CoChat
Sign Up
Cited by 240Circadian rhythm and melatoninRegulation of Appetite and ObesityAdipokines, Inflammation, and Metabolic Diseases

Independent circadian and sleep/wake regulation of adipokines and glucose in humans

Open access
Shea, Steven A., Hilton, Michael F., Orlova, Christine, Ayers, R. Timothy, Mantzoros, Christos S.·2005·The Journal of Clinical Endocrinology & Metabolism
DOI 10.1210/jc.2004-2232PMC PMC2885832
Open this paper in CoChat — free accountOpen PDF

Abstract

Leptin and adiponectin play important physiological roles in regulating appetite, food intake, and energy balance and have pathophysiological roles in obesity and anorexia nervosa. To assess the relative contributions of day/night patterns in behaviors (sleep/wake cycle and food intake) and of the endogenous circadian pacemaker on observed day/night patterns of adipokines, in six healthy subjects we measured circulating leptin, soluble leptin receptor, adiponectin, glucose, and insulin levels throughout a constant routine protocol (38 h of wakefulness with constant posture, temperature, and dim light, as well as identical snacks every 2 h) and throughout sleep and fasting periods before and after the constant routine. There were significant endogenous circadian rhythms in leptin, glucose, and insulin, with peaks around the usual time of awakening. Sleep/fasting resulted in additional systematic decreases in leptin, glucose, and insulin, whereas wakefulness/food intake resulted in a systematic increase in leptin. Thus, the day/night pattern in leptin is likely caused by combined effects from the endogenous circadian pacemaker and day/night patterns in behaviors. Our data imply that alterations in the sleep/wake schedule would lead to an increased daily range in circulating leptin, with lowest leptin upon awakening, which, by influencing food intake and energy balance, could be implicated in the increased prevalence of obesity in the shift work population.

AI snapshot

Written from the paper’s full text.

TL;DR

In six healthy subjects, a 38-h constant routine separated endogenous circadian effects from sleep/wake and fasting/feeding effects on adipokines and glucose. Leptin, glucose, and insulin had significant endogenous circadian rhythms peaking near usual awakening, while sleep/fasting and wakefulness/meals produced independent changes in leptin, glucose, and insulin.

Key findings

  • Significant group mean circadian rhythms were found for leptin (peak-to-trough 16% of mesor; individual amplitudes averaged 1.4 ng/ml, 21% around a leptin mesor of 6.5 ng/ml; 4/6 subjects significant), insulin (22%, P = 0.02), and glucose (10%, P = 0.001), with peaks around the usual time of awakening. No group mean circadian rhythm was detected for soluble leptin receptor (sOB-R) or adiponectin.
  • Independent of circadian effects, all six subjects had a significant linear increase in leptin during prolonged wakefulness/meals: average +3.33 ng/ml over 16 h, a 51% fluctuation around the leptin mesor of 6.5 ng/ml. sOB-R decreased by 3.2 ng/ml per 16 h (19% around mesor 16.3 ng/ml), and adiponectin showed a small significant group decline of 0.18 g/ml over 16 h (4% around mesor 4.05 g/ml), though only one subject had a significant individual decline.
  • Independent of circadian effects, each subject had a significant decrease in leptin across sleep/fasting: mean −0.6 ng/ml per hour (range −0.34 to −1.10), equivalent to −4.8 ng/ml over 8 h, a 74% fluctuation around the leptin mesor of 6.5 ng/ml. Sleep/fasting also decreased insulin by −0.45 IU/ml per hour (−3.6 IU/ml over 8 h; 36% around mesor 10.1 IU/ml) and glucose by −0.65 mg/dl per hour (−5.2 mg/dl over 8 h; 5% around mesor 103.4 mg/dl), with no independent sleep-related changes in sOB-R or adiponectin.
  • The authors conclude that the day/night leptin pattern reflects combined endogenous circadian and behavioral effects, and that altered sleep/wake schedules could increase the daily range in circulating leptin, with lowest leptin upon awakening, potentially relevant to shift-work-related obesity.

Methods

  • Six healthy subjects were studied with a 38-h constant routine protocol: continuous wakefulness, constant semirecumbent posture, constant temperature (~23 ± 2 C), dim light (<8 lux), and identical snacks every 2 h. Sleep and fasting periods were also measured before and after the constant routine, each with 10-h sleep opportunities.
  • Hourly blood samples were assayed for leptin, sOB-R, adiponectin, glucose, and insulin; core body temperature was recorded rectally as a circadian phase marker, and sleep was scored from EEG, EOG, and submental EMG.
  • Circadian phase and amplitude were estimated by cosinor analysis relative to the core body temperature minimum (CBTmin); group circadian effects were assessed after subtracting individual linear trends, and behavioral effects were assessed after subtracting individual circadian rhythms, using linear regression aligned to the sleep/wake schedule. The average circadian period was 24.6 h (SEM = 0.2 h).

Limitations

  • The paper states that separating circadian and behavioral effects relies on the assumption that these effects are additive; this needs direct testing, such as a forced desynchrony study.
  • The paper states that it could not independently assess meals from wakefulness, or fasting from sleep, though it argues fasting and meals likely have greater effects than sleep and wakefulness.
  • The paper notes that its findings differ from sleep-restriction studies, raising the possibility that incremental sleep restriction differs from acute sleep deprivation, and calls for longer experiments. Evident from the text: the sample was small (six subjects), and the analysis of sleep periods before and after the constant routine relied on extrapolating the circadian component from constant-routine data.

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

Integrity signals

Registry

Crossref · 10.1210/jc.2004-2232

Cites

56 of 56 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 37 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    There were significant mean group circadian variations in both glucose and insulin.

    “There were significant mean group circadian variations in both glucose and insulin (Fig. 2, lower left).”
    Quote in the paperSubstantial claim
  • Findingown data

    There were no independent sleep-related changes in sOB-R or adiponectin.

    “There were no independent sleep-related changes in sOB-R or adiponectin, but there were independent sleeprelated decreases in both glucose and insulin.”
    Quote in the paperSubstantial claim
  • Findingown data

    Prolonged wakefulness was associated with a significant group mean decrease in sOB-R equivalent to 3.2 ng/ml per 16 h of continuous wakefulness (19% variability around the sOB-R mesor of 16.3 ng/ml).

    “As leptin was increasing, prolonged wakefulness was associated with a significant group mean decrease in sOB-R equivalent to 3.2 ng/ml per 16 h of continuous wakefulness (i.e.19% variability around the sOB-R mesor of 16.3 ng/ml).”
    Quote in the paperSubstantial claim
  • Findingown data

    In overweight but nonobese subjects (average BMI 25 kg/m2), there is no significant circadian rhythm of adiponectin.

    “Results in our overweight, but nonobese, subjects in the current study (average BMI, 25 kg/m 2 ) indicated a lack of a significant circadian rhythm of adiponectin.”
    • Also stated in: § Discussion · plain
      “In contrast, there was no detectable circadian rhythm in either circulating sOB-R or adiponectin levels (right panels).”
    • Also stated in: § Discussion · plain
      “but no circadian rhythms in sOB-R or adiponectin.”
    Quote in the paperSubstantial claim
  • Findingown data

    Four of the six subjects had a significant circadian rhythm in circulating leptin (P < 0.05).

    “Four of the six subjects had a significant circadian rhythm in circulating leptin (P Ͻ 0.05).”
    Quote in the paperNot a substantial claim
  • May combine two claims. 24
  • Classified as probably not a substantial claim. 17

  • May combine two claims.

    Findingown data

    Sleep/fasting causes significant systematic reductions in both glucose and insulin.

    “We found that sleep/fasting causes significant systematic reductions in both glucose and insulin, which is consistent with data from the second half of the sleep periods in these earlier studies.”
    • Also stated in: § Discussion · plain
      “In addition, we detected systematic decreases in leptin, glucose, and insulin attributable to the effects of sleep/fasting, and a systematic increase in leptin attributable to wakefulness/food intake.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The mean reduction in circulating glucose was -0.65 mg/dl per hour, equivalent to -5.2 mg/dl over the usual sleep period of 8 h (reduction in glucose of 5% around the mesor of 103.4 mg/dl).

    “The mean reduction in circulating glucose was Ϫ0.65 mg/dl per hour, equivalent to Ϫ5.2 mg/dl over the usual sleep period of 8 h (reduction in glucose of 5% around the mesor of 103.4 mg/dl).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Both insulin and glucose levels were highest in the morning, with a substantial peak in the circadian component of insulin around the time of usual awakening.

    “Both the insulin and glucose levels were highest in the morning, with a substantial peak in the circadian component of insulin around the time of usual awakening (although all of these measurements were made during continued wakefulness and with regular small snacks).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    This is equivalent to 4.8 ng/ml over the usual period of 8 h of sleep, representing an independent sleep/fasting-related fluctuation of 74% around the leptin mesor of 6.5 ng/ml.

    “This is equivalent to 4.8 ng/ml over the usual period of 8 h of sleep, representing an independent sleep/fasting-related fluctuation of 74% around the leptin mesor of 6.5 ng/ml (Fig. 3).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    None of the subjects had a significant circadian rhythm in sOB-R, and there was no group mean circadian rhythm.

    “None of the subjects had a significant circadian rhythm in sOB-R, and there was no group mean circadian rhythm although a very small amplitude, approximately 12 h harmonic, was detected (P ϭ 0.04), presumably representing a small ultradian rhythm in sOB-R as shown in Fig. 2 (top right).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The endogenous circadian system caused a steady increase in leptin across the time that corresponds to the habitual sleep period, with a peak just after the usual time of awakening and a trough in the afternoon.

    “Although all of these measurements were made during continued wakefulness, it can be seen that the endogenous circadian system caused a steady increase in leptin across the time that corresponds to the habitual sleep period in this group of subjects (with a peak just after the usual time of awakening, and a trough in the afternoon).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The peak-to-trough amplitude of the circadian rhythms was approximately 22% for insulin (P = 0.02) and 10% for glucose (P = 0.001).

    “The peak-totrough amplitude of the circadian rhythms was approximately 22% for insulin (P ϭ 0.02) and 10% for glucose (P ϭ 0.001).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The rate of fall of circulating leptin during sleep/fasting was almost identical in the baseline period and during recovery sleep, despite improvements in average sleep efficiency, decreased sleep onset latency, and an average increase in nonrapid-eye-movement sleep stages III and IV.

    “The rate of fall of circulating leptin during sleep/fasting was almost identical in the baseline period and during recovery sleep (Fig. 3), despite improvements in average sleep efficiency (5.5% absolute increase; P Ͻ 0.01, paired t test), decreased sleep onset latency (13 min; not significant), and an average increase in nonrapid-eye-movement sleep stages III and IV (6.1% absolute increase; P Ͻ 0”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Healthy humans have an endogenous circadian rhythm of glucose and insulin, with a peak at the usual time of awakening, similar to the circadian-related peak in leptin.

    “We show that healthy humans do have an endogenous circadian rhythm of glucose and insulin, with a peak at the usual time of awakening, at a time similar to that of the circadian-related peak in leptin (Fig. 2).”
    • Also stated in: § Discussion · plain
      “There were significant circadian rhythms in circulating leptin, glucose, and insulin (left panels).”
    • Also stated in: § Discussion · plain
      “The circadian system caused a steady increase in leptin across the usual sleep period and increases in both insulin and glucose around the time of habitual awakening.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Adiponectin concentrations were relatively stable, with only one subject showing an endogenous circadian rhythm, and there was no group mean circadian rhythm in adiponectin.

    “Adiponectin concentrations were relatively stable, with only one subject showing an endogenous circadian rhythm, and there was no group mean circadian rhythm in adiponectin (Fig. 2, lower right).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    For the group, the circadian variation in circulating leptin was highly significant (P < 0.0001), with a peak-to-trough value, over the 24 h, of 16% of the mesor.

    “For the group, the circadian variation in circulating leptin was highly significant (P Ͻ 0.0001), with a peak-totrough value, over the 24 h, of 16% of the mesor.”
    Quote in the paperSubstantial claim

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

    Findingown data

    A very small amplitude, approximately 12 h harmonic, was detected in sOB-R (P = 0.04).

    “None of the subjects had a significant circadian rhythm in sOB-R, and there was no group mean circadian rhythm although a very small amplitude, approximately 12 h harmonic, was detected (P ϭ 0.04), presumably representing a small ultradian rhythm in sOB-R as shown in Fig. 2 (top right).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingreasoning

    With sleep occurring at the usual phase of the circadian rhythm, circadian and behavioral fluctuations are almost out of phase and cancel each other to a large extent, producing a leptin profile that peaks during the usual sleep period, declines throughout the rest of the night, increases throughout the morning, plateaus for approximately 8 h during the daytime, and rises again in the 3 h before

    “With sleep occurring at the usual phase of the circadian rhythm (left panel of Fig. 4), circadian and behavioral fluctuations are almost out of phase and cancel each other to a large extent: leptin reaches a peak during the usual sleep period, declines throughout the rest of the night, begins to increase throughout the morning, reaches a plateau for approximately 8 h during the daytime, and then”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: The circadian and behavioral effects on the measured variables are additive.

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

    Study design and conductnone given

    Plasma leptin levels were measured using a RIA with a sensitivity of 0.5 ng/ml and intraassay CV of 8.3%.

    “Plasma leptin levels were measured using a RIA (DSL) with a sensitivity of 0.5 ng/ml and intraassay CV of 8.3%.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Plasma insulin was assayed using a paramagnetic-particle chemiluminescent immunoassay with a sensitivity of 0.03 IU/ml and an average intraassay CV of 3.1-5.6%.

    “Plasma insulin was assayed using a commercially available paramagnetic-particle chemiluminescent immunoassay (Beckman Access B; Diamond Diagnostics, Holliston, MA) with a sensitivity of 0.03 IU/ml and an average intraassay CV of 3.1-5.6%.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Adipokines play important physiological and pathophysiological roles in obesity and the metabolic syndrome.

    “Because adipokines play important physiological and pathophysiological roles in obesity and the metabolic syndrome (31), these findings may provide potentially important implications in situations when physiological behaviors and the circadian system become misaligned, such as with jet lag, shift work, or clinical conditions such as the nocturnal eating syndrome (32)(33)(34).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31]

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Core body temperature was recorded throughout using a rectal temperature sensor to provide a marker of the endogenous circadian pacemaker.

    “Core body temperature was recorded throughout using a rectal temperature sensor (Yellow Springs Instrument Co., Inc., Yellow Springs, OH) to provide a marker of the endogenous circadian pacemaker.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    There are day/night patterns in plasma leptin and adiponectin concentrations, with leptin rising and adiponectin falling during the night.

    “There are day/night patterns in plasma leptin and adiponectin concentrations, with leptin rising (8 -12) and adiponectin falling during the night (13).”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [8]

      Not checked in the free run.

    • cites [9]

      Not checked in the free run.

    • cites [10]

      Not checked in the free run.

    • cites [11]

      Not checked in the free run.

    • cites [12]

      Not checked in the free run.

    • cites [13]

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The decline in adiponectin during wakefulness is presumably of little physiological consequence because only one of the six subjects had a significant linear decline in adiponectin across the constant routine.

    “However, this is presumably of little physiological consequence because only one of the six subjects had a significant linear decline in adiponectin across the constant routine.”
    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

    Plasma glucose was assayed using an ACE glucose reagent with a sensitivity of 1 mg/dl and an average intraassay CV less than 2%.

    “Plasma glucose was assayed using a commercially available assay (ACE glucose reagent; Alfa Wassermann, West Caldwell, NJ) with a sensitivity of 1 mg/dl and an average intraassay CV less than 2%.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    The schedule was verified by time-logged telephone calls of bedtimes and waketimes for 2 wk as well as activity monitoring for 3-7 d.

    “This schedule was verified by time-logged telephone calls of bedtimes and waketimes for 2 wk as well as activity monitoring for 3-7 d (wrist-worn Actigraph; Ambulatory Monitoring, Ardsley, NY).”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    Plasma adiponectin levels were measured using a RIA with a sensitivity of 2 ng/ml and intraassay CV of 6.6%.

    “Plasma adiponectin levels were measured using a RIA from Diagnostics Systems Laboratory (DSL, Webster, TX) with a sensitivity of 2 ng/ml and intraassay coefficient of variation (CV) of 6.6%.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Because the circadian fluctuation in sOB-R was less than the fluctuation in total leptin, the biologically active free leptin had a circadian variation.

    “Because the circadian fluctuation in sOB-R was less than the fluctuation in total leptin, this implies that the biologically active free leptin had a circadian variation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    These data suggest that the previously documented day/night pattern in leptin is caused by the combined effects of the endogenous circadian pacemaker and the day/night patterns in behaviors, with the latter having the greater effect across the 24-h cycle.

    “Therefore, these data suggest that the previously documented day/night pattern in leptin is caused by the combined effects of the endogenous circadian pacemaker and the day/night patterns in behaviors, with the latter having the greater effect across the 24-h cycle.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationreasoning

    These findings may provide potentially important implications in situations when physiological behaviors and the circadian system become misaligned, such as with jet lag, shift work, or clinical conditions such as the nocturnal eating syndrome.

    “Because adipokines play important physiological and pathophysiological roles in obesity and the metabolic syndrome (31), these findings may provide potentially important implications in situations when physiological behaviors and the circadian system become misaligned, such as with jet lag, shift work, or clinical conditions such as the nocturnal eating syndrome (32)(33)(34).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Leptin levels have a robust 24-h rhythm, with leptin increasing monotonically from the morning through the afternoon and evening and peaking in the early part of the nocturnal sleep period.

    “Leptin levels have a robust 24-h rhythm (8 -12), with leptin increasing monotonically from the morning through the afternoon and evening and peaking in the early part of the nocturnal sleep period.”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [8]

      Not checked in the free run.

    • cites [9]

      Not checked in the free run.

    • cites [10]

      Not checked in the free run.

    • cites [11]

      Not checked in the free run.

    • cites [12]

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    All temperature, hormonal and glucose data collected in the first 5 h of the constant routine were excluded from analysis to avoid the effects of altered posture and sleep-wake transition.

    “All temperature, hormonal and glucose data collected in the first 5 h of the constant routine were excluded from analysis to avoid the effects of altered posture and sleep-wake transition.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Alterations in the sleep/wake schedule would lead to an increased daily range in circulating leptin, with lowest leptin upon awakening.

    “Our data imply that alterations in the sleep/wake schedule would lead to an increased daily range in circulating leptin, with lowest leptin upon awakening”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    The constant routine protocol is designed to unmask underlying circadian rhythms as it reduces or eliminates other physiological influences from the environment, varied behaviors, large meals, and sleep.

    “The constant routine protocol is designed to unmask underlying circadian rhythms as it reduces or eliminates other physiological influences from the environment, varied behaviors, large meals, and sleep.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [25]

      Not checked in the free run.

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

    Study design and conductnone given

    Plasma sOB-R levels were measured using an ELISA with a sensitivity of 0.8 ng/ml and intraassay CV between 5.5 and 6.6%.

    “Plasma sOB-R levels were measured using a commercially available ELISA (DSL) with a sensitivity of 0.8 ng/ml and intraassay CV between 5.5 and 6.6%.”
    Quote in the paperNot a substantial claim

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

    Interpretationown data

    The 12 h harmonic in sOB-R presumably represents a small ultradian rhythm.

    “None of the subjects had a significant circadian rhythm in sOB-R, and there was no group mean circadian rhythm although a very small amplitude, approximately 12 h harmonic, was detected (P ϭ 0.04), presumably representing a small ultradian rhythm in sOB-R as shown in Fig. 2 (top right).”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Leptin administration is effective in regulating insulin resistance in hypoleptinemic states, including both congenital leptin deficiency and acquired states of leptin deficiency.

    “In addition, leptin administration is also effective in regulating insulin resistance in hypoleptinemic states, including both congenital leptin deficiency and acquired states of leptin deficiency (1,31,49).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [1]

      Not checked in the free run.

    • cites [31]

      Not checked in the free run.

    • cites [49]

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The increased peak-to-trough daily swing in circulating free leptin may influence food intake and energy balance and could be implicated in the increased obesity and cardiovascular disease in the shift work population.

    “Our data imply that alterations in the sleep/wake schedule can lead to an increased peak-to-trough daily swing in the physiologically active circulating free leptin, which may influence food intake and energy balance and could thus be implicated in the increased obesity and cardiovascular disease in the shift work population (15).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [15]

      Not checked in the free run.

    • The authors state this as an assumption: The circadian and behavioral effects on the measured variables are additive.

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

    Premisecitation

    Common obesity is associated with hyperleptinemia in humans.

    “Although common obesity is associated with hyperleptinemia in humans (44 -46), subjects with leptin receptor mutation(s), as well as hypoleptinemic subjects with either congenital or acquired leptin deficiency, are also obese (47-48).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [44]

      Not checked in the free run.

    • cites [45]

      Not checked in the free run.

    • cites [46]

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    In this model, a person awakening at an unusual circadian phase would have a very low level of leptin, which would be expected to increase appetite and alter neuroendocrine function at that time.

    “Moreover, in this model, the person would awaken with a very low level of leptin, which would be expected to increase appetite and alter neuroendocrine function at this time (4, 43).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [4]

      Not checked in the free run.

    • cites [43]

      Not checked in the free run.

    • The authors state this as an assumption: The circadian and behavioral effects on the measured variables are additive.

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

    Premisecitation

    Subjects with leptin receptor mutations, as well as hypoleptinemic subjects with either congenital or acquired leptin deficiency, are also obese.

    “Although common obesity is associated with hyperleptinemia in humans (44 -46), subjects with leptin receptor mutation(s), as well as hypoleptinemic subjects with either congenital or acquired leptin deficiency, are also obese (47-48).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [47]

      Not checked in the free run.

    • cites [48]

      Not checked in the free run.

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

    Interpretationcitation

    The nocturnal eating in patients with nocturnal eating disorders could be a result of the absence of a nocturnal anorexic signal provided by leptin.

    “suggesting that their nocturnal eating could be a result of the absence of a nocturnal anorexic signal provided by leptin (14).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14]

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The day/night pattern in adiponectin in lean individuals is mainly attributable to day/night patterns in behaviors (sleep/fasting and wakefulness/meals) rather than the endogenous circadian cycle, and this effect can be observed in obese individuals.

    “These differences among studies suggest that the day/night pattern in adiponectin (13) in lean individuals is mainly attributable to day/night patterns in behaviors (sleep/fasting and wakefulness/meals) rather than the endogenous circadian cycle and that this effect can be observed in obese individuals.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13]

      Not checked in the free run.

38 of 38

  • The authors state this as an assumption.

    The circadian component could be extrapolated from the constant routine data to the sleep periods on either side of the constant routine.

    “Because circadian rhythmicity was calculated during the constant routine, this last analysis relied upon our assumption that the circadian component could be extrapolated from the constant routine data to the sleep periods on either side of the constant routine.”

  • The paper relies on this without support.

    To the authors' knowledge, this study is the first to directly assess the independent influences of the endogenous circadian pacemaker and various physiological behaviors on adipocyte and glucose physiology using a validated circadian protocol.

    “to our knowledge, this study is the first to directly assess the independent influences of the endogenous circadian pacemaker and various physiological behaviors on adipocyte and glucose physiology using a validated circadian protocol.”

  • The authors state this as an assumption.

    The circadian and behavioral effects on the measured variables are additive.

    “Limitations of the study include the fact that our separation of circadian and behavioral effects relies upon the assumption that these effects are additive, as suggested by the statistical analyses.”
3 of 3

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?

  • Human endogenous circadian rhythms have been observed in glucose, insulin, cortisol, epinephrine, norepinephrine, and leptin.

    “For example, glucose, insulin, cortisol, epinephrine, norepinephrine, and leptin display endogenous circadian variation (Morgan et al., 1998; Scheer et al., 2009, 2010; Shea et al., 2005; Van Cauter et al., 1994; Wehr et al., 2001).”

    From The impact of the circadian timing system on cardiovascular and metabolic function (2012) · cites this paper as Shea et al., 2005

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.

  • Wakefulness-related leptin increase uses conflicting units

    Minor

    The wakefulness-related increase is reported as 3.33 ng/ml over 16 hours, but later as 0.21 mg/ml per hour. The hourly figure is consistent with the earlier increase only if its unit is ng/ml, not mg/ml.

  • Adiponectin variation in obese subjects is both absent and observable

    Minor

    The discussion says a study in obese subjects failed to demonstrate the day/night variation in adiponectin, then says that this effect can be observed in obese individuals.

2 of 2

Cites

Flagged first, then by citations

2 of the 58 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

Related

Authors
Shea, S. A., Hilton, M. F., Orlova, C., Ayers, R. T., & Mantzoros, C. S.
Affiliations
  • Brigham and Women's Hospital (US)
  • Beth Israel Deaconess Medical Center (US)
Corresponding author
Shea, Steven A.
ORCID
Venue
The Journal of Clinical Endocrinology & Metabolism
Publisher
The Endocrine Society
Published
2005-05
Volume
90
Issue
5
Pages
2537-2544
ISSN
  • 0021-972X (ISSN-L)
  • 1945-7197
DOI
10.1210/jc.2004-2232
PMC
PMC2885832
OpenAlex
W2077495163
Semantic Scholar
78d3fa1949c6630e0a7605ffdbbbdaf3318ad438
Cited by
240
References
58
Citations by year
2026: 2 · 2025: 8 · 2024: 7 · 2023: 12 · 2022: 14 · 2021: 9 · 2020: 10 · 2019: 11 · 2018: 10 · 2017: 14 · 2016: 18 · 2015: 14 · 2014: 12 · 2013: 11 · 2012: 17
FWCI
3.18
Type
journal article
Language
en
Open access
Locations
  • The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Brigham and Women's Hospital
  • U.S. Public Health Service (R01 57875)
  • National Heart, Lung, and Blood Institute (K24-HL76446, K24HL076446, R01HL076409, R01HL064815, R01 HL64815)
  • National Institute of Diabetes and Digestive and Kidney Diseases
  • National Center for Research Resources (M01 RR 02635, M01RR002635)
Topics
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
  • Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
Keywords
circadian rhythm, leptin, adiponectin, soluble leptin receptor, glucose, insulin, sleep-wake cycle, dietary intake, energy balance, obesity, shift work, constant routine, fasting
MeSH terms
Adult, Blood Glucose, Circadian Rhythm, Humans, Insulin, Male, Middle Aged, Obesity, Sleep, Wakefulness, Work Schedule Tolerance, Leptin, Intercellular Signaling Peptides and Proteins, Adiponectin

About these checks

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

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

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

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 ›

Are you an author, or do you see a problem with this page? Request a review