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1.
Semin Cell Dev Biol ; 126: 56-65, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-33975754

RESUMO

Circadian rhythms are ~24 h cycles of behavior and physiology that are generated by a network of molecular clocks located in nearly every tissue in the body. In mammals, the circadian system is organized hierarchically such that the suprachiasmatic nucleus (SCN) is the main circadian clock that receives light information from the eye and entrains to the light-dark cycle. The SCN then coordinates the timing of tissue clocks so internal rhythms are aligned with environmental cycles. Estrogens interact with the circadian system to regulate biological processes. At the molecular level, estrogens and circadian genes interact to regulate gene expression and cell biology. Estrogens also regulate circadian behavior across the estrous cycle. The timing of ovulation during the estrous cycle requires coincident estrogen and SCN signals. Studies using circadian gene reporter mice have also elucidated estrogen regulation of peripheral tissue clocks and metabolic rhythms. This review synthesizes current understanding of the interplay between estrogens and the circadian system, with a focus on female rodents, in regulating molecular, physiological, and behavioral processes.


Assuntos
Relógios Circadianos , Estrogênios , Animais , Relógios Circadianos/fisiologia , Ritmo Circadiano/fisiologia , Estrogênios/metabolismo , Feminino , Mamíferos , Camundongos , Fotoperíodo , Núcleo Supraquiasmático
2.
Am J Physiol Regul Integr Comp Physiol ; 320(5): R619-R629, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33626995

RESUMO

Abnormal meal timing, like skipping breakfast and late-night snacking, is associated with obesity in humans. Disruption of daily eating rhythms also contributes to obesity in mice. When fed a high-fat diet, male C57BL/6J mice have disrupted eating behavior rhythms and they become obese. In contrast to obesity-prone C57BL/6J mice, some inbred strains of mice are resistant to high-fat diet-induced obesity. In this study, we sought to determine whether there are distinct effects of high-fat feeding on daily eating behavior rhythms in obesity-prone and obesity-resistant male mice. Male obesity-prone (C57BL/6J and 129X1/SvJ) and obesity-resistant (SWR/J and BALB/cJ) mice were fed low-fat diet or high-fat diet for 6 wk. Consistent with previous studies, obesity-prone male mice gained more weight and adiposity during high-fat diet feeding than obesity-resistant male mice. The amplitude of the daily rhythm of eating behavior was markedly attenuated in male obesity-prone mice fed high-fat diet, but not in obesity-resistant males. In contrast, high-fat feeding did not differentially affect locomotor activity rhythms in obesity-prone and obesity-resistant male mice. Together, these data suggest that regulation of the daily rhythm of eating may underlie the propensity to develop diet-induced obesity in male mice.


Assuntos
Ritmo Circadiano , Dieta Hiperlipídica , Comportamento Alimentar , Refeições , Obesidade/psicologia , Adiposidade , Animais , Modelos Animais de Doenças , Locomoção , Masculino , Camundongos da Linhagem 129 , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Obesidade/etiologia , Obesidade/fisiopatologia , Especificidade da Espécie , Fatores de Tempo , Aumento de Peso
3.
Am J Physiol Endocrinol Metab ; 317(6): E1172-E1181, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31689145

RESUMO

The circadian system is a critical regulator of metabolism and obesity in males, but its role in regulating obesity in females is poorly understood. Because there are sex differences in the development of obesity and susceptibility to obesity-related disorders, we sought to determine the role of estrogens in regulating the circadian mechanisms underlying diet-induced obesity. When fed high-fat diet, C57BL/6J male mice gain weight, whereas females are resistant to diet-induced obesity. Here, we demonstrate that estradiol regulates circadian rhythms in females to confer resistance to diet-induced obesity. We found that ovariectomized females with undetectable circulating estrogens became obese and had disrupted daily rhythms of eating behavior and locomotor activity when fed a high-fat diet. The phase of the liver molecular circadian rhythm was also altered by high-fat diet feeding in ovariectomized mice. Estradiol replacement in ovariectomized females a fed high-fat diet rescued these behavioral and tissue rhythms. Additionally, restoring the daily rhythm of eating behavior in ovariectomized females with time-restricted feeding inhibited diet-induced obesity and insulin resistance. Together, these data suggest that the circadian system is a target for treating obesity and its comorbidities in women after menopause, when circulating levels of estrogens are too low to protect their circadian rhythms.


Assuntos
Ritmo Circadiano/fisiologia , Dieta Hiperlipídica , Estradiol/metabolismo , Estrogênios/metabolismo , Comportamento Alimentar/fisiologia , Locomoção/fisiologia , Obesidade/metabolismo , Ovariectomia , Animais , Estradiol/farmacologia , Estrogênios/farmacologia , Comportamento Alimentar/efeitos dos fármacos , Métodos de Alimentação , Feminino , Resistência à Insulina , Locomoção/efeitos dos fármacos , Camundongos
4.
Yale J Biol Med ; 92(2): 327-335, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31249493

RESUMO

Circadian rhythms are ~24-hour cycles of physiology and behavior that are synchronized to environmental cycles, such as the light-dark cycle. During the 20th century, most research focused on establishing the fundamental properties of circadian rhythms and discovering circadian pacemakers that were believed to reside in the nervous system of animals. During this time, studies that suggested the existence of circadian oscillators in peripheral organs in mammals were largely dismissed. The discovery of a single-locus circadian pacemaker in the nervous system of several animals affirmed the single-oscillator model of the circadian system. However, the discovery of the genes that constituted the molecular timekeeping system provided the tools for demonstrating the existence of bona fide circadian oscillators in nearly every peripheral tissue in animals, including rodents, in the late 1990s and early 2000s. These studies led to our current understanding that the circadian system in animals is a hierarchical multi-oscillatory network, composed of master pacemaker(s) in the brain and oscillators in peripheral organs. Further studies showed that altering the temporal relationship between these oscillators by simulating jet-lag and metabolic challenges in rodents caused adverse physiological outcomes. Herein we review the studies that led to our current understanding of the function and pathology of the hierarchical multi-oscillator circadian system.


Assuntos
Relógios Circadianos/fisiologia , Ritmo Circadiano/fisiologia , Sistema Nervoso Periférico/fisiologia , Fotoperíodo , Animais , Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/genética , Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/metabolismo , Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/fisiologia , Regulação da Expressão Gênica , Humanos , Músculos/inervação , Músculos/fisiologia , Núcleo Supraquiasmático/fisiologia
5.
Proc Natl Acad Sci U S A ; 109(35): 14218-23, 2012 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-22891330

RESUMO

Daily rhythmic processes are coordinated by circadian clocks, which are present in numerous central and peripheral tissues. In mammals, two circadian clocks, the food-entrainable oscillator (FEO) and methamphetamine-sensitive circadian oscillator (MASCO), are "black box" mysteries because their anatomical loci are unknown and their outputs are not expressed under normal physiological conditions. In the current study, the investigation of the timekeeping mechanisms of the FEO and MASCO in mice with disruption of all three paralogs of the canonical clock gene, Period, revealed unique and convergent findings. We found that both the MASCO and FEO in Per1(-/-)/Per2(-/-)/Per3(-/-) mice are circadian oscillators with unusually short (∼21 h) periods. These data demonstrate that the canonical Period genes are involved in period determination in the FEO and MASCO, and computational modeling supports the hypothesis that the FEO and MASCO use the same timekeeping mechanism or are the same circadian oscillator. Finally, these studies identify Per1(-/-)/Per2(-/-)/Per3(-/-) mice as a unique tool critical to the search for the elusive anatomical location(s) of the FEO and MASCO.


Assuntos
Ritmo Circadiano/fisiologia , Comportamento Alimentar/fisiologia , Metanfetamina/farmacologia , Proteínas Circadianas Period/fisiologia , Núcleo Supraquiasmático/fisiologia , Animais , Antecipação Psicológica/fisiologia , Estimulantes do Sistema Nervoso Central/farmacologia , Ritmo Circadiano/efeitos dos fármacos , Feminino , Privação de Alimentos/fisiologia , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora/fisiologia , Proteínas Circadianas Period/genética , Fotoperíodo
6.
J Biol Rhythms ; 39(5): 413-422, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39082411

RESUMO

The estrous cycle regulates rhythms of locomotor activity, body temperature, and circadian gene expression. In female mice, activity increases on the night of proestrus, when elevated estrogens cause ovulation. Exogenous estradiol regulates eating behavior rhythms in female mice fed a high-fat diet, but it is unknown whether endogenous estrogens regulate eating rhythms. In this study, we investigated whether diurnal and circadian eating behavior rhythms change systematically across the estrous cycle. We first studied diurnal eating behavior rhythms in female C57BL/6J mice in 12L:12D. Estrous cycle stages were determined by vaginal cytology while eating behavior and wheel revolutions were continuously measured. The mice had regular 4- to 5-day estrous cycles. Consistent with prior studies, the greatest number of wheel revolutions occurred on the night of proestrus into estrus when systemic levels of estrogens peak. The amplitude, or robustness, of the eating behavior rhythm also fluctuated with 4- to 5-day cycles and peaked primarily during proestrus or estrus. The phases of eating behavior rhythms fluctuated, but not at 4- or 5-day intervals, and phases did not correlate with estrous cycle stages. After ovariectomy, the eating behavior rhythm amplitude fluctuated at irregular intervals. In constant darkness, the amplitude of the circadian eating behavior rhythm peaked every 4 or 5 days and coincided with the circadian day that had the greatest number of wheel revolutions, a marker of proestrus. These data suggest that fluctuations of ovarian hormones across the estrous cycle temporally organize the robustness of circadian eating behavior rhythms so that it peaks during ovulation and sexual receptivity.


Assuntos
Ritmo Circadiano , Ciclo Estral , Comportamento Alimentar , Camundongos Endogâmicos C57BL , Animais , Feminino , Ciclo Estral/fisiologia , Comportamento Alimentar/fisiologia , Camundongos , Atividade Motora , Ovariectomia , Fotoperíodo , Estrogênios , Estradiol
7.
Physiol Rep ; 12(3): e15924, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38296465

RESUMO

Circadian rhythms differ between young adult males and females. For example, males tend to be later chronotypes, preferring later timing of sleep and activity, than females. Likewise, there are sex differences in body composition and cardiorespiratory fitness. Few studies have investigated the association between circadian rhythms, cardiorespiratory fitness, and body composition. We sought to determine whether chronotype and circadian phase were associated with cardiorespiratory fitness, body composition, and anthropometric measures in sedentary males and females. Fifty-nine adults participated in the study. Circadian phase and chronotype were measured using dim light melatonin onset (DLMO) and the Morningness-Eveningness Questionnaire (MEQ) score. We used peak oxygen uptake (VO2peak ) results from a maximal graded exercise test to assess cardiorespiratory fitness. Body composition, BMI, and circumferences were collected as markers of adiposity. We observed a sex difference in the association between DLMO and VO2peak . For males, a later DLMO was associated with a lower VO2peak . VO2peak did not vary based on DLMO in females. Later circadian phase was also associated with increased body fat percentage, fat mass index, and abdominal circumference in males, but not females. Collectively, these results suggest that males who are later chronotypes may be at risk of obesity and low cardiorespiratory fitness.


Assuntos
Aptidão Cardiorrespiratória , Melatonina , Adulto Jovem , Humanos , Masculino , Feminino , Cronotipo , Sono , Ritmo Circadiano
8.
Eur J Neurosci ; 38(7): 3044-53, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23869717

RESUMO

The methamphetamine-sensitive circadian oscillator (MASCO) is an enigmatic circadian clock whose output is observed during continuous consumption of low-dose methamphetamine. The MASCO rhythm persists when the light-entrainable pacemaker in the suprachiasmatic nucleus (SCN) is lesioned, but the anatomical location of MASCO is unknown. We recently found that the period of the MASCO rhythm is unusually short (21 h) in mice with disruption of all three paralogs of the canonical clock gene, Period. In this study, we investigated the contribution of each Period paralog to timekeeping in MASCO. We measured wheel-running activity rhythms in intact and SCN-lesioned Per1-, 2- and 3-mutant mice administered methamphetamine, and found that none of the mice displayed a short (21-h) period, demonstrating that no single Period gene is responsible for the short-period MASCO rhythm of Per1(-/-) /Per2(-/-) /Per3(-/-) mice. We also found that the periods of activity rhythms in constant darkness were lengthened by methamphetamine treatment in intact wild-type, Per1(-/-) and Per3(-/-) mice but not Per2(-/-) mice, and Per2(-/-) mice had two distinct activity rhythms upon release to constant light. These data suggest that the SCN and MASCO are not coupled in Per2(-/-) mice. The MASCO rhythm in Per1(-/-) /Per2(-/-) mice in constant darkness alternated between a short (22-h) and a long (27-h) period. This pattern could result from two coupled oscillators that are not synchronised to each other, or from a single oscillator displaying birhythmicity. Finally, we propose a working model of the in vivo relationship between MASCO and the SCN that poses testable hypotheses for future studies.


Assuntos
Estimulantes do Sistema Nervoso Central/farmacologia , Ritmo Circadiano/fisiologia , Metanfetamina/farmacologia , Proteínas Circadianas Period/metabolismo , Animais , Ritmo Circadiano/efeitos dos fármacos , Feminino , Luz , Masculino , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Proteínas Circadianas Period/genética , Núcleo Supraquiasmático/efeitos dos fármacos , Núcleo Supraquiasmático/lesões , Núcleo Supraquiasmático/fisiologia
9.
Eur J Neurosci ; 37(8): 1350-6, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23331763

RESUMO

The organisation of timing in mammalian circadian clocks optimally coordinates behavior and physiology with daily environmental cycles. Chronic consumption of a high-fat diet alters circadian rhythms, but the acute effects on circadian organisation are unknown. To investigate the proximate effects of a high-fat diet on circadian physiology, we examined the phase relationship between central and peripheral clocks in mice fed a high-fat diet for 1 week. By 7 days, the phase of the liver rhythm was markedly advanced (by 5 h), whereas rhythms in other tissues were not affected. In addition, immediately upon consumption of a high-fat diet, the daily rhythm of eating behavior was altered. As the tissue rhythm of the suprachiasmatic nucleus was not affected by 1 week of high-fat diet consumption, the brain nuclei mediating the effect of a high-fat diet on eating behavior are likely to be downstream of the suprachiasmatic nucleus.


Assuntos
Ritmo Circadiano/fisiologia , Dieta Hiperlipídica/efeitos adversos , Comportamento Alimentar/fisiologia , Atividade Motora/fisiologia , Animais , Medições Luminescentes , Masculino , Camundongos , Camundongos Endogâmicos C57BL
10.
Proc Natl Acad Sci U S A ; 107(21): 9665-70, 2010 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-20457900

RESUMO

Two prominent timekeeping systems, the cell cycle, which controls cell division, and the circadian system, which controls 24-h rhythms of physiology and behavior, are found in nearly all living organisms. A distinct feature of circadian rhythms is that they are temperature-compensated such that the period of the rhythm remains constant (approximately 24 h) at different ambient temperatures. Even though the speed of cell division, or growth rate, is highly temperature-dependent, the cell-mitosis rhythm is temperature-compensated. Twenty-four-hour fluctuations in cell division have also been observed in numerous species, suggesting that the circadian system is regulating the timing of cell division. We tested whether the cell-cycle rhythm was coupled to the circadian system in immortalized rat-1 fibroblasts by monitoring cell-cycle gene promoter-driven luciferase activity. We found that there was no consistent phase relationship between the circadian and cell cycles, and that the cell-cycle rhythm was not temperature-compensated in rat-1 fibroblasts. These data suggest that the circadian system does not regulate the cell-mitosis rhythm in rat-1 fibroblasts. These findings are inconsistent with numerous studies that suggest that cell mitosis is regulated by the circadian system in mammalian tissues in vivo. To account for this discrepancy, we propose two possibilities: (i) There is no direct coupling between the circadian rhythm and cell cycle but the timing of cell mitosis is synchronized with the rhythmic host environment, or (ii) coupling between the circadian rhythm and cell cycle exists in normal cells but it is disconnected in immortalized cells.


Assuntos
Fibroblastos/citologia , Mitose , Animais , Linhagem Celular , Sobrevivência Celular , Ritmo Circadiano , Fibroblastos/metabolismo , Regulação da Expressão Gênica , Ratos , Temperatura
11.
Front Physiol ; 14: 1167858, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37064902

RESUMO

Shift work chronically disrupts circadian rhythms and increases the risk of developing cardiovascular disease. However, the mechanisms linking shift work and cardiovascular disease are largely unknown. The goal of this study was to investigate the effects of chronically shifting the light-dark (LD) cycle, which models the disordered exposure to light that may occur during shift work, on atherosclerosis. Atherosclerosis is the progressive accumulation of lipid-filled lesions within the artery wall and is the leading cause of cardiovascular disease. We studied ApolipoproteinE-deficient (ApoE -/- ) mice that are a well-established model of atherosclerosis. Male and female ApoE -/- mice were housed in control 12L:12D or chronic LD shift conditions for 12 weeks and fed low-fat diet. In the chronic LD shift condition, the light-dark cycle was advanced by 6 h every week. We found that chronic LD shifts exacerbated atherosclerosis in female, but not male, ApoE -/- mice. In females, chronic LD shifts increased total serum cholesterol concentrations with increased atherogenic VLDL/LDL particles. Chronic LD shifts did not affect food intake, activity, or body weight in male or female ApoE -/- mice. We also examined eating behavior in female ApoE -/- mice since aberrant meal timing has been linked to atherosclerosis. The phases of eating behavior rhythms, like locomotor activity rhythms, gradually shifted to the new LD cycle each week in the chronic LD shift group, but there was no effect of the LD shift on the amplitudes of the eating rhythms. Moreover, the duration of fasting intervals was not different in control 12L:12D compared to chronic LD shift conditions. Together these data demonstrate that female ApoE -/- mice have increased atherosclerosis when exposed to chronic LD shifts due to increased VLDL/LDL cholesterol, independent of changes in energy balance or feeding-fasting cycles.

12.
Heliyon ; 9(6): e16970, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37484286

RESUMO

Many female mammals have recurring cycles of ovulation and sexual behaviors that are regulated by reproductive hormones and confer reproductive success. In addition to sexual behaviors, circadian behavioral rhythms of locomotor activity also fluctuate across the estrous cycle in rodents. Moreover, there is a bidirectional relationship between circadian rhythms and estrous cyclicity since mice with disrupted circadian rhythms also have compromised estrous cycles resulting in fewer pregnancies. In the present study, we assessed whether extending day length, which alters circadian rhythms, normalizes estrous cyclicity in mice. We found that Period (Per) 1/2/3 triple knockout (KO) mice, that have disabled canonical molecular circadian clocks, have markedly disrupted estrous cycles. Surprisingly, extending the day length by only 2 h per day restored regular 4- or 5-day estrous cycles to Per1/2/3 KO mice. Longer days also induced consistent 4-day, rather than 5-day, estrous cycles in wild-type C57BL/6J mice. These data demonstrate that extending daytime light exposure could be used for enhancing reproductive success.

13.
J Clin Exerc Physiol ; 11(2): 44-53, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-36466304

RESUMO

Background: Cardiorespiratory fitness, typically measured as peak oxygen uptake (VO2peak) during maximal graded exercise testing (GXTmax), is a predictor of morbidity, mortality, and cardiovascular disease. However, measuring VO2peak is costly and inconvenient and thus not widely used in clinical settings. Alternatively, postexercise heart rate recovery (HRRec), which is an index of vagal reactivation, is a valuable assessment of VO2peak in older adults and athletes. However, the validity of HRRec as a clinical indicator of cardiorespiratory fitness in young, sedentary adults, who are a rapidly growing population at risk for developing obesity and cardiovascular disease, has not been fully elucidated. Methods: We investigated the association between cardiorespiratory fitness, measured by VO2peak (mL·kg-1·min-1), and HRRec measures after a GXTmax in 61 young (25.2 ± 6.1 years), sedentary adults (40 females) using 3 methods. We examined the relationship between VO2peak and absolute (b·min-1) and relative (%) HRRec measures at 1, 2, and 3 min post GXTmax, as well as a measure of the slow component HRRec (HRRec 1 min minus HRR 2 min), using Pearson's correlation analysis. Results: VO2peak (36.5 ± 7.9 mL·kg-1·min-1) was not significantly correlated with absolute HRRec at 1 min (r = 0.18), 2 min (r = 0.04) or 3 min (r = 0.01). We also found no significant correlations between VO2peak and relative HRRec at 1 min (r = 0.09), 2 min (r = -0.06) or 3 min (r = -0.10). Lastly, we found no correlation between the measure of the slow component HRRec and VO2peak (r = -0.14). Conclusions: Our results indicate that HRRec measures are not a valid indicator of cardiorespiratory fitness in young, sedentary adults.

14.
F1000Res ; 11: 1018, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36226037

RESUMO

The last 50 years have witnessed extraordinary discoveries in the field of circadian rhythms. However, there are still several mysteries that remain. One of these chronobiological mysteries is the circadian rhythm that is revealed by administration of stimulant drugs to rodents. Herein we describe the discovery of this circadian rhythm and its underlying oscillator, which is frequently called the methamphetamine-sensitive circadian oscillator, or MASCO. This oscillator is distinct from canonical circadian oscillators because it controls robust activity rhythms independently of the suprachiasmatic nucleus and circadian genes are not essential for its timekeeping. We discuss these fundamental properties of MASCO and integrate studies of strain, sex, and circadian gene mutations on MASCO. The anatomical loci of MASCO are not known, so it has not been possible thus far to discover its novel molecular timekeeping mechanism or its functional significance. However, studies in mutant mice suggest that genetic approaches can be used to identify the neural network involved in the rhythm generation of MASCO. We also discuss parallels between human and rodent studies that support our working hypothesis that a function of MASCO may be to regulate sleep-wake cycles.


Assuntos
Estimulantes do Sistema Nervoso Central , Metanfetamina , Camundongos , Humanos , Animais , Metanfetamina/farmacologia , Camundongos Endogâmicos C57BL , Atividade Motora/fisiologia , Núcleo Supraquiasmático/fisiologia , Estimulantes do Sistema Nervoso Central/farmacologia , Ritmo Circadiano/genética
15.
J Neurosci ; 30(36): 12179-84, 2010 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-20826680

RESUMO

A fundamental property of circadian clocks is that they entrain to environmental cues. The circadian genes, Period1 and Period2, are involved in entrainment of the mammalian circadian system. To investigate the roles of the Period genes in photic entrainment, we constructed phase response curves (PRC) to light pulses for C57BL/6J wild-type, Per1(-/-), Per2(-/-), and Per3(-/-) mice and tested whether the PRCs accurately predict entrainment to non-24 light-dark cycles (T-cycles) and constant light (LL). The PRCs of wild-type and Per3(-/-) mice are similar in shape and amplitude and have relatively large delay zones and small advance zones, resulting in successful entrainment to 26 h T-cycles (T26), but not T21, with similar phase angles. Per1(-/-) mice have a high-amplitude PRC, resulting in entrainment to a broad range of T-cycles. Per2(-/-) mice also entrain to a wide range of T-cycles because the advance portion of their PRC is larger than wild types. Period aftereffects following entrainment to T-cycles were similar among all genotypes. We found that the ratio of the advance portion to the delay portion of the PRC accurately predicts the lengthening of the period of the activity rhythm in LL. Wild-type, Per1(-/-), and Per3(-/-) mice had larger delay zones than advance zones and lengthened (>24 h) periods in LL, whereas Per2(-/-) mice had delay and advance zones that were equal in size and no period lengthening in LL. Together, these results demonstrate that PRCs are powerful tools for predicting and understanding photic entrainment of circadian mutant mice.


Assuntos
Atividade Motora/genética , Mutação/genética , Proteínas Circadianas Period/genética , Fotoperíodo , Animais , Luz , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Circadianas Period/classificação , Proteínas Circadianas Period/deficiência , Estimulação Luminosa/métodos , Fatores de Tempo
16.
J Neurosci ; 29(46): 14681-6, 2009 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-19923301

RESUMO

The mammalian circadian pacemaker in the suprachiasmatic nuclei (SCN) controls daily rhythms of behavior and physiology. Lesions of the SCN cause arrhythmicity of locomotor activity, and transplants of fetal SCN tissue restore rhythmic behavior that is consistent with the periodicity of the donor's genotype, suggesting that the SCN determines the period of the circadian behavioral rhythm. While several studies have demonstrated that the circadian characteristics of in vitro SCN rhythms represent circadian behavior, others have shown that the periods of explanted SCN are not always congruent with locomotor activity. We find that the aberrant rhythms of ex vivo SCN lacking functional Period1 (Per1(-/-)) do not represent the behavioral rhythms of the mutant animals. Surprisingly, in C57BL/6J Per1(-/-) mice, the real-time circadian gene promoter activity rhythm is weak or absent in adult SCN slices in vitro even though the free-running wheel-running activity rhythm is indistinguishable from wild-type (Per1(+/+)) mice. While some neurons in Per1(-/-) SCN explants exhibit robust circadian rhythms, others have irregular and/or low-amplitude rhythms. Together, these data suggest that either a small population of rhythmic neurons in the Per1(-/-) SCN is sufficient to control wheel-running activity or that in vivo physiological factors can compensate for the aberrant endogenous rhythms of Per1(-/-) SCN.


Assuntos
Ritmo Circadiano/genética , Mutação , Proteínas Circadianas Period/genética , Núcleo Supraquiasmático/fisiologia , Animais , Cruzamentos Genéticos , Feminino , Masculino , Camundongos , Camundongos Congênicos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Atividade Motora/genética , Neurônios Motores/fisiologia , Proteínas Circadianas Period/deficiência , Proteínas Circadianas Period/fisiologia , Núcleo Supraquiasmático/citologia
17.
Sci Rep ; 10(1): 9920, 2020 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-32555251

RESUMO

Disruption of the circadian system caused by disordered exposure to light is pervasive in modern society and increases the risk of cardiovascular disease. The mechanisms by which this happens are largely unknown. ApolipoproteinE-deficient (ApoE-/-) mice are studied commonly to elucidate mechanisms of atherosclerosis. In this study, we determined the effects of light-induced circadian disruption on atherosclerosis in ApoE-/- mice. We first characterized circadian rhythms of behavior, light responsiveness, and molecular timekeeping in tissues from ApoE-/- mice that were indistinguishable from rhythms in ApoE+/+ mice. These data showed that ApoE-/- mice had no inherent circadian disruption and therefore were an appropriate model for our study. We next induced severe disruption of circadian rhythms by exposing ApoE-/- mice to constant light for 12 weeks. Constant light exposure exacerbated atherosclerosis in male, but not female, ApoE-/- mice. Male ApoE-/- mice exposed to constant light had increased serum cholesterol concentrations due to increased VLDL/LDL fractions. Taken together, these data suggest that ApoE-/- mice are an appropriate model for studying light-induced circadian disruption and that exacerbated dyslipidemia may mediate atherosclerotic lesion formation caused by constant light exposure.


Assuntos
Aterosclerose/patologia , Ritmo Circadiano , Dislipidemias/patologia , Inflamação/patologia , Luz/efeitos adversos , Animais , Aterosclerose/etiologia , Dislipidemias/etiologia , Feminino , Inflamação/etiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE
18.
JCI Insight ; 5(3)2020 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-31895695

RESUMO

BACKGROUNDThe circadian system entrains behavioral and physiological rhythms to environmental cycles, and modern lifestyles disrupt this entrainment. We investigated a timed exercise intervention to phase shift the internal circadian rhythm.METHODSIn 52 young, sedentary adults, dim light melatonin onset (DLMO) was measured before and after 5 days of morning (10 hours after DLMO; n = 26) or evening (20 hours after DLMO; n = 26) exercise. Phase shifts were calculated as the difference in DLMO before and after exercise.RESULTSMorning exercise induced phase advance shifts (0.62 ± 0.18 hours) that were significantly greater than phase shifts from evening exercise (-0.02 ± 0.18 hours; P = 0.01). Chronotype also influenced the effect of timed exercise. For later chronotypes, both morning and evening exercise induced phase advances (0.54 ± 0.29 hours and 0.46 ±0.25 hours, respectively). In contrast, earlier chronotypes had phase advances from morning exercise (0.49 ± 0.25 hours) but had phase delays from evening exercise (-0.41 ± 0.29 hours).CONCLUSIONLate chronotypes - those who experience the most severe circadian misalignment - may benefit from phase advances induced by exercise in the morning or evening, but evening exercise may exacerbate circadian misalignment in early chronotypes. Thus, personalized exercise timing prescription, based on chronotype, could alleviate circadian misalignment in young adults.TRIAL REGISTRATIONTrial registration can be found at www.clinicaltrials.gov (NCT04097886).FUNDINGFunding was supplied by NIH grants UL1TR001998 and TL1TR001997, the Barnstable Brown Diabetes and Obesity Center, the Pediatric Exercise Physiology Laboratory Endowment, the Arvle and Ellen Turner Thacker Research Fund, and the University of Kentucky.


Assuntos
Ritmo Circadiano , Exercício Físico , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Comportamento Sedentário , Adulto Jovem
19.
Neurosci Res ; 61(2): 136-42, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18336944

RESUMO

The circadian clock system regulates daily rhythms of physiology and behavior. The mammalian master clock in the suprachiasmatic nuclei orchestrates these biological rhythms in peripheral tissues. Since blood is the most accessible tissue source, we sought to dissect the human circadian clock system by characterizing clock gene expression in human peripheral blood mononuclear cells (PBMCs) isolated from eight young, healthy subjects. By evaluating the temporal expression profiles of 10 circadian clock genes, we found that Period 1 (Per1), Per2, and Per3 are rhythmically expressed in human blood samples. Our results suggest that evaluating the rhythmic expression of human Per genes could reveal an individual's circadian phenotype.


Assuntos
Ritmo Circadiano/genética , Perfilação da Expressão Gênica , Leucócitos Mononucleares/fisiologia , Adulto , Expressão Gênica , Humanos , Masculino , RNA Mensageiro/análise , Reação em Cadeia da Polimerase Via Transcriptase Reversa
20.
J Biol Rhythms ; 33(5): 458-474, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30033846

RESUMO

The food-entrainable oscillator (FEO) is a mysterious circadian clock because its anatomical location(s) and molecular timekeeping mechanism are unknown. Food anticipatory activity (FAA), which is defined as the output of the FEO, emerges during temporally restricted feeding. FAA disappears immediately during ad libitum feeding and reappears during subsequent fasting. A free-running FAA rhythm has been observed only in rare circumstances when food was provided with a period outside the range of entrainment. Therefore, it is difficult to study the circadian properties of the FEO. Numerous studies have attempted to identify the critical molecular components of the FEO using mutant and genetically engineered mouse models. Herein we critically review the experimental protocols and findings of these studies in mouse models. Several themes emerge from these studies. First, there is little consistency in restricted feeding protocols between studies. Moreover, the protocols were sometimes not optimal, resulting in erroneous conclusions that FAA was absent in some mouse models. Second, circadian genes are not necessary for FEO timekeeping. Thus, another noncanonical timekeeping mechanism must exist in the FEO. Third, studies of mouse models have shown that signaling pathways involved in circadian timekeeping, reward (dopaminergic), and feeding and energy homeostasis can modulate, but are not necessary for, the expression of FAA. In sum, the approaches to date have been largely unsuccessful in discovering the timekeeping mechanism of the FEO. Moving forward, we propose the use of standardized and optimized experimental protocols that focus on identifying genes that alter the period of FAA in mutant and engineered mouse models. This approach is likely to permit discovery of molecular components of the FEO timekeeping mechanism.


Assuntos
Relógios Biológicos , Ritmo Circadiano/genética , Jejum , Alimentos , Animais , Animais Geneticamente Modificados , Comportamento Alimentar , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora , Proteínas Circadianas Period/genética
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