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Cited by 258Circadian rhythm and melatoninDietary Effects on HealthNutrition, Genetics, and Disease

Circadian rhythms, metabolism, and chrononutrition in rodents and humans

Open access
Johnston, Jonathan D, Ordovás, José M, Scheer, Frank A, Turek, Fred W·2016·Advances in Nutrition
DOI 10.3945/an.115.010777PMC PMC4785478
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Abstract

Chrononutrition is an emerging discipline that builds on the intimate relation between endogenous circadian (24-h) rhythms and metabolism. Circadian regulation of metabolic function can be observed from the level of intracellular biochemistry to whole-organism physiology and even postprandial responses. Recent work has elucidated the metabolic roles of circadian clocks in key metabolic tissues, including liver, pancreas, white adipose, and skeletal muscle. For example, tissue-specific clock disruption in a single peripheral organ can cause obesity or disruption of whole-organism glucose homeostasis. This review explains mechanistic insights gained from transgenic animal studies and how these data are being translated into the study of human genetics and physiology. The principles of chrononutrition have already been demonstrated to improve human weight loss and are likely to benefit the health of individuals with metabolic disease, as well as of the general population.

AI snapshot

Written from the paper’s full text.

TL;DR

This review synthesizes evidence that endogenous circadian clocks regulate metabolism across tissues and that chrononutrition—the timing of food intake—can influence weight, glucose control, and energy expenditure in rodents and humans. It links clock-gene variants and circadian misalignment to metabolic disease risk and suggests timed eating as a potential therapeutic strategy.

Key findings

  • Circadian regulation is pervasive: ~10% of the transcriptome in any given mouse tissue is under circadian control, 43% of protein-coding genes show rhythmicity in one or more of 12 mouse organs, 6–20% of the murine proteome is rhythmic in tissues such as SCN and liver, and up to 20% of detectable human plasma and saliva metabolites exhibit daily rhythms.
  • Clock disruption impairs metabolism: Clock mutant mice on a high-fat diet develop obesity and metabolic syndrome features; they consume ~50% of daily calories during the dark phase versus the typical 75–80% in nocturnal mice, and pancreatic clock disruption causes early diabetes due to insufficient insulin secretion.
  • Human clock-gene variants associate with metabolic traits and weight-loss response: in GOLDN (n ≈ 1100), 3 of 5 CLOCK SNPs were significantly associated with BMI, blood pressure, glycemic traits, and dietary markers; rs4580704 minor allele carriers had a 46% lower risk of hypertension, with effects modified by MUFA intake >13.2% or SFA intake >11.8% of energy. In a 28-wk weight-loss program, CLOCK rs1801260 variant carriers lost significantly less weight, and PER2 variants were associated with greater dropout and eating-behavior phenotypes.
  • Circadian misalignment and meal timing affect human physiology: simulated shift work/misalignment decreased glucose tolerance, insulin sensitivity, and leptin, and increased wake-time blood pressure; early diet-induced thermogenesis was approximately twice as large at 0800 h versus 2000 h, independent of the behavioral cycle, though it contributes only ~10% of daily energy expenditure.

Methods

  • Design: narrative review from the symposium “Is ‘When’ We Eat as Important as ‘What’ We Eat?”; it synthesizes mechanistic rodent studies, human genetic association and intervention studies, and controlled human circadian protocols.
  • Data/sample: cited transgenic mouse models (e.g., Clock mutant, Bmal1 null, tissue-specific clock disruption), human cohorts including GOLDN (n ≈ 1100), weight-loss cohorts of 500 and 1495 overweight/obese subjects, a type 2 diabetes case-control study (n = 302 cases, n = 300 controls), and controlled laboratory studies of circadian misalignment and meal timing.
  • Analysis: qualitative synthesis of published literature; no new primary data, systematic search, or meta-analysis is described.

Limitations

  • Stated in the paper: most animal models are nocturnal and lack some of the psychologic and social complexity of human eating behavior; long-term controlled laboratory studies in humans are very expensive and demanding.
  • Evident from the text: as a narrative review, it does not report a systematic search strategy or formal quality appraisal, and many conclusions rely on cited studies with varying designs and sample sizes.
  • Stated in the paper: the mechanism underlying the effect of the timing of caloric intake on weight-loss success is unknown.

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

Integrity signals

Registry

Crossref · 10.3945/an.115.010777

Cites

96 of 96 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 90 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    The effects of circadian misalignment were sustained for several days upon repeated exposure.

    “This study further supported the notion that the effects of circadian misalignment cannot be fully explained by disturbances in sleep and showed that these effects were sustained for several days upon repeated exposure.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [72] Morris, 2015, Endogenous circadian system and circadian misalignment impact glucose tolerance via separate mechanisms in humans, Proc Natl Acad Sci USA source

      Not checked in the free run.

  • Findingcitation

    In the GOLDN study, 3 of 5 selected CLOCK single-nucleotide polymorphisms (rs4580704, rs1801260, and rs3749474) yielded statistically significant associations with BMI, blood pressure, glycemic traits, and markers of dietary intake.

    “We investigated 5 selected CLOCK single-nucleotide polymorphisms (SNPs) (rs 4864548, rs4580704, rs1464490, rs1801260, and rs3749474), of which 3 (rs4580704, rs1801260, and rs3749474) yielded statistically significant associations with BMI (in kg/m 2 ), blood pressure, glycemic traits, and markers of dietary intake (red blood cell membrane fatty acids).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [53] Garaulet, 2009, CLOCK genetic variation and metabolic syndrome risk: modulation by monounsaturated fatty acids, Am J Clin Nutr source

      Not checked in the free run.

  • Findingown data

    The protective effect of the minor allele at rs4580704 on insulin sensitivity was only present when MUFA intake was above the median (>13.2% of energy in the GOLDN population).

    “However, when we investigated further the potential modulating effect of diet, we observed that the protective effect of the minor allele on insulin sensitivity was only present when MUFA intake was above the median (>13.2% of energy in this population).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [53] Garaulet, 2009, CLOCK genetic variation and metabolic syndrome risk: modulation by monounsaturated fatty acids, Am J Clin Nutr source

      Not checked in the free run.

  • Findingcitation

    The SIRT1-rs1467568 and CLOCK-rs1801260 SNPs have an additive effect on resistance to weight loss.

    “In this study, carried out in subjects attending the same outpatient obesity clinics, we analyzed the combined effects of the SIRT1-rs1467568 and the CLOCK-rs1801260 SNPs on the effectiveness of the weight-loss program and demonstrated that SIRT1 and CLOCK SNPs have an additive effect on resistance to weight loss that could be driven by effects on chronotype, plasma ghrelin concentrations, and”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [61] Garaulet, 2012, SIRT1 and CLOCK 3111T> C combined genotype is associated with evening preference and weight loss resistance in a behavioral therapy treatment for obesity, Int J Obes (Lond) source

      Not checked in the free run.

  • Findingown data

    PER2 SNPs rs2304672 and rs4663302 were associated with abdominal obesity.

    “Our results show that PER2 SNPs rs2304672 and rs4663302 were associated with abdominal obesity.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [60] Garaulet, 2010, PERIOD2 variants are associated with abdominal obesity, psycho-behavioral factors, and attrition in the dietary treatment of obesity, J Am Diet Assoc source

      Not checked in the free run.

  • May combine two claims. 25
  • Classified as probably not a substantial claim. 2

  • May combine two claims.

    Findingown data

    Carriers of the minor allele at PER2 SNPs rs2304672 and rs4663302 had a greater probability of dropping out from the weight-loss program and displaying extreme snacking, experiencing stress with dieting, eating when bored, and skipping breakfast than noncarriers.

    “Moreover, carriers of the minor allele at these PER2 SNPs had a greater probability of dropping out from the weight-loss program as well as displaying extreme snacking, experiencing stress with dieting, eating when bored, and skipping breakfast than noncarriers.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [60] Garaulet, 2010, PERIOD2 variants are associated with abdominal obesity, psycho-behavioral factors, and attrition in the dietary treatment of obesity, J Am Diet Assoc source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Circadian misalignment causes decreased glucose tolerance, decreased concentrations of the satiety hormone leptin, and increased wake time blood pressure.

    “In an initial study, we showed that circadian misalignment causes decreased glucose tolerance, decreased concentrations of the satiety hormone leptin, and increased wake time blood pressure (69).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [69] Scheer, 2009, Adverse metabolic and cardiovascular consequences of circadian misalignment, Proc Natl Acad Sci USA source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Temperature was associated with blood pressure but did not modulate the associations with genetic markers in either whites or Hispanics.

    “Moreover, we demonstrated that whereas temperature was associated with blood pressure, it did not modulate the associations with genetic markers in either whites or Hispanics.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [54] Dashti, 2015, Clock genes explain a large proportion of phenotypic variance in systolic blood pressure and this control is not modified by environmental temperature, Am J Hypertens source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    All CLOCK SNPs were associated with plasma cytokine concentrations, particularly monocyte chemotactic protein 1, IL-6, and adiponectin.

    “Moreover, all CLOCK SNPs were associated with plasma cytokine concentrations, in particular with those that were highly correlated with energy intake (i.e., monocyte chemotactic protein 1, IL-6, and adiponectin).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [55] Garaulet, 2010, Genetic variants in human CLOCK associate with total energy intake and cytokine sleep factors in overweight subjects (GOLDN population), Eur J Hum Genet source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    A history of 3 weeks of circadian misalignment plus sleep restriction caused a decrease in glucose tolerance and a decrease in insulin release, with recovery after a week of sleep extension.

    “A second study showed that a history of 3 wk of circadian misalignment plus sleep restriction caused a decrease in glucose tolerance and a decrease in insulin release, with recovery after a week of sleep extension (70).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [70] Buxton, 2012, Adverse metabolic consequences in humans of prolonged sleep restriction combined with circadian disruption, Sci Transl Med source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Compared with TT subjects, carriers of the minor C allele at CLOCK rs1801260 had shorter sleep duration, higher plasma ghrelin concentrations, delayed breakfast time, evening preference, and less compliance with a Mediterranean diet pattern.

    “In addition, our data show that compared with TT subjects, those carrying the minor C allele had statistically significant 1) shorter sleep duration, 2) higher plasma ghrelin concentrations, 3) delayed breakfast time, 4) evening preference, and 5) less compliance with a Mediterranean diet pattern.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [57] Garaulet, 2011, Ghrelin, sleep reduction and evening preference: relationships to CLOCK 3111 T/C SNP and weight loss, PLoS One source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    In the study, there was no effect of the behavioral cycle but a strong effect of the endogenous circadian phase, with diet-induced thermogenesis approximately twice as large in the biological morning (0800 h) compared with the biological evening (2000 h), independent of the behavioral cycle.

    “However, remarkably, we found no effect of the behavioral cycle but a strong effect of the endogenous circadian phase, with diet-induced thermogenesis again being approximately twice as large in the biological morning (0800 h) compared with the biological evening (2000 h), independent of the behavioral cycle.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [90] Morris, 2015, The human circadian system has a dominating role in causing the morning/evening difference in diet-induced thermogenesis, Obesity (Silver Spring) source

      Not checked in the free run.

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

    Premisecitation

    The mammalian transcriptional-translational feedback loop model consists of multiple interlocking loops.

    “The mammalian TTFL model consists of multiple interlocking loops that are described in detail elsewhere (19).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] Partch, 2014, Molecular architecture of the mammalian circadian clock, Trends Cell Biol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Fetal SCN tissue transplanted into the hypothalamus of SCN-lesioned animals restores behavioral rhythms, and the circadian period of the recipient is determined by the donor animal rather than the host.

    “Not only did these transplants restore behavioral rhythms, but the circadian period of the recipient also was determined by the period of the donor animal and not the previous period of the host (7).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7] Ralph, 1990, Transplanted suprachiasmatic nucleus determines circadian period, Science source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CLOCK-BMAL1 heterodimers drive rhythmic expression of nicotinamide phosphoribosyltransferase, a rate-limiting enzyme in the NAD+ salvage pathway; NAD+ acts as a cofactor for SIRT1, which regulates the activity of CLOCK-BMAL1.

    “For example, CLOCK-BMAL1 heterodimers drive rhythmic expression of nicotinamide phosphoribosyltransferase, which is a rate-limiting enzyme involved in the NAD+ salvage pathway; NAD+ acts as a cofactor for Sirtuin (SIRT1), which regulates the activity of CLOCK-BMAL1 among its other metabolic functions (23,24).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [23] Sassone-Corsi, 2012, Minireview: NAD+, a circadian metabolite with an epigenetic twist, Endocrinology source

      Not checked in the free run.

    • cites [24] Peek, 2015, Circadian regulation of cellular physiology, Methods Enzymol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CLOCK-BMAL1 dimers drive circadian transcription of Rev-erba (Nr1d1) through E-box regulatory elements; the resulting REVERBa/NR1D1 protein inhibits Bmal1 transcription through retinoic acid-related orphan receptor response elements, resulting in circadian rhythms of Bmal1 mRNA expression.

    “The best characterized of these secondary loops involves the circadian transcription of the nuclear receptor Rev-erba (Nr1d1) by CLOCK-BMAL1 dimers acting through E-box regulatory elements; the resulting REVERBa/NR1D1 protein then inhibits Bmal1 transcription through retinoic acid-related orphan receptor response elements, resulting in circadian rhythms of Bmal1 mRNA expression (21).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Preitner, 2002, The orphan nuclear receptor REV-ERBalpha controls circadian transcription within the positive limb of the mammalian circadian oscillator, Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In mammals, light detection requires the retina and occurs via melanopsin-positive retinal ganglion cells working in conjunction with rod and cone cells.

    “In mammals, light detection requires the retina and occurs via melanopsinpositive retinal ganglion cells working in conjunction with the rod and cone cells (15).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] Lucas, 2012, How rod, cone, and melanopsin photoreceptors come together to enlighten the mammalian circadian clock, Prog Brain Res source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The SCN influence sleep-wake cycles that themselves influence circadian rhythmicity and partially dictate feed-fast behavior, which is believed to be a key synchronizer of peripheral clocks.

    “Furthermore, the SCN influence sleep-wake cycles that themselves influence circadian rhythmicity (17) and partially dictate feed-fast behavior, which is believed to be a key synchronizer of peripheral clocks (see below).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Laing, 2015, Exploiting human and mouse transcriptomic data: Identification of circadian genes and pathways influencing health, BioEssays source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Shift work is a risk factor for diabetes, obesity, and cardiovascular disease.

    “Shift work is a risk factor for diabetes, obesity, and cardiovascular disease (63)(64)(65)(66).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [63] Morris, 2012, The impact of the circadian timing system on cardiovascular and metabolic function, Prog Brain Res source

      Not checked in the free run.

    • cites [64] Antunes, 2010, Obesity and shift work: chronobiological aspects, Nutr Res Rev source

      Not checked in the free run.

    • cites [65] Lowden, 2010, Eating and shift work - effects on habits, metabolism and performance, Scand J Work Environ Health source

      Not checked in the free run.

    • cites [66] Tucker, 2012, Shiftwork and metabolic dysfunction, Chronobiol Int source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Clock mutants exhibit reduced overall expression levels and a blunted diurnal rhythm of orexin mRNA.

    “The Clock mutants were also shown to exhibit reduced overall expression levels and a blunted diurnal rhythm of orexin mRNA, a hypothalamic neuropeptide involved in energy regulation (49).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] Summa, 2014, Chronobiology and obesity: Interactions between circadian rhythms and energy regulation, Adv Nutr source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Timed feeding regulates clock gene rhythms in most peripheral tissues and may also regulate SCN rhythmicity when combined with hypocaloric feeding paradigms.

    “As reviewed elsewhere, it is now known that timed feeding regulates clock gene rhythms in most peripheral tissues and may also regulate SCN rhythmicity when combined with hypocaloric feeding paradigms (81,82).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [81] Johnston, 2014, Physiological responses to food intake throughout the day, Nutr Res Rev source

      Not checked in the free run.

    • cites [82] Asher, 2015, Time for food: the intimate interplay between nutrition, metabolism, and the circadian clock, Cell source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Temporal rhythms in energy intake are relevant for energy balance, and timed feeding schedules designed according to the properties of the circadian clock system may be strategies for weight management and the treatment of obesity.

    “This finding suggested that temporal rhythms in energy intake are relevant for energy balance, perhaps identifying approaches involving timed feeding schedules, designed according to the properties of the circadian clock system, as possible strategies for weight management and the treatment of obesity (49).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [49] Summa, 2014, Chronobiology and obesity: Interactions between circadian rhythms and energy regulation, Adv Nutr source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Time-restricted feeding prevents body weight gain and decelerates cardiac aging in Drosophila.

    “Interestingly, the ability of TRF to prevent body weight gain and decelerate cardiac aging in Drosophila (86) indicates that it may represent a beneficial aspect of chrononutrition across species.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [86] Gill, 2015, Time-restricted feeding attenuates age-related cardiac decline in Drosophila, Science source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Chrononutrition may be an important tool to enhance the metabolic health of the general population and to benefit the health of particular population groups (e.g., shift workers) and treatment of certain metabolic diseases.

    “In conclusion, evidence to date suggests that chrononutrition may be an important tool, not only to enhance the metabolic health of the general population but also to benefit the health of particular population groups (e.g., shift workers) and treatment of certain metabolic diseases.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [49] Summa, 2014, Chronobiology and obesity: Interactions between circadian rhythms and energy regulation, Adv Nutr source

      Not checked in the free run.

    • cites [63] Morris, 2012, The impact of the circadian timing system on cardiovascular and metabolic function, Prog Brain Res source

      Not checked in the free run.

    • cites [81] Johnston, 2014, Physiological responses to food intake throughout the day, Nutr Res Rev source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In mice on a 12-h:12-h light-dark cycle fed a high-fat diet for 6 wk, exclusive feeding during the light phase led to greater weight gain than feeding during the dark phase, with no significant differences in calorie intake or activity.

    “The group fed during the light phase gained more weight, despite the absence of any significant differences in calorie intake or activity over the course of the experiment.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [83] Arble, 2009, Circadian timing of food intake contributes to weight gain, Obesity (Silver Spring) source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Timed feeding may enhance weight loss and glycemic control in humans.

    “Although much work remains to be done, human studies already suggest that timed feeding may translate into a beneficial approach to enhance weight loss and glycemic control in humans (87)(88)(89).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [87] Jakubowicz, 2013, High caloric intake at breakfast vs. dinner differentially influences weight loss of overweight and obese women, Obesity (Silver Spring) source

      Not checked in the free run.

    • cites [88] Jakubowicz, 2015, High-energy breakfast with low-energy dinner decreases overall daily hyperglycaemia in type 2 diabetic patients: a randomised clinical trial, Diabetologia source

      Not checked in the free run.

    • cites [89] Garaulet, 2013, Timing of food intake predicts weight loss effectiveness, Int J Obes (Lond) source

      Not checked in the free run.

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

    Premisecitation

    Another study did not find a difference in diet-induced thermogenesis between morning and afternoon.

    “This result is consistent with an earlier study that showed larger diet-induced thermogenesis assessed over 6 h in the morning (0900 h) compared with the afternoon (1700 h) and at night (0100 h) (91), although another study did not find a difference between morning and afternoon (92).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [92] Weststrate, 1989, Diurnal variation in postabsorptive resting metabolic rate and diet-induced thermogenesis, Am J Clin Nutr source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The principles of chrononutrition are likely to benefit the health of individuals with metabolic disease, as well as of the general population.

    “The principles of chrononutrition have already been demonstrated to improve human weight loss and are likely to benefit the health of individuals with metabolic disease, as well as of the general population.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The principles of chrononutrition have already been demonstrated to improve human weight loss.

  • May combine two claims.

    Premisecitation

    In the human studies of timed feeding, there were no differences in self-reported physical activity level and caloric intake.

    “In the human studies mentioned above, there were no differences in self-reported physical activity level and caloric intake.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [87] Jakubowicz, 2013, High caloric intake at breakfast vs. dinner differentially influences weight loss of overweight and obese women, Obesity (Silver Spring) source

      Not checked in the free run.

    • cites [88] Jakubowicz, 2015, High-energy breakfast with low-energy dinner decreases overall daily hyperglycaemia in type 2 diabetic patients: a randomised clinical trial, Diabetologia source

      Not checked in the free run.

    • cites [89] Garaulet, 2013, Timing of food intake predicts weight loss effectiveness, Int J Obes (Lond) source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In mice, restricting feeding to the middle of the light or dark phase reduces body weight and improves markers of metabolic health compared with ad libitum feeding, despite equivalent calorie consumption.

    “Restriction of feeding to either the middle of the light (84) or dark (42) phase reduces body weight and improves markers of metabolic health in mice compared with ad libitum fed controls.”
    • Also stated in: § Effects of Meal Timing on Circadian Synchronization and Metabolism · plain
      “Importantly, these effects occurred despite equivalent calorie consumption in the TRF and ad libitum groups.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [84] Sherman, 2012, Timed high-fat diet resets circadian metabolism and prevents obesity, FASEB J source

      Not checked in the free run.

    • cites [42] Hatori, 2012, Time-restricted feeding without reducing caloric intake prevents metabolic diseases in mice fed a high-fat diet, Cell Metab source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Circadian organization is a clinically significant factor in the pathophysiology of metabolic diseases and in potential targeted strategies for treating them.

    “Given the growing body of evidence linking the circadian clock system to energy regulation and metabolic physiology, circadian organization emerges as a clinically significant factor that should be considered in the understanding of the pathophysiology of these diseases and in potential targeted strategies for treating them (49,63,81).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [49] Summa, 2014, Chronobiology and obesity: Interactions between circadian rhythms and energy regulation, Adv Nutr source

      Not checked in the free run.

    • cites [63] Morris, 2012, The impact of the circadian timing system on cardiovascular and metabolic function, Prog Brain Res source

      Not checked in the free run.

    • cites [81] Johnston, 2014, Physiological responses to food intake throughout the day, Nutr Res Rev source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Tissue-specific clock disruption in a single peripheral organ can cause obesity or disruption of whole-organism glucose homeostasis.

    “For example, tissue-specific clock disruption in a single peripheral organ can cause obesity or disruption of whole-organism glucose homeostasis.”
    Quote in the paperSubstantial claim
27 of 27

  • The paper relies on this without support.

    The principles of chrononutrition have already been demonstrated to improve human weight loss.

    “The principles of chrononutrition have already been demonstrated to improve human weight loss and are likely to benefit the health of individuals with metabolic disease, as well as of the general population.”

  • The paper relies on this without support.

    The adverse health effects of shift work cannot be fully explained by traditional risk factors.

    “This effect cannot be fully explained by traditional risk factors.”

  • The paper relies on this without support.

    Circadian rhythms are generated by clocks that are endogenous in nature and oscillate even in the absence of environmental cues.

    “They are generated by clocks that are endogenous in nature and oscillate even in the absence of environmental cues.”

  • The paper relies on this without support.

    Large multicellular organisms contain numerous clocks found within all major tissues and possibly within most individual cells of the body.

    “It is now recognized that large multicellular organisms contain numerous clocks found within all major tissues and possibly within most individual cells of the body.”

  • The paper relies on this without support.

    Most animal models are nocturnal and lack some of the psychologic and social complexity of human eating behavior.

    “Weaknesses include the fact that most animal models are nocturnal and lack some of the psychologic and social complexity of human eating behavior.”
5 of 5

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?

  • Misalignment between the sleep-awake, fasting-feeding cycles, and the light-dark cycle disrupts natural oscillations of glucose, lipid metabolism, and blood pressure, eventually increasing risk of type 2 diabetes and cardiovascular disease.

    “The resulting misalignment between the sleep-awake, fasting-feeding cycles, and the light-dark cycle subsequently disrupts the natural oscillations of physiologic processes such as glucose, lipid metabolism, and blood pressure, eventually manifesting itself as heightened risk of developing type 2 diabetes and cardiovascular disease (1–4).”

    From Chronotype: Implications for Epidemiologic Studies on Chrono-Nutrition and Cardiometabolic Health (2019) · cites this paper as [2]

  • Food can regulate various peripheral body clocks and metabolic rhythms and is often referred to as a zeitgeber.

    “Food is often referred to as a zeitgeber (14) because of its ability to regulate various peripheral body clocks and metabolic rhythms (2, 15, 16).”

    From Chronotype: Implications for Epidemiologic Studies on Chrono-Nutrition and Cardiometabolic Health (2019) · cites this paper as [2]

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Related

Authors
Johnston, J. D., Ordovás, J. M., Scheer, F. A., & Turek, F. W.
Affiliations
  • University of Surrey (GB)
  • Madrid Institute for Advanced Studies (ES)
  • Brigham and Women's Hospital (US)
  • Northwestern University (US)
Corresponding author
Johnston, Jonathan D
ORCID
Venue
Advances in Nutrition
Publisher
Elsevier BV
Published
2016-03
Volume
7
Issue
2
Pages
399-406
ISSN
  • 2156-5376 (ISSN-L)
  • 2161-8313
DOI
10.3945/an.115.010777
PMC
PMC4785478
OpenAlex
W2297363507
Semantic Scholar
96b99cb19c2cac33748981685af44d57378149ab
Cited by
258
References
96
Citations by year
2026: 22 · 2025: 23 · 2024: 31 · 2023: 32 · 2022: 34 · 2021: 35 · 2020: 24 · 2019: 25 · 2018: 15 · 2017: 13 · 2016: 3
FWCI
11.87
Type
journal article
Language
en
Open access
Licence
Locations
  • Advances in Nutrition (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Surrey Research Insight Open Access (The University of Surrey) (submittedVersion)
Funders
  • U.S. Department of Agriculture (58-1950-9-001, 53‐K06‐5‐10)
  • PepsiCo
  • Kellogg's
  • National Institutes of Health (58-1950-9-001)
  • Directorate for Biological Sciences
  • Biotechnology and Biological Sciences Research Council (BB/I008470/1)
  • National Heart, Lung, and Blood Institute (R01HL118601)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK099512)
Topics
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
  • Health Sciences › Medicine › Physiology › Dietary Effects on Health
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Nutrition, Genetics, and Disease
Keywords
chrononutrition, circadian rhythm, circadian clock, metabolism, obesity, glucose homeostasis, liver, pancreas, white adipose tissue, skeletal muscle, postprandial response, weight loss, metabolic disorders, transgenic animal models
MeSH terms
Animals, Animal Nutritional Physiological Phenomena, Chronobiology Phenomena, Circadian Rhythm, Congresses as Topic, Diabetes Mellitus, Type 2, Energy Metabolism, Humans, Mice, Mutant Strains, Mice, Transgenic, Nerve Tissue Proteins, Neurons, Nutritional Physiological Phenomena, Suprachiasmatic Nucleus, Genetic Variation, Metabolic Syndrome, Mice, Rats, CLOCK Proteins, Meals

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 ›

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