [46]
- Not checked yetcites [47]
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“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).”
§ Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight > Discussion
What the sources say
- Not checked yetcites [74]
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The intraassay coefficients of variation for these assays are less than 5%.”
§ Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight > Skeletal muscle.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. The quote only partly states this claim.
In the paper
“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).”
§ Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight > Skeletal muscle.
What the sources say
- Not checked yetcites [84]
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
In the paper
“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).”
§ Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight > Subjects.
What the sources say
- Not checked yetcites [83]
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The interassay coefficients of variation for assays of dopamine, epinephrine, and norepinephrine are, respectively, 6.2%, 5.7%, and 7.1%.”
§ Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight > Skeletal muscle.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- 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.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All women were in the follicular phase of their menstrual cycle at the start of testing.”
§ Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight > Skeletal muscle.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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).”
§ Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight > Skeletal muscle.
What the sources say
- Not checked yetcites [2]
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight > Subjects.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The intra-and interassay coefficients of variation for each of these assays are less than 5%.”
§ Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight > Skeletal muscle.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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”
§ Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight > Subjects.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may state two separate claims as one.
In the paper
“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).”
§ Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight > Subjects.
What the sources say
- Not checked yetcites [82]
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may state two separate claims as one.
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.”
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?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In fact, replacing leptin during maintenance of reduced weight reversed two-thirds of the fall in TEE and AEE while increasing work efficiency in skeletal muscle [64, 65•].”
From Changes in energy expenditure with weight gain and weight loss in humans (2016) · cites this paper as [64]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Taken together, there was no thermogenic effect of leptin in subjects at usual weight and during weight loss.”
From Changes in energy expenditure with weight gain and weight loss in humans (2016) · cites this paper as [64]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“It should be mentioned that controlling body weight after gradual weight loss (as done in ref) [17, 64, 65•] does not follow a physiological response but may interfere with biology.”
From Changes in energy expenditure with weight gain and weight loss in humans (2016) · cites this paper as [64]
The cited source says what the claim attributes to it.
In the citing paper
“By contrast, an effect of exogenous leptin administration was seen in weight-stable-weight-reduced subjects only [64, 75•].”
From Changes in energy expenditure with weight gain and weight loss in humans (2016) · cites this paper as [64]
In the citing paper
“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 the citing paper
“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 the citing paper
“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
MinorThe 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.
“Skeletal muscle work efficiency was expressed as gross mechanical efficiency (GME): the ratio of power generated in kcal/ min to change in energy expenditure above REE in kcal/min at power outputs of 10 W and 25 W (3).”
“Effects of weight loss and exogenous leptin on skeletal muscle gross mechanical work efficiency (kcal/min energy expended above resting per kcal/min work generated) and fuel utilization (derived from RQ; ref. 87) were only evident at low levels of work (bicycling to generate 10 W of power).”
Citations
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Congenital leptin deficiency is associated with severe early-onset obesity in humans
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Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase
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Self-citationEffects of Recombinant Leptin Therapy in a Child with Congenital Leptin Deficiency
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Flagged first, then by citations
4 of the 98 references couldn’t be matched to a known paper.
Research works printed but not linked: 2
- 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.
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Aproximaciones farmacológicas para el tratamiento de la obesidad
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Sympathetic vascular tone in human obesity
Correia, M. (2007) · doi:10.17077/etd.v54kf0if · Cited by 1
Fetal and Infant Origins of Obesity
Gillman, M. W. (2009) · Wiley eBooks · doi:10.1002/9781444307627.ch8 · Cited by 1
How humans economize: energy restriction and end energy expenditure
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Shimer, S. E. (2012) · ResearchWorks at the University of Washington (University of Washington) · Cited by 1
Weight management and exercise: any advantage?
Bray, G. A. (2016) · American Journal of Clinical Nutrition · doi:10.3945/ajcn.116.141499 · Cited by 1
Glucagon-like peptide-1 (GLP-1) and satiation
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Gene analysis for studying the process of weight regain after weight loss
Roumans (2017) · Research Publications (Maastricht University) · doi:10.26481/dis.20170623nr · Cited by 1
The Physiology of Bodyweight Regulation
Coll, A. P. (2022) · doi:10.1093/med/9780198870197.003.0222 · Cited by 1
Caron, N. (2017) · theses.fr (ABES) · doi:10.70675/1e6fa961ze502z41d8za0f1zbe09d9b80e6f · Cited by 1
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Wabitsch, M., Fuchs, M., Horenburg, S., Denzer, C., von Puttkamer, J., Moß, A., Lahr, G., & Fischer‐Posovszky, P. (2008) · KARGER eBooks · doi:10.1159/000158563
The Neurogenetics of Energy Balance
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Examining the Effects of Weight Loss on Energy Expenditure in Humans
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Wuorinen, E. C., Cowens, K., Wuorinen, S., LeClerc, S., & Wuorinen, J. (2014) · Open Journal of Molecular and Integrative Physiology · doi:10.4236/ojmip.2014.43005
Cell volume: Role in obesity and its maintenance minireview
Vladimír, S. (2013) · Serbian Journal of Experimental and Clinical Research · doi:10.5937/sjecr14-4141
Pharmacological Management of the Obese Patient
Schumacher, D. (2013) · American Journal of Lifestyle Medicine · doi:10.1177/1559827613504733
Advanced neuroimaging in obesity
Dunn, J. P., & Abumrad, N. N. (2010) · Expert Review of Endocrinology & Metabolism · doi:10.1586/eem.09.77
Modulació farmacològica de l'oleoil-estrona sobre la ingesta i la composició corporal
Lorente, R. F. (2007) · LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas)
The role of leptin in eating disorders - current views
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Gibt es die Adaptive Thermogenese?
Enderle, J., Braun, W., Pourhassan, M., Bosy‐Westphal, A., & Müller, M. J. (2015) · Adipositas - Ursachen Folgeerkrankungen Therapie · doi:10.1055/s-0037-1618940 · Cited by 1
Leptin Therapy in Women with Hypothalamic Amenorrhea
Chou, S. H.-H., & Mantzoros, C. S. (2014) · Springer eBooks · doi:10.1007/978-3-319-09915-6_19
Wechselwirkungen zwischen Fettzellen und Gehirn
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Modification and Incorporation of an At-Home Exercise Regimen
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Nusbaum, M. J., Rothkopf, M. M., & Haverstick, L. P. (2014) · CRC Press eBooks · doi:10.1201/b17616-5
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Ravussin, É. (2015) · Cahiers de Nutrition et de Diététique · doi:10.1016/s0007-9960(15)30012-2
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Advances in Pharmacological Treatment of Pediatric Obesity
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Ahima, R. S., Scolaro, L. M., & Park, H.-K. (2017) · Springer eBooks · doi:10.1007/978-3-319-12125-3_24-2
Bray, G. A. (2010) · Elsevier eBooks · doi:10.1016/b978-1-4160-6189-2.00006-8
(2006) · Current Opinion in Endocrinology & Diabetes · doi:10.1097/01.med.0000244230.06529.0f
Clinical Evaluation, Lifestyle, and Pharmacological Management of Obesity
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Leptin and the Intersection of Cardiovascular Disease, Metabolism, and Adipose Tissue
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Energy Balance and Body Weight Homeostasis
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Anti-Obesity Agents on the Horizon
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Weight Loss Plateau: Reasons, Challenges, and Solutions: A Narrative Review
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Metadata
- Authors
- Rosenbaum, M.
- Affiliations
- Columbia University Irving Medical Center (US)
- Corresponding author
- Rosenbaum, M.
- ORCID
- Rosenbaum, M.
- Venue
- Journal of Clinical Investigation
- Published
- 2005-12-01
- Volume
- 115
- Issue
- 12
- Pages
- 3579-3586
- ISSN
- 0021-9738 (ISSN-L)
- 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
- bronze
- doi.org
- 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 › Endocrinology, Diabetes and Metabolism › 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.
A language model drew the claims from the paper on 2026-10-09, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-09 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
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