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McHill AW, Butler MP. Eating Around the Clock: Circadian Rhythms of Eating and Metabolism. Annu Rev Nutr 2024; 44:25-50. [PMID: 38848598 PMCID: PMC11849495 DOI: 10.1146/annurev-nutr-062122-014528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/09/2024]
Abstract
The time of day that we eat is increasingly recognized as contributing as importantly to overall health as the amount or quality of the food we eat. The endogenous circadian clock has evolved to promote intake at optimal times when an organism is intended to be awake and active, but electric lights and abundant food allow eating around the clock with deleterious health outcomes. In this review, we highlight literature pertaining to the effects of food timing on health, beginning with animal models and then translation into human experiments. We emphasize the pitfalls and opportunities that technological advances bring in bettering understanding of eating behaviors and their association with health and disease. There is great promise for restricting the timing of food intake both in clinical interventions and in public health campaigns for improving health via nonpharmacological therapies.
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Affiliation(s)
- Andrew W McHill
- Sleep, Chronobiology, and Health Laboratory, School of Nursing, Oregon Health & Science University, Portland, Oregon, USA
- Oregon Institute of Occupational Health Sciences, Oregon Health & Science University, Portland, Oregon, USA
| | - Matthew P Butler
- Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, Oregon, USA;
- Oregon Institute of Occupational Health Sciences, Oregon Health & Science University, Portland, Oregon, USA
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2
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Dial MB, Malek EM, Cooper AR, Neblina GA, Vasileva NI, Hines DJ, McGinnis GR. Social jet lag impairs exercise volume and attenuates physiological and metabolic adaptations to voluntary exercise training. J Appl Physiol (1985) 2024; 136:996-1006. [PMID: 38450426 PMCID: PMC11305643 DOI: 10.1152/japplphysiol.00632.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Revised: 01/31/2024] [Accepted: 02/26/2024] [Indexed: 03/08/2024] Open
Abstract
Social jet lag (SJL) is a misalignment between sleep and wake times on workdays and free days. SJL leads to chronic circadian rhythm disruption and may affect nearly 70% of the general population, leading to increased risk for cardiometabolic diseases. This study investigated the effects of SJL on metabolic health, exercise performance, and exercise-induced skeletal muscle adaptations in mice. Ten-week-old C57BL/6J mice (n = 40) were allocated to four groups: control sedentary (CON-SED), control exercise (CON-EX), social jet lag sedentary (SJL-SED), and social jet lag exercise (SJL-EX). CON mice were housed under a 12:12-h light-dark cycle. SJL was simulated by implementing a 4-h phase delay for 3 days to simulate "weekends," followed by a 4-h phase advance back to "weekdays," for 6 wk. EX mice had free access to a running wheel. Graded exercise tests (GXTs) and glucose tolerance tests (GTTs) were performed at baseline and after intervention to monitor the effects of exercise and social jet lag on cardiorespiratory and metabolic health, respectively. SJL led to alterations in activity and running patterns and clock gene expression in skeletal muscle and decreased average running distance (P < 0.05). SJL-SED mice gained significantly more weight compared with CON-SED and SJL-EX mice (P < 0.01). SJL impaired fasting blood glucose and glucose tolerance compared with CON mice (P < 0.05), which was partially restored by exercise in SJL-EX mice. SJL also blunted improvements in exercise performance and mitochondrial content in the quadriceps. These data suggest that SJL blunted some cardiometabolic adaptations to exercise and that proper circadian hygiene is necessary for maintaining health and performance.NEW & NOTEWORTHY In mice, disrupting circadian rhythms with social jet lag for 6 wk caused significant weight gain, higher fasting blood glucose, and impaired glucose tolerance compared with control. Voluntary exercise in mice experiencing social jet lag prevented weight gain, though the mice still experienced increased fasting blood glucose and impaired exercise performance compared with trained mice not experiencing social jet lag. Social jet lag seems to be a potent circadian rhythm disruptor that impacts exercise-induced training adaptations.
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Affiliation(s)
- Michael B Dial
- Department of Kinesiology and Nutrition Sciences, School of Integrated Health Sciences, University of Nevada, Las Vegas, Nevada, United States
| | - Elias M Malek
- Department of Kinesiology and Nutrition Sciences, School of Integrated Health Sciences, University of Nevada, Las Vegas, Nevada, United States
| | - Austin R Cooper
- Department of Kinesiology and Nutrition Sciences, School of Integrated Health Sciences, University of Nevada, Las Vegas, Nevada, United States
| | - Greco A Neblina
- Department of Kinesiology and Nutrition Sciences, School of Integrated Health Sciences, University of Nevada, Las Vegas, Nevada, United States
| | - Nikoleta I Vasileva
- Department of Kinesiology and Nutrition Sciences, School of Integrated Health Sciences, University of Nevada, Las Vegas, Nevada, United States
| | - Dustin J Hines
- Department of Psychology, Psychological and Brain Sciences and Interdisciplinary Neuroscience Programs, University of Nevada, Las Vegas, Nevada, United States
| | - Graham R McGinnis
- Department of Kinesiology and Nutrition Sciences, School of Integrated Health Sciences, University of Nevada, Las Vegas, Nevada, United States
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Zhang K, Mi F, Li X, Wang Z, Jiang F, Song E, Guo P, Lan X. Detection of genetic variation in bovine CRY1 gene and its associations with carcass traits. Anim Biotechnol 2023; 34:3387-3394. [PMID: 36448652 DOI: 10.1080/10495398.2022.2149547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
The biological clock (also known as circadian clock) is closely related to growth and development, metabolism, and diseases in animals. As a part of the circadian clock, the cryptochrome circadian regulator 1 (CRY1) gene is involved in the regulation of biological processes such as osteogenesis, energy metabolism and cell proliferation, however, few studies have been reported on the relationship between this gene and animal carcass traits. Herein, a total of four insertion/deletion (InDel) loci within the CRY1 gene were detected in Shandong Black Cattle Genetic Resource (SDBCGR) population (n = 433). Among them, the P1-6-bp-del locus was polymorphic in population of interest. Moreover, the P1-6-bp-del locus showed two genotypes, with a higher insertion/insertion (II) genotype frequency (0.751) than insertion/deletion (ID) genotype frequency (0.249). Correlation analysis showed that the P1-6-bp-del locus polymorphisms were significantly associated with twenty carcass traits (e.g., slaughter weight, limb weight, and belly meat weight). Individuals with II genotype were significantly better than those with ID genotype for eighteen carcass traits. Therefore, the P1-6-bp-del locus of the CRY1 gene can be used as a molecular marker for beef cattle breeding.
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Affiliation(s)
- Kejing Zhang
- College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Fang Mi
- College of Animal Science and Technology, Northwest A&F University, Yangling, China
- National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xuelan Li
- College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Zhiying Wang
- College of Animal Science and Technology, Northwest A&F University, Yangling, China
| | - Fugui Jiang
- Shandong Key Laboratory of Animal Disease Control and Breeding, Institute of Animal Science and Veterinary Medicine, Shandong Academy of Agricultural Sciences, Jinan, China
| | - Enliang Song
- Shandong Key Laboratory of Animal Disease Control and Breeding, Institute of Animal Science and Veterinary Medicine, Shandong Academy of Agricultural Sciences, Jinan, China
| | - Peng Guo
- College of Computer and Information Engineering, Tianjin Agricultural University, Tianjin, China
| | - Xianyong Lan
- College of Animal Science and Technology, Northwest A&F University, Yangling, China
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Zhang L, Malkemper EP. Cryptochromes in mammals: a magnetoreception misconception? Front Physiol 2023; 14:1250798. [PMID: 37670767 PMCID: PMC10475740 DOI: 10.3389/fphys.2023.1250798] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Accepted: 08/01/2023] [Indexed: 09/07/2023] Open
Abstract
Cryptochromes are flavoproteins related to photolyases that are widespread throughout the plant and animal kingdom. They govern blue light-dependent growth in plants, control circadian rhythms in a light-dependent manner in invertebrates, and play a central part in the circadian clock in vertebrates. In addition, cryptochromes might function as receptors that allow animals to sense the Earth's magnetic field. As cryptochromes are also present in mammals including humans, the possibility of a magnetosensitive protein is exciting. Here we attempt to provide a concise overview of cryptochromes in mammals. We briefly review their canonical role in the circadian rhythm from the molecular level to physiology, behaviour and diseases. We then discuss their disputed light sensitivity and proposed role in the magnetic sense in mammals, providing three mechanistic hypotheses. Specifically, mammalian cryptochromes could form light-induced radical pairs in particular cellular milieus, act as magnetoreceptors in darkness, or as secondary players in a magnetoreception signalling cascade. Future research can test these hypotheses to investigate if the role of mammalian cryptochromes extends beyond the circadian clock.
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Affiliation(s)
| | - E. Pascal Malkemper
- Max Planck Research Group Neurobiology of Magnetoreception, Max Planck Institute for Neurobiology of Behavior—caesar, Bonn, Germany
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Firouzabadi FD, Mirzababaei A, Shiraseb F, Tangestani H, Mirzaei K. The interaction between CRY1 Polymorphism and Alternative Healthy Eating Index (AHEI) on cardiovascular risk factors in overweight women and women with obesity: a cross-sectional study. BMC Endocr Disord 2023; 23:172. [PMID: 37580741 PMCID: PMC10424458 DOI: 10.1186/s12902-023-01429-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2021] [Accepted: 08/01/2023] [Indexed: 08/16/2023] Open
Abstract
BACKGROUND According to some studies, diet can be interaction with CRY1 polymorphism and may be related to obesity and the risk of cardiovascular diseases (CVD). So, this study examined the interaction between CRY1 polymorphism and AHEI on cardiovascular risk factors in overweight women and women with obesity. METHODS This cross-sectional study was performed on 377 Iranian women with overweight and obesity aged 18-48(BMI ≥ 25 kg/m2). Dietary intake was evaluated by the use of a food frequency questionnaire (FFQ) with 147 items. The AHEI was calculated based on previous studies. Anthropometric and biochemical measurements were assessed and the bioelectrical impedance analysis method was used for body analysis. The rs2287161 was genotyped by the restriction fragment length polymorphism (PCR-RFLP) method. Objects were divided into three groups based on rs2287161 genotypes. RESULTS Our findings determined that the prevalence of the C allele was 51.9% and the G allele was 48.0%. The mean age and BMI were 36.6 ± 9.1years and 31 ± 4 kg/m2 respectively. After controlling for confounders (BMI, age, total energy intake, and physical activity), this study demonstrated that there was a significant interaction between CC genotype and adherence to AHEI on odds of hyper LDL (OR = 1.94, 95% CI = 1.24-3.05, P for interaction = 0.004), hypertension (OR = 1.80, 95% CI = 1.11-2.93, P for interaction = 0.01) and hyperglycemia (OR = 1.56, 95% CI = 0.98-2.47, P for interaction = 0.05). CONCLUSIONS This study indicated that adherence to AHEI can reduce the odds of hyper LDL, hypertension, and hyperglycemia in the CC genotype of rs2287161.
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Affiliation(s)
- Fatemeh Dehghani Firouzabadi
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), P.O. Box: 14155-6117, Tehran, Iran
| | - Atieh Mirzababaei
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), P.O. Box: 14155-6117, Tehran, Iran
| | - Farideh Shiraseb
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), P.O. Box: 14155-6117, Tehran, Iran
| | - Hadith Tangestani
- Department of Nutrition, Persian Gulf Tropical Medicine Research Center, Bushehr University of Medical Sciences, Bushehr, Iran
| | - Khadijeh Mirzaei
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), P.O. Box: 14155-6117, Tehran, Iran.
- Department of Nutrition, Persian Gulf Tropical Medicine Research Center, Bushehr University of Medical Sciences, Bushehr, Iran.
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Gallop MR, Tobin SY, Chaix A. Finding balance: understanding the energetics of time-restricted feeding in mice. Obesity (Silver Spring) 2023; 31 Suppl 1:22-39. [PMID: 36513496 PMCID: PMC9877167 DOI: 10.1002/oby.23607] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 08/17/2022] [Accepted: 09/06/2022] [Indexed: 12/15/2022]
Abstract
Over the course of mammalian evolution, the ability to store energy likely conferred a survival advantage when food became scarce. A long-term increase in energy storage results from an imbalance between energy intake and energy expenditure, two tightly regulated parameters that generally balance out to maintain a fairly stable body weight. Understanding the molecular determinants of this feat likely holds the key to new therapeutic development to manage obesity and associated metabolic dysfunctions. Time-restricted feeding (TRF), a dietary intervention that limits feeding to the active phase, can prevent and treat obesity and metabolic dysfunction in rodents fed a high-fat diet, likely by exerting effects on energetic balance. Even when body weight is lower in mice on active-phase TRF, food intake is generally isocaloric as compared with ad libitum fed controls. This discrepancy between body weight and energy intake led to the hypothesis that energy expenditure is increased during TRF. However, at present, there is no consensus in the literature as to how TRF affects energy expenditure and energy balance as a whole, and the mechanisms behind metabolic adaptation under TRF are unknown. This review examines our current understanding of energy balance on TRF in rodents and provides a framework for future studies to evaluate the energetics of TRF and its molecular determinants.
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Affiliation(s)
- Molly R Gallop
- Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT
| | - Selene Y Tobin
- Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT
| | - Amandine Chaix
- Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT
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Does a high-fat diet affect the circadian clock, or is it the other way around? A systematic review. Nutr Res 2020; 84:1-13. [PMID: 33213889 DOI: 10.1016/j.nutres.2020.10.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Revised: 09/25/2020] [Accepted: 10/08/2020] [Indexed: 10/23/2022]
Abstract
This paper reviews studies that addressed the influence of diet on circadian rhythmicity in mice and, in turn, circadian clock chronodisruption and its role in the development of metabolic disorders. Studies from the past 14 years were selected via a systematic search conducted using the PubMed electronic database. After applying the inclusion and exclusion criteria, 291 studies were selected, of which 13 were chosen using the following inclusion criteria: use of a high-fat diet for mice, evaluation of clock gene expression, and the association between chronodisruption and lipid metabolism disorders. These studies reported changes in animals' biological clock when they developed metabolic disorders by consuming a high-fat diet. It was also evident that some clock gene mutations or deletions triggered metabolic changes. Disturbances of clock gene machinery may play important roles in lipid metabolism and the development of atherosclerotic processes. However, many metabolic processes also affect the function of clock genes and circadian systems. In summary, this review's results may provide new insights into the reciprocal regulation of energy homeostasis and the biological clock.
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8
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Man AWC, Xia N, Li H. Circadian Rhythm in Adipose Tissue: Novel Antioxidant Target for Metabolic and Cardiovascular Diseases. Antioxidants (Basel) 2020; 9:E968. [PMID: 33050331 PMCID: PMC7601443 DOI: 10.3390/antiox9100968] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Revised: 09/29/2020] [Accepted: 10/03/2020] [Indexed: 12/11/2022] Open
Abstract
Obesity is a major risk factor for most metabolic and cardiovascular disorders. Adipose tissue is an important endocrine organ that modulates metabolic and cardiovascular health by secreting signaling molecules. Oxidative stress is a common mechanism associated with metabolic and cardiovascular complications including obesity, type 2 diabetes, and hypertension. Oxidative stress can cause adipose tissue dysfunction. Accumulating data from both humans and experimental animal models suggest that adipose tissue function and oxidative stress have an innate connection with the intrinsic biological clock. Circadian clock orchestrates biological processes in adjusting to daily environmental changes according to internal or external cues. Recent studies have identified the genes and molecular pathways exhibiting circadian expression patterns in adipose tissue. Disruption of the circadian rhythmicity has been suggested to augment oxidative stress and aberrate adipose tissue function and metabolism. Therefore, circadian machinery in the adipose tissue may be a novel therapeutic target for the prevention and treatment of metabolic and cardiovascular diseases. In this review, we summarize recent findings on circadian rhythm and oxidative stress in adipose tissue, dissect the key components that play a role in regulating the clock rhythm, oxidative stress and adipose tissue function, and discuss the potential use of antioxidant treatment on metabolic and cardiovascular diseases by targeting the adipose clock.
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Affiliation(s)
| | | | - Huige Li
- Department of Pharmacology, Johannes Gutenberg University Medical Center, Langenbeckstr, 1, 55131 Mainz, Germany; (A.W.C.M.); (N.X.)
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9
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Qi X, Mitter SK, Yan Y, Busik JV, Grant MB, Boulton ME. Diurnal Rhythmicity of Autophagy Is Impaired in the Diabetic Retina. Cells 2020; 9:cells9040905. [PMID: 32272782 PMCID: PMC7226792 DOI: 10.3390/cells9040905] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2020] [Revised: 03/27/2020] [Accepted: 04/02/2020] [Indexed: 12/28/2022] Open
Abstract
Retinal homeostasis is under both diurnal and circadian regulation. We sought to investigate the diurnal expression of autophagy proteins in normal rodent retina and to determine if this is impaired in diabetic retinopathy. C57BL/6J mice and Bio-Breeding Zucker (BBZ) rats were maintained under a 12h/12h light/dark cycle and eyes, enucleated over a 24 h period. Eyes were also collected from diabetic mice with two or nine-months duration of type 1 diabetes (T1D) and Bio-Breeding Zucker diabetic rat (BBZDR/wor rats with 4-months duration of type 2 diabetes (T2D). Immunohistochemistry was performed for the autophagy proteins Atg7, Atg9, LC3 and Beclin1. These autophagy proteins (Atgs) were abundantly expressed in neural retina and endothelial cells in both mice and rats. A differential staining pattern was observed across the retinas which demonstrated a distinctive diurnal rhythmicity. All Atgs showed localization to retinal blood vessels with Atg7 being the most highly expressed. Analysis of the immunostaining demonstrated distinctive diurnal rhythmicity, of which Atg9 and LC3 shared a biphasic expression cycle with the highest level at 8:15 am and 8:15 pm. In contrast, Beclin1 revealed a 24-h cycle with the highest level observed at midnight. Atg7 was also on a 24-h cycle with peak expression at 8:15 am, coinciding with the first peak expression of Atg9 and LC3. In diabetic animals, there was a dramatic reduction in all four Atgs and the distinctive diurnal rhythmicity of these autophagy proteins was significantly impaired and phase shifted in both T1D and T2D animals. Restoration of diurnal rhythmicity and facilitation of autophagy protein expression may provide new treatment strategies for diabetic retinopathy.
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Affiliation(s)
- Xiaoping Qi
- Department of Ophthalmology and Visual Sciences, University of Alabama at Birmingham, AL 35294, USA; (X.Q.); (S.K.M.); (M.B.G.)
| | - Sayak K. Mitter
- Department of Ophthalmology and Visual Sciences, University of Alabama at Birmingham, AL 35294, USA; (X.Q.); (S.K.M.); (M.B.G.)
| | - Yuanqing Yan
- Department of Neurosurgery, The University of Texas Health Science Center, Houston, TX 77030, USA;
| | - Julia V. Busik
- Department of Physiology, Michigan State University, East Lansing, MI 48824, USA;
| | - Maria B. Grant
- Department of Ophthalmology and Visual Sciences, University of Alabama at Birmingham, AL 35294, USA; (X.Q.); (S.K.M.); (M.B.G.)
| | - Michael E. Boulton
- Department of Ophthalmology and Visual Sciences, University of Alabama at Birmingham, AL 35294, USA; (X.Q.); (S.K.M.); (M.B.G.)
- Correspondence:
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Chaix A, Lin T, Le HD, Chang MW, Panda S. Time-Restricted Feeding Prevents Obesity and Metabolic Syndrome in Mice Lacking a Circadian Clock. Cell Metab 2019; 29:303-319.e4. [PMID: 30174302 PMCID: PMC7751278 DOI: 10.1016/j.cmet.2018.08.004] [Citation(s) in RCA: 424] [Impact Index Per Article: 70.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Revised: 04/25/2018] [Accepted: 08/01/2018] [Indexed: 12/21/2022]
Abstract
Increased susceptibility of circadian clock mutant mice to metabolic diseases has led to the idea that a molecular clock is necessary for metabolic homeostasis. However, these mice often lack a normal feeding-fasting cycle. We tested whether time-restricted feeding (TRF) could prevent obesity and metabolic syndrome in whole-body Cry1;Cry2 and in liver-specific Bmal1 and Rev-erbα/β knockout mice. When provided access to food ad libitum, these mice rapidly gained weight and showed genotype-specific metabolic defects. However, when fed the same diet under TRF (food access restricted to 10 hr during the dark phase) they were protected from excessive weight gain and metabolic diseases. Transcriptome and metabolome analyses showed that TRF reduced the accumulation of hepatic lipids and enhanced cellular defenses against metabolic stress. These results suggest that the circadian clock maintains metabolic homeostasis by sustaining daily rhythms in feeding and fasting and by maintaining balance between nutrient and cellular stress responses.
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Affiliation(s)
- Amandine Chaix
- The Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Terry Lin
- The Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Hiep D Le
- The Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Max W Chang
- Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
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Onaolapo AY, Onaolapo OJ. Circadian dysrhythmia-linked diabetes mellitus: Examining melatonin’s roles in prophylaxis and management. World J Diabetes 2018; 9:99-114. [PMID: 30079146 PMCID: PMC6068738 DOI: 10.4239/wjd.v9.i7.99] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2018] [Revised: 06/01/2018] [Accepted: 06/08/2018] [Indexed: 02/05/2023] Open
Abstract
Diabetes mellitus is a chronic, life-threatening metabolic disorder that occurs worldwide. Despite an increase in the knowledge of the risk factors that are associated with diabetes mellitus, its worldwide prevalence has continued to rise; thus, necessitating more research into its aetiology. Recent researches are beginning to link a dysregulation of the circadian rhythm to impairment of intermediary metabolism; with evidences that circadian rhythm dysfunction might play an important role in the aetiology, course or prognosis of some cases of diabetes mellitus. These evidences thereby suggest possible relationships between the circadian rhythm regulator melatonin, and diabetes mellitus. In this review, we discuss the roles of the circadian rhythm in the regulation of the metabolism of carbohydrates and other macronutrients; with emphasis on the importance of melatonin and the impacts of its deficiency on carbohydrate homeostasis. Also, the possibility of using melatonin and its analogs for the “prophylaxis” or management of diabetes mellitus is also considered.
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Affiliation(s)
- Adejoke Y Onaolapo
- Behavioural Neuroscience/Neurobiology Unit, Department of Anatomy, Ladoke Akintola University of Technology, Ogbomosho 210211, Oyo State, Nigeria
| | - Olakunle J Onaolapo
- Behavioural Neuroscience/Neuropharmacology Unit, Department of Pharmacology, Ladoke Akintola University of Technology, Osogbo 230263, Osun State, Nigeria
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12
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Lee J, Ma K, Moulik M, Yechoor V. Untimely oxidative stress in β-cells leads to diabetes - Role of circadian clock in β-cell function. Free Radic Biol Med 2018; 119:69-74. [PMID: 29458148 PMCID: PMC5910243 DOI: 10.1016/j.freeradbiomed.2018.02.022] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2017] [Revised: 02/12/2018] [Accepted: 02/14/2018] [Indexed: 12/31/2022]
Abstract
Diabetes results from a loss of β-cell function. With the number of people with diabetes reaching epidemic proportions globally, understanding mechanisms that are contributing to this increasing prevalence is critical. One such factor has been circadian disruption, with shift-work, light pollution, jet-lag, increased screen time, all acting as potential contributory factors. Though circadian disruption has been epidemiologically associated with diabetes and other metabolic disorders for many decades, it is only recently that there has been a better understanding of the underlying molecular mechanisms. Experimental circadian disruption, via manipulation of environmental or genetic factors using gene-deletion mouse models, has demonstrated the importance of circadian rhythms in whole body metabolism. Genetic disruption of core clock genes, specifically in the β-cells in mice, have, now demonstrated the importance of the intrinsic β-cell clock in regulating function. Recent work has also shown the interaction of the circadian clock and enhancers in β-cells, indicating a highly integrated regulation of transcription and cellular function by the circadian clock. Disruption of either the whole body or only the β-cell clock leads to significant impairment of mitochondrial function, uncoupling, impaired vesicular transport, oxidative stress in β-cells and finally impaired glucose-stimulated insulin secretion and diabetes. In this review, we explore the role of the circadian clock in mitigating oxidative stress and preserving β-cell function.
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Affiliation(s)
- J Lee
- Diabetes and Beta Cell Biology Center, Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, University of Pittsburgh, 200 Lothrop, BST-1058W, Pittsburgh, PA 15261, United States
| | - K Ma
- Diabetes and Metabolism Research Institute, City of Hope, Duarte, CA, United States
| | - M Moulik
- Division of Cardiology, Department of Pediatrics, Children's Hospital of Pittsburgh and University of Pittsburgh, Pittsburgh, PA, United States
| | - V Yechoor
- Diabetes and Beta Cell Biology Center, Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, University of Pittsburgh, 200 Lothrop, BST-1058W, Pittsburgh, PA 15261, United States.
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13
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Huang Y, Wang H, Li Y, Tao X, Sun J. Poor Sleep Quality Is Associated with Dawn Phenomenon and Impaired Circadian Clock Gene Expression in Subjects with Type 2 Diabetes Mellitus. Int J Endocrinol 2017; 2017:4578973. [PMID: 28352282 PMCID: PMC5352967 DOI: 10.1155/2017/4578973] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2016] [Revised: 01/16/2017] [Accepted: 01/30/2017] [Indexed: 12/18/2022] Open
Abstract
Aims. We investigated whether poor sleep quality is associated with both dawn phenomenon and impaired circadian clock gene expression in subjects with diabetes. Methods. 81 subjects with diabetes on continuous glucose monitoring were divided into two groups according to the Pittsburgh Sleep Quality Index. The magnitude of dawn phenomenon was quantified by its increment from nocturnal nadir to prebreakfast. Peripheral leucocytes were sampled from 81 subjects with diabetes and 28 normal controls at 09:00. Transcript levels of circadian clock genes (BMAL1, PER1, PER2, and PER3) were determined by real-time quantitative polymerase chain reaction. Results. The levels of HbA1c and fasting glucose and the magnitude of dawn phenomenon were significantly higher in the diabetes group with poor sleep quality than that with good sleep quality. Peripheral leucocytes from subjects with poor sleep quality expressed significantly lower transcript levels of BMAL1 and PER1 compared with those with good sleep quality. Poor sleep quality was significantly correlated with magnitude of dawn phenomenon. Multiple linear regression showed that sleep quality and PER1 were significantly independently correlated with dawn phenomenon. Conclusions. Dawn phenomenon is associated with sleep quality. Furthermore, mRNA expression of circadian clock genes is dampened in peripheral leucocytes of subjects with poor sleep quality.
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Affiliation(s)
- Yuxin Huang
- Department of Endocrinology, Huadong Hospital Affiliated to Fudan University, 221 Yananxi Road, Shanghai 200040, China
- Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai, China
| | - Haidong Wang
- Department of Endocrinology, Huadong Hospital Affiliated to Fudan University, 221 Yananxi Road, Shanghai 200040, China
- Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai, China
| | - Yuan Li
- Department of Endocrinology, Huadong Hospital Affiliated to Fudan University, 221 Yananxi Road, Shanghai 200040, China
- Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai, China
| | - Xiaoming Tao
- Department of Endocrinology, Huadong Hospital Affiliated to Fudan University, 221 Yananxi Road, Shanghai 200040, China
- Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai, China
| | - Jiao Sun
- Department of Endocrinology, Huadong Hospital Affiliated to Fudan University, 221 Yananxi Road, Shanghai 200040, China
- Shanghai Key Laboratory of Clinical Geriatric Medicine, Shanghai, China
- *Jiao Sun:
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14
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Zarrinpar A, Chaix A, Panda S. Daily Eating Patterns and Their Impact on Health and Disease. Trends Endocrinol Metab 2016; 27:69-83. [PMID: 26706567 PMCID: PMC5081399 DOI: 10.1016/j.tem.2015.11.007] [Citation(s) in RCA: 177] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2015] [Revised: 11/10/2015] [Accepted: 11/13/2015] [Indexed: 12/26/2022]
Abstract
Cyclical expression of cell-autonomous circadian clock components and key metabolic regulators coordinate often discordant and distant cellular processes for efficient metabolism. Perturbation of these cycles, either by genetic manipulation, disruption of light/dark cycles, or, most relevant to the human population, via eating patterns, contributes to obesity and dysmetabolism. Time-restricted feeding (TRF), during which time of access to food is restricted to a few hours, without caloric restriction, supports robust metabolic cycles and protects against nutritional challenges that predispose to obesity and dysmetabolism. The mechanism by which TRF imparts its benefits is not fully understood but likely involves entrainment of metabolically active organs through gut signaling. Understanding the relationship of feeding pattern and metabolism could yield novel therapies for the obesity pandemic.
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Affiliation(s)
- Amir Zarrinpar
- Regulatory Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Division of Gastroenterology, University of California, San Diego, La Jolla, CA 92093, USA.
| | - Amandine Chaix
- Regulatory Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Satchidananda Panda
- Regulatory Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
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15
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Lee J, Liu R, de Jesus D, Kim BS, Ma K, Moulik M, Yechoor V. Circadian control of β-cell function and stress responses. Diabetes Obes Metab 2015; 17 Suppl 1:123-33. [PMID: 26332977 PMCID: PMC4762487 DOI: 10.1111/dom.12524] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2015] [Accepted: 05/27/2015] [Indexed: 12/20/2022]
Abstract
Circadian disruption is the bane of modern existence and its deleterious effects on health; in particular, diabetes and metabolic syndrome have been well recognized in shift workers. Recent human studies strongly implicate a 'dose-dependent' relationship between circadian disruption and diabetes. Genetic and environmental disruption of the circadian clock in rodents leads to diabetes secondary to β-cell failure. Deletion of Bmal1, a non-redundant core clock gene, leads to defects in β-cell stimulus-secretion coupling, decreased glucose-stimulated ATP production, uncoupling of OXPHOS and impaired glucose-stimulated insulin secretion. Both genetic and environmental circadian disruptions are sufficient to induce oxidative stress and this is mediated by a disruption of the direct transcriptional control of the core molecular clock and Bmal1 on Nrf2, the master antioxidant transcription factor in the β-cell. In addition, circadian disruption also leads to a dysregulation of the unfolded protein response and leads to endoplasmic reticulum stress in β-cells. Both the oxidative and endoplasmic reticulum (ER) stress contribute to an impairment of mitochondrial function and β-cell failure. Understanding the basis of the circadian control of these adaptive stress responses offers hope to target them for pharmacological modulation to prevent and mitigate the deleterious metabolic consequences of circadian disruption.
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Affiliation(s)
- J Lee
- Diabetes Research Center & Division of Diabetes, Endocrinology & Metabolism, Department of Medicine, Baylor College of Medicine, Houston Texas USA 77030
| | - R Liu
- Diabetes Research Center & Division of Diabetes, Endocrinology & Metabolism, Department of Medicine, Baylor College of Medicine, Houston Texas USA 77030
| | - D de Jesus
- Diabetes Research Center & Division of Diabetes, Endocrinology & Metabolism, Department of Medicine, Baylor College of Medicine, Houston Texas USA 77030
| | - BS Kim
- Diabetes Research Center & Division of Diabetes, Endocrinology & Metabolism, Department of Medicine, Baylor College of Medicine, Houston Texas USA 77030
| | - K Ma
- Center for Diabetes Research, The Methodist Hospital Research Institute, Houston Texas USA 77030
| | - M Moulik
- Division of Cardiology, Department of Pediatrics, University of Texas Medical School at Houston, Houston Texas USA 77030
| | - V Yechoor
- Diabetes Research Center & Division of Diabetes, Endocrinology & Metabolism, Department of Medicine, Baylor College of Medicine, Houston Texas USA 77030
- Dept of Molecular & Cellular Biology, Baylor College of Medicine; Houston Texas USA 77030
- Corresponding Author: Vijay Yechoor, MD, R612, One Baylor Plaza, Baylor College of Medicine, DERC & Division of Diabetes, Endocrinology & Metabolism, Department of Medicine, Houston TX 77030, Phone: 713-798-4146; Fax: 713-798-8764,
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16
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Renström F, Koivula RW, Varga TV, Hallmans G, Mulder H, Florez JC, Hu FB, Franks PW. Season-dependent associations of circadian rhythm-regulating loci (CRY1, CRY2 and MTNR1B) and glucose homeostasis: the GLACIER Study. Diabetologia 2015; 58:997-1005. [PMID: 25707907 DOI: 10.1007/s00125-015-3533-8] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2014] [Accepted: 02/02/2015] [Indexed: 12/21/2022]
Abstract
AIMS/HYPOTHESIS The association of single nucleotide polymorphisms (SNPs) proximal to CRY2 and MTNR1B with fasting glucose is well established. CRY1/2 and MTNR1B encode proteins that regulate circadian rhythmicity and influence energy metabolism. Here we tested whether season modified the relationship of these loci with blood glucose concentration. METHODS SNPs rs8192440 (CRY1), rs11605924 (CRY2) and rs10830963 (MTNR1B) were genotyped in a prospective cohort study from northern Sweden (n = 16,499). The number of hours of daylight exposure during the year ranged from 4.5 to 22 h daily. Owing to the non-linear distribution of daylight throughout the year, season was dichotomised based on the vernal and autumnal equinoxes. Effect modification was assessed using linear regression models fitted with a SNP × season interaction term, marginal effect terms and putative confounding variables, with fasting or 2 h glucose concentrations as outcomes. RESULTS The rs8192440 (CRY1) variant was only associated with fasting glucose among participants (n = 2,318) examined during the light season (β = -0.04 mmol/l per A allele, 95% CI -0.08, -0.01, p = 0.02, p interaction = 0.01). In addition to the established association with fasting glucose, the rs11605924 (CRY2) and rs10830963 (MTNR1B) loci were associated with 2 h glucose concentrations (β = 0.07 mmol/l per A allele, 95% CI 0.03, 0.12, p = 0.0008, n = 9,605, and β = -0.11 mmol/l per G allele, 95% CI -0.15, -0.06, p < 0.0001, n = 9,517, respectively), but only in participants examined during the dark season (p interaction = 0.006 and 0.04, respectively). Repeated measures analyses including data collected 10 years after baseline (n = 3,500) confirmed the results for the CRY1 locus (p interaction = 0.01). CONCLUSIONS/INTERPRETATION In summary, these observations suggest a biologically plausible season-dependent association between SNPs at CRY1, CRY2 and MTNR1B and glucose homeostasis.
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Affiliation(s)
- Frida Renström
- Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Lund University, Clinical Research Center Building 91, Level 10, Jan Waldenströms gata 35, SE-205 02, Malmö, Sweden,
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17
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Kovanen L, Donner K, Kaunisto M, Partonen T. CRY1, CRY2 and PRKCDBP genetic variants in metabolic syndrome. Hypertens Res 2014; 38:186-92. [PMID: 25391456 DOI: 10.1038/hr.2014.157] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2014] [Revised: 08/29/2014] [Accepted: 09/03/2014] [Indexed: 11/09/2022]
Abstract
The circadian clock affects metabolic cycles, and there is a link between circadian clock genes and metabolic syndrome. Therefore, we wanted to investigate whether variants of the core circadian clock genes, cryptochrome circadian clocks 1 and 2 (CRY1 and CRY2), or those of protein kinase C, delta binding protein (PRKCDBP), which regulate the interactions and abundance of dimers of the period and cryptochrome proteins, are associated with metabolic syndrome or its components. The association of 48 single-nucleotide polymorphisms (SNPs) from CRY1, CRY2 and PRKCDBP genes with metabolic disorder or its components was analyzed in a sample of 5910 individuals. Genotyping was performed using the Sequenom MassARRAY system. SNPs and haplotypes were analyzed using linear or logistic regression with additive models controlling for age and sex. Continuous phenotypes were permuted 10,000 times. False discovery rate q-values were calculated to correct for multiple testing. Overall, CRY1 and CRY2 variants showed nominal association with the metabolic syndrome components, hypertension and triglyceride levels, and one CRY2 variant had an association with metabolic syndrome, although none of these associations yielded significant q-values. However, the haplotype analysis of these variants supported the association of CRY1 with arterial hypertension and elevated blood pressure. Further studies are warranted regarding the role of CRY1 in cardiovascular diseases.
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Affiliation(s)
- Leena Kovanen
- Department of Mental Health and Substance Abuse Services, National Institute for Health and Welfare (THL), Helsinki, Finland
| | - Kati Donner
- Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
| | - Mari Kaunisto
- 1] Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland [2] Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland
| | - Timo Partonen
- Department of Mental Health and Substance Abuse Services, National Institute for Health and Welfare (THL), Helsinki, Finland
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18
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Janich P, Meng QJ, Benitah SA. Circadian control of tissue homeostasis and adult stem cells. Curr Opin Cell Biol 2014; 31:8-15. [PMID: 25016176 DOI: 10.1016/j.ceb.2014.06.010] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2014] [Revised: 06/17/2014] [Accepted: 06/19/2014] [Indexed: 01/21/2023]
Abstract
The circadian timekeeping mechanism adapts physiology to the 24-hour light/dark cycle. However, how the outputs of the circadian clock in different peripheral tissues communicate and synchronize each other is still not fully understood. The circadian clock has been implicated in the regulation of numerous processes, including metabolism, the cell cycle, cell differentiation, immune responses, redox homeostasis, and tissue repair. Accordingly, perturbation of the machinery that generates circadian rhythms is associated with metabolic disorders, premature ageing, and various diseases including cancer. Importantly, it is now possible to target circadian rhythms through systemic or local delivery of time cues or compounds. Here, we summarize recent findings in peripheral tissues that link the circadian clock machinery to tissue-specific functions and diseases.
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Affiliation(s)
- Peggy Janich
- Center for Integrative Genomics, University of Lausanne, CH-1015 Lausanne, Switzerland
| | - Qing-Jun Meng
- MRC Career Development Award Fellow, Faculty of Life Sciences, University of Manchester, United Kingdom
| | - Salvador Aznar Benitah
- Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain; Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain.
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19
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Affiliation(s)
- Takeshi Kurose
- Division of Diabetes, Clinical Nutrition and Endocrinology,
Department of Medicine, Kansai Electric Power Hospital,
Fukushima Ward, Osaka City
| | - Daisuke Yabe
- Division of Diabetes, Clinical Nutrition and Endocrinology,
Department of Medicine, Kansai Electric Power Hospital,
Fukushima Ward, Osaka City
| | - Nobuya Inagaki
- Department of Diabetes and Clinical Nutrition,
Kyoto University Graduate School of Medicine, Kyoto, Japan
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20
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Griebel G, Ravinet-Trillou C, Beeské S, Avenet P, Pichat P. Mice deficient in cryptochrome 1 (cry1 (-/-)) exhibit resistance to obesity induced by a high-fat diet. Front Endocrinol (Lausanne) 2014; 5:49. [PMID: 24782829 PMCID: PMC3988402 DOI: 10.3389/fendo.2014.00049] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2014] [Accepted: 03/26/2014] [Indexed: 12/03/2022] Open
Abstract
Disruption of circadian clock enhances the risk of metabolic syndrome, obesity, and type 2 diabetes. Circadian clocks rely on a highly regulated network of transcriptional and translational loops that drive clock-controlled gene expression. Among these transcribed clock genes are cryptochrome (CRY) family members, which comprise Cry1 and Cry2. While the metabolic effects of deletion of several core components of the clock gene machinery have been well characterized, those of selective inactivation of Cry1 or Cry2 genes have not been described. In this study, we demonstrate that ablation of Cry1, but not Cry2, prevents high-fat diet (HFD)-induced obesity in mice. Despite similar caloric intake, Cry1 (-/-) mice on HFD gained markedly less weight (-18%) at the end of the 16-week experiment and displayed reduced fat accumulation compared to wild-type (WT) littermates (-61%), suggesting increased energy expenditure. Analysis of serum lipid and glucose profiles showed no difference between Cry1 (-/-) and WT mice. Both Cry1 (-/-) and Cry2 (-/-) mice are indistinguishable from WT controls in body weight, fat and protein contents, and food consumption when they are allowed unlimited access to a standard rodent diet. We conclude that although CRY signaling may not be essential for the maintenance of energy homeostasis under steady-state nutritional conditions, Cry1 may play a role in readjusting energy balance under changing nutritional circumstances. These studies reinforce the important role of circadian clock genes in energy homeostasis and suggest that Cry1 is a plausible target for anti-obesity therapy.
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Affiliation(s)
- Guy Griebel
- Exploratory Unit, Sanofi R&D, Chilly-Mazarin, France
- *Correspondence: Guy Griebel, Exploratory Unit, Sanofi R&D, 1 Avenue Pierre Brossolette, Chilly-Mazarin 91385, France e-mail:
| | | | - Sandra Beeské
- Exploratory Unit, Sanofi R&D, Chilly-Mazarin, France
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21
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Shostak A, Husse J, Oster H. Circadian regulation of adipose function. Adipocyte 2013; 2:201-6. [PMID: 24052895 PMCID: PMC3774695 DOI: 10.4161/adip.26007] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2013] [Revised: 08/01/2013] [Accepted: 08/01/2013] [Indexed: 11/19/2022] Open
Abstract
Adipose physiology shows prominent variation over the course of the day, responding to changing demands in energy metabolism. In the last years the tight interaction between the endogenous circadian timing system and metabolic function has been increasingly acknowledged. Recent work suggests that clock and adipose function go hand in hand, regulating each other to ensure optimal adaptation to environmental changes over the 24-h cycle. In this review we describe the current knowledge on the mechanistic basis of this interaction and summarize recent findings on the impact of clock dysfunction on adipose physiology and energy homeostasis.
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22
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Richards J, All S, Skopis G, Cheng KY, Compton B, Srialluri N, Stow L, Jeffers LA, Gumz ML. Opposing actions of Per1 and Cry2 in the regulation of Per1 target gene expression in the liver and kidney. Am J Physiol Regul Integr Comp Physiol 2013; 305:R735-47. [PMID: 23824961 DOI: 10.1152/ajpregu.00195.2013] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Mounting evidence suggests that the circadian clock plays an integral role in the regulation of many physiological processes including blood pressure, renal function, and metabolism. The canonical molecular clock functions via activation of circadian target genes by Clock/Bmal1 and repression of Clock/Bmal1 activity by Per1-3 and Cry1/2. However, we have previously shown that Per1 activates genes important for renal sodium reabsorption, which contradicts the canonical role of Per1 as a repressor. Moreover, Per1 knockout (KO) mice exhibit a lowered blood pressure and heavier body weight phenotype similar to Clock KO mice, and opposite that of Cry1/2 KO mice. Recent work has highlighted the potential role of Per1 in repression of Cry2. Therefore, we postulated that Per1 potentially activates target genes through a Cry2-Clock/Bmal1-dependent mechanism, in which Per1 antagonizes Cry2, preventing its repression of Clock/Bmal1. This hypothesis was tested in vitro and in vivo. The Per1 target genes αENaC and Fxyd5 were identified as Clock targets in mpkCCDc14 cells, a model of the renal cortical collecting duct. We identified PPARα and DEC1 as novel Per1 targets in the mouse hepatocyte cell line, AML12, and in the liver in vivo. Per1 knockdown resulted in upregulation of Cry2 in vitro, and this result was confirmed in vivo in mice with reduced expression of Per1. Importantly, siRNA-mediated knockdown of Cry2 and Per1 demonstrated opposing actions for Cry2 and Per1 on Per1 target genes, supporting the potential Cry2-Clock/Bmal1-dependent mechanism underlying Per1 action in the liver and kidney.
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Affiliation(s)
- Jacob Richards
- Department of Medicine, University of Florida, Gainesville, Florida; and
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23
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24
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Barclay JL, Shostak A, Leliavski A, Tsang AH, Jöhren O, Müller-Fielitz H, Landgraf D, Naujokat N, van der Horst GTJ, Oster H. High-fat diet-induced hyperinsulinemia and tissue-specific insulin resistance in Cry-deficient mice. Am J Physiol Endocrinol Metab 2013; 304:E1053-63. [PMID: 23531614 DOI: 10.1152/ajpendo.00512.2012] [Citation(s) in RCA: 106] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Perturbation of circadian rhythmicity in mammals, either by environmental influences such as shiftwork or by genetic manipulation, has been associated with metabolic disturbance and the development of obesity and diabetes. Circadian clocks are based on transcriptional/translational feedback loops, comprising positive and negative components. Whereas the metabolic effects of deletion of the positive arm of the clock gene machinery, as in Clock- or Bmal1-deficient mice, have been well characterized, inactivation of Period genes (Per1-3) as components of the negative arm have more complex, sometimes contradictory effects on energy homeostasis. The CRYPTOCHROMEs are critical interaction partners of PERs, and simultaneous deletion of Cry1 and -2 results in behavioral and molecular circadian arrhythmicity. We show that, when challenged with a high-fat diet, Cry1/2(-/-) mice rapidly gain weight and surpass that of wild-type mice, despite displaying hypophagia. Transcript analysis of white adipose tissue reveals upregulated expression of lipogenic genes, many of which are insulin targets. High-fat diet-induced hyperinsulinemia, as a result of potentiated insulin secretion, coupled with selective insulin sensitivity in adipose tissue of Cry1/2(-/-) mice, correlates with increased lipid uptake. Collectively, these data indicate that Cry deficiency results in an increased vulnerability to high-fat diet-induced obesity that might be mediated by increased insulin secretion and lipid storage in adipose tissues.
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Affiliation(s)
- Johanna L Barclay
- Circadian Rhythms Group, Max Planck Institute of Biophysical Chemistry, Göttingen, Germany
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25
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Fu L, Kettner NM. The circadian clock in cancer development and therapy. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2013; 119:221-82. [PMID: 23899600 PMCID: PMC4103166 DOI: 10.1016/b978-0-12-396971-2.00009-9] [Citation(s) in RCA: 175] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Most aspects of mammalian function display circadian rhythms driven by an endogenous clock. The circadian clock is operated by genes and comprises a central clock in the brain that responds to environmental cues and controls subordinate clocks in peripheral tissues via circadian output pathways. The central and peripheral clocks coordinately generate rhythmic gene expression in a tissue-specific manner in vivo to couple diverse physiological and behavioral processes to periodic changes in the environment. However, with the industrialization of the world, activities that disrupt endogenous homeostasis with external circadian cues have increased. This change in lifestyle has been linked to an increased risk of diseases in all aspects of human health, including cancer. Studies in humans and animal models have revealed that cancer development in vivo is closely associated with the loss of circadian homeostasis in energy balance, immune function, and aging, which are supported by cellular functions important for tumor suppression including cell proliferation, senescence, metabolism, and DNA damage response. The clock controls these cellular functions both locally in cells of peripheral tissues and at the organismal level via extracellular signaling. Thus, the hierarchical mammalian circadian clock provides a unique system to study carcinogenesis as a deregulated physiological process in vivo. The asynchrony between host and malignant tissues in cell proliferation and metabolism also provides new and exciting options for novel anticancer therapies.
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Affiliation(s)
- Loning Fu
- Department of Pediatrics/U.S. Department of Agriculture/Agricultural Research Service/Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX, USA
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
- Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA
| | - Nicole M. Kettner
- Department of Pediatrics/U.S. Department of Agriculture/Agricultural Research Service/Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX, USA
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
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26
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Waddell B, Wharfe M, Crew R, Mark P. A rhythmic placenta? Circadian variation, clock genes and placental function. Placenta 2012; 33:533-9. [DOI: 10.1016/j.placenta.2012.03.008] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2012] [Accepted: 03/22/2012] [Indexed: 12/19/2022]
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27
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Lee J, Kim MS, Li R, Liu VY, Fu L, Moore DD, Ma K, Yechoor VK. Loss of Bmal1 leads to uncoupling and impaired glucose-stimulated insulin secretion in β-cells. Islets 2011; 3:381-8. [PMID: 22045262 PMCID: PMC3329519 DOI: 10.4161/isl.3.6.18157] [Citation(s) in RCA: 94] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
The circadian clock has been shown to regulate metabolic homeostasis. Mice with a deletion of Bmal1, a key component of the core molecular clock, develop hyperglycemia and hypoinsulinemia, suggesting β-cell dysfunction. However, the underlying mechanisms are not fully known. In this study, we investigated the mechanisms underlying the regulation of β-cell function by Bmal1. We studied β-cell function in global Bmal1-/- mice, in vivo and in isolated islets ex vivo, as well as in rat insulinoma cell lines with shRNA-mediated Bmal1 knockdown. Global Bmal1-/- mice develop diabetes secondary to a significant impairment in glucose-stimulated insulin secretion (GSIS). There is a blunting of GSIS in both isolated Bmal1-/- islets and in Bmal1 knockdown cells, as compared to controls, suggesting that this is secondary to a loss of cell-autonomous effect of Bmal1. In contrast to previous studies, in these Bmal1-/- mice on a C57Bl/6 background, the loss of stimulated insulin secretion, interestingly, is with glucose but not to other depolarizing secretagogues, suggesting that events downstream of membrane depolarization are largely normal in Bmal1-/- islets. This defect in GSIS occurs as a result increased mitochondrial uncoupling with consequent impairment of glucose-induced mitochondrial potential generation and ATP synthesis, due to an upregulation of Ucp2. Inhibition of Ucp2, in isolated islets, leads to a rescue of the glucose-induced ATP production and insulin secretion in Bmal1-/- islets. Thus, Bmal1 regulates mitochondrial energy metabolism to maintain normal GSIS and its disruption leads to diabetes due to a loss of GSIS.
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Affiliation(s)
- Jeongkyung Lee
- DERC & Division of Diabetes, Endocrinology & Metabolism; Department of Medicine; Baylor College of Medicine; Houston, TX USA
| | - Mi-Sun Kim
- DERC & Division of Diabetes, Endocrinology & Metabolism; Department of Medicine; Baylor College of Medicine; Houston, TX USA
| | - Rongying Li
- DERC & Division of Diabetes, Endocrinology & Metabolism; Department of Medicine; Baylor College of Medicine; Houston, TX USA
| | - Victoria Y. Liu
- DERC & Division of Diabetes, Endocrinology & Metabolism; Department of Medicine; Baylor College of Medicine; Houston, TX USA
| | - Loning Fu
- CNRC Pediatrics-Nutrition; Baylor College of Medicine; Houston, TX USA
| | - David D. Moore
- Dept of Molecular & Cellular Biology; Baylor College of Medicine; Houston, TX USA
| | - Ke Ma
- Center for Diabetes Research; The Methodist Hospital Research Institute; Houston, TX USA
| | - Vijay K. Yechoor
- DERC & Division of Diabetes, Endocrinology & Metabolism; Department of Medicine; Baylor College of Medicine; Houston, TX USA
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28
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Yu EA, Weaver DR. Disrupting the circadian clock: gene-specific effects on aging, cancer, and other phenotypes. Aging (Albany NY) 2011; 3:479-93. [PMID: 21566258 PMCID: PMC3156599 DOI: 10.18632/aging.100323] [Citation(s) in RCA: 172] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The circadian clock imparts 24-hour rhythmicity on gene expression and cellular physiology in virtually all cells. Disruption of the genes necessary for the circadian clock to function has diverse effects, including aging-related phenotypes. Some circadian clock genes have been described as tumor suppressors, while other genes have less clear functions in aging and cancer. In this Review, we highlight a recent study [Dubrovsky et al., Aging 2: 936-944, 2010] and discuss the much larger field examining the relationship between circadian clock genes, circadian rhythmicity, aging-related phenotypes, and cancer.
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Affiliation(s)
- Elizabeth A Yu
- Department of Neurobiology, MD/PhD Program, University of Massachusetts Medical School, Worcester, 01605, USA
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29
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HASHIMOTO H, EBUKURO S, NOZU R, UENO M, ARAI T, KAWAI K, HIRATA H, OGAWA M, MIZUSAWA T, IMAI K, HIGUCHI Y, SUEMIZU H, ITO M, SAITO M, HIOKI K. Vinyl Isolator Breeding Induces Insulin Resistance in C57BL/6JJcl Mice. Exp Anim 2011; 60:497-508. [DOI: 10.1538/expanim.60.497] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022] Open
Affiliation(s)
| | | | - Ryoko NOZU
- Central Institute for Experimental Animals
| | | | - Toshiro ARAI
- Department of Veterinary Science, School of Veterinary Medicine, Nippon Veterinary and Life Science University
| | | | | | - Maya OGAWA
- Central Institute for Experimental Animals
| | | | | | | | | | - Mamoru ITO
- Central Institute for Experimental Animals
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Okano S, Hayasaka K, Igarashi M, Iwai H, Togashi Y, Nakajima O. Non-obese early onset diabetes mellitus in mutant cryptochrome1 transgenic mice. Eur J Clin Invest 2010; 40:1011-7. [PMID: 20678120 DOI: 10.1111/j.1365-2362.2010.02359.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
BACKGROUND An earlier report described that transgenic mice ubiquitously expressing cryptochrome1 (CRY1) with a mutation in cystein414 (CRY1-AP Tg mice) display diabetes mellitus in addition to anomalous circadian behaviours. This study examined characteristic aspects of symptoms to clarify the diabetes type and pathogenesis. MATERIALS AND METHODS The body weights and blood glucose levels of CRY1-AP Tg mice were measured for 7weeks starting at 3weeks after birth. Glucose tolerance test for the mice of various ages and insulin tolerance test at 6weeks of age were conducted. Immunohistochemical analysis of islets was carried out for the mice of 19 and 40weeks of age. Basal and glucose-stimulated serum insulin levels of mice at 27weeks were also measured. RESULTS Three-week-old CRY1-AP Tg mice, which showed mild retardation in growth, already displayed glucose intolerance. Hyperglycaemia progressed with age, without accompanying insulin resistance. Insulin-stained areas in islets in CRY1-AP Tg mice were smaller than that in wild-type controls. Both basal and glucose-stimulated secretion of insulin decreased in CRY1-AP Tg mice. CONCLUSION The symptoms of diabetes in CRY1-AP Tg mice turned out to be similar to those of maturity onset diabetes of the young (MODY) in humans in terms of early onset, non-obesity and primary dysfunction of beta cells. The CRY1-AP Tg mice might serve as an animal model of early onset insulin-secretory defect of diabetes.
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Affiliation(s)
- Satoshi Okano
- Research Laboratory for Molecular Genetics, Yamagata University School of Medicine, Yamagata, Japan
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Mittag J, Davis B, Vujovic M, Arner A, Vennström B. Adaptations of the autonomous nervous system controlling heart rate are impaired by a mutant thyroid hormone receptor-alpha1. Endocrinology 2010; 151:2388-95. [PMID: 20228172 DOI: 10.1210/en.2009-1201] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Thyroid hormone has profound direct effects on cardiac function, but the hormonal interactions with the autonomic control of heart rate are unclear. Because thyroid hormone receptor (TR)-alpha1 has been implicated in the autonomic control of brown adipose energy metabolism, it might also play an important role in the central autonomic control of heart rate. Thus, we aimed to analyze the role of TRalpha1 signaling in the autonomic control of heart rate using an implantable radio telemetry system. We identified that mice expressing the mutant TRalpha1R384C (TRalpha1+m mice) displayed a mild bradycardia, which becomes more pronounced during night activity or on stress and is accompanied by a reduced expression of nucleotide-gated potassium channel 2 mRNA in the heart. Pharmacological blockage with scopolamine and the beta-adrenergic receptor antagonist timolol revealed that the autonomic control of cardiac activity was similar to that in wild-type mice at room temperature. However, at thermoneutrality, in which the regulation of heart rate switches from sympathetic to parasympathetic in wild-type mice, TRalpha1+m mice maintained sympathetic stimulation and failed to activate parasympathetic signaling. Our findings demonstrate a novel role for TRalpha1 in the adaptation of cardiac activity by the autonomic nervous system and suggest that human patients with a similar mutation in TRalpha1 might exhibit a deficit in cardiac adaptation to stress or physical activity and an increased sensitivity to beta-blockers.
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Affiliation(s)
- Jens Mittag
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
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Wang K, Xiang XH, He F, Lin LB, Zhang R, Ping XJ, Han JS, Guo N, Zhang QH, Cui CL, Zhao GP. Transcriptome profiling analysis reveals region-distinctive changes of gene expression in the CNS in response to different moderate restraint stress. J Neurochem 2010; 113:1436-46. [PMID: 20218974 DOI: 10.1111/j.1471-4159.2010.06679.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
It is generally believed that temporary moderate stress to a living organism has protective and adaptive effects, but little is known about the responses of CNS to the moderate stresses at molecular level. This study aims to investigate the gene expression changes induced by moderate stress in CNS stress- and nociception-related regions of rats. Moderate restraint was applied to rats for 50 min and cDNA microarrays were used to detect the differential gene expression in different CNS regions. Transcriptome profiling analysis showed that at acute stage stress-related genes were up-regulated in arcuate nucleus; fight-or-flight behavior-related genes were up-regulated in periaqueductal gray, while nitric oxide and GABA signal transmission-related genes were up-regulated in spinal dorsal horn. In addition, immune-related genes were broadly regulated, especially at the late stage. These results suggested that specific genes of certain gene ontology categories were spatiotemporally regulated in specific CNS regions related to relevant functions under moderate external stimuli at acute stage, while immune response was broadly regulated at the late stage. The co-regulated genes among the three different CNS regions may play general roles in CNS when exposed to moderate stress. Furthermore, these results will help to elucidate the physiological processes involved in moderate stress in CNS.
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Affiliation(s)
- Ke Wang
- Graduate School, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Abstract
Diurnal rhythms influence cardiovascular physiology such as heart rate and blood pressure and the incidence of adverse cardiac events such as heart attack and stroke. For example, shift workers and patients with sleep disturbances, such as obstructive sleep apnea, have an increased risk of heart attack, stroke, and sudden death. Diurnal variation is also evident at the molecular level, as gene expression in the heart and blood vessels is remarkably different in the day as compared to the night. Much of the evidence presented here indicates that growth and renewal (structural remodeling) are highly dependent on processes that occur during the subjective night. Myocardial metabolism is also dynamic with substrate preference also differing day from night. The risk/benefit ratio of some therapeutic strategies and the appearance of biomarkers also vary across the 24-hour diurnal cycle. Synchrony between external and internal diurnal rhythms and harmony among the molecular rhythms within the cell is essential for normal organ biology. Cell physiology is 4 dimensional; the substrate and enzymatic components of a given metabolic pathway must be present not only in the right compartmental space within the cell but also at the right time. As a corollary, we show disrupting this integral relationship has devastating effects on cardiovascular, renal and possibly other organ systems. Harmony between our biology and our environment is vital to good health.
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Affiliation(s)
- Tami A Martino
- Department of Biomedical Sciences, OVC, University of Guelph, Guelph, ON, Canada, N1G2W1.
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Busik JV, Tikhonenko M, Bhatwadekar A, Opreanu M, Yakubova N, Caballero S, Player D, Nakagawa T, Afzal A, Kielczewski J, Sochacki A, Hasty S, Li Calzi S, Kim S, Duclas SK, Segal MS, Guberski DL, Esselman WJ, Boulton ME, Grant MB. Diabetic retinopathy is associated with bone marrow neuropathy and a depressed peripheral clock. ACTA ACUST UNITED AC 2009; 206:2897-906. [PMID: 19934019 PMCID: PMC2806461 DOI: 10.1084/jem.20090889] [Citation(s) in RCA: 185] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
The present epidemic of diabetes is resulting in a worldwide increase in cardiovascular and microvascular complications including retinopathy. Current thinking has focused on local influences in the retina as being responsible for development of this diabetic complication. However, the contribution of circulating cells in maintenance, repair, and dysfunction of the vasculature is now becoming appreciated. Diabetic individuals have fewer endothelial progenitor cells (EPCs) in their circulation and these cells have diminished migratory potential, which contributes to their decreased reparative capacity. Using a rat model of type 2 diabetes, we show that the decrease in EPC release from diabetic bone marrow is caused by bone marrow neuropathy and that these changes precede the development of diabetic retinopathy. In rats that had diabetes for 4 mo, we observed a dramatic reduction in the number of nerve terminal endings in the bone marrow. Denervation was accompanied by increased numbers of EPCs within the bone marrow but decreased numbers in circulation. Furthermore, denervation was accompanied by a loss of circadian release of EPCs and a marked reduction in clock gene expression in the retina and in EPCs themselves. This reduction in the circadian peak of EPC release led to diminished reparative capacity, resulting in the development of the hallmark feature of diabetic retinopathy, acellular retinal capillaries. Thus, for the first time, diabetic retinopathy is related to neuropathy of the bone marrow. This novel finding shows that bone marrow denervation represents a new therapeutic target for treatment of diabetic vascular complications.
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Affiliation(s)
- Julia V Busik
- Department of Physiology, Michigan State University, East Lansing, MI 48824, USA.
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Koshiyama H, Ogawa Y, Tanaka K, Tanaka I. Integrated network systems and evolutionary developmental endocrinology. Med Hypotheses 2009; 74:132-8. [PMID: 19674847 DOI: 10.1016/j.mehy.2009.07.028] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2009] [Revised: 07/04/2009] [Accepted: 07/06/2009] [Indexed: 10/20/2022]
Abstract
Endocrine system has been considered to be a linear one, but the 'real world endocrine system' is a complex system, which is difficult to investigate using conventional strategies, such as single nucleotide polymorphism, genome-wide analysis, or gene targeting in animals. Here we propose a new strategy to comprehend the endocrine system as a complex network system. We introduced several novel concepts, such as complex system, network analysis, systems biology and evolutionary medicine, into the comprehension of endocrine system as a whole complex network system. This system is considered to be a scale-free network with key molecules such as acetyl CoA, NAD or ATP as 'hubs'. This system is robust against simple mutations, but various complex diseases may attack hubs. The system is also 'fractals', since there exist similar network systems among cells, proteins, and transcription factors in the lower levels, and there are similar ones among disease and social network in the higher levels. We propose to call this model 'Integrated Network Systems and Evolutionary DEvelopmental ENdocrinology (INS-EDEN)'. This novel framework will facilitate us to develop a new approach for understanding and treatment of various complex diseases related to endocrinology, and identify a unified theory of complex diseases.
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Affiliation(s)
- Hiroyuki Koshiyama
- Center for Diabetes and Endocrinology, The Tazuke Kofukai Foundation Medical Research Institute Kitano Hospital, Osaka, Japan.
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