Misalignment with the external light environment drives metabolic and cardiac dysfunction

West, Alexander C.; Smith, Laura C.; Ray, David; Loudon, A. S. I.; Brown, T. M.; Bechtold, David A.

doi:10.1038/s41467-017-00462-2

Cited by 133 publications

(119 citation statements)

References 69 publications

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“…219,220 Mice that have a misalignment between the internal clock and the external environment (ie housed under a day/night cycle of 20 hours or 30 hours instead of the normal 24 hour cycle) showed altered daily patterns of energy expenditure and carbohydrate and fat oxidation, leading to longer QT intervals. 221 The metabolic alterations were associated with a lower cardiac mitochondrial content. 222 Furthermore, expression of Pgc1a, Mfn1 and Opa1 was downregulated in mice with disturbed circadian rhythms, suggesting that the molecular clock plays a role in the regulation of cardiac mitochondrial dynamics.…”

Section: Interplay Between Circadian Rhythm and Myocardial Functionmentioning

confidence: 99%

“…For example ex vivo experiments on rat heart demonstrated that oxidation of exogenous glucose showed significant diurnal variation, whereas no such variations were seen in the oxidation of exogenous oleate . Mice that have a misalignment between the internal clock and the external environment (ie housed under a day/night cycle of 20 hours or 30 hours instead of the normal 24 hour cycle) showed altered daily patterns of energy expenditure and carbohydrate and fat oxidation, leading to longer QT intervals . The metabolic alterations were associated with a lower cardiac mitochondrial content .…”

Section: Lifestyle and Pharmacological Interventions To Target Mitochmentioning

confidence: 99%

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Altered mitochondrial metabolism in the insulin‐resistant heart

et al. 2019

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Obesity‐induced insulin resistance and type 2 diabetes mellitus can ultimately result in various complications, including diabetic cardiomyopathy. In this case, cardiac dysfunction is characterized by metabolic disturbances such as impaired glucose oxidation and an increased reliance on fatty acid (FA) oxidation. Mitochondrial dysfunction has often been associated with the altered metabolic function in the diabetic heart, and may result from FA‐induced lipotoxicity and uncoupling of oxidative phosphorylation. In this review, we address the metabolic changes in the diabetic heart, focusing on the loss of metabolic flexibility and cardiac mitochondrial function. We consider the alterations observed in mitochondrial substrate utilization, bioenergetics and dynamics, and highlight new areas of research which may improve our understanding of the cause and effect of cardiac mitochondrial dysfunction in diabetes. Finally, we explore how lifestyle (nutrition and exercise) and pharmacological interventions can prevent and treat metabolic and mitochondrial dysfunction in diabetes.

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Section: Interplay Between Circadian Rhythm and Myocardial Functionmentioning

confidence: 99%

Section: Lifestyle and Pharmacological Interventions To Target Mitochmentioning

confidence: 99%

Altered mitochondrial metabolism in the insulin‐resistant heart

et al. 2019

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“…The resulting 24-hour oscillations in protein expression can be disrupted through environmental disruption (e.g. shift-work schedules), or genetic deletion of core clock components producing inflammatory and metabolic phenotypes (5,21,22).…”

Section: Introductionmentioning

confidence: 99%

The circadian clock protein REVERBα inhibits pulmonary fibrosis development

Cunningham¹,

Meijer²,

Nazgiewicz³

et al. 2019

Preprint

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Pulmonary inflammatory responses lie under circadian control; however the importance of circadian mechanisms in fibrosis is not understood. Here, we identify a striking change to these mechanisms resulting in a gain of amplitude and lack of synchrony within pulmonary fibrotic tissue. These changes result from an infiltration of mesenchymal cells, an important cell type in the pathogenesis of pulmonary fibrosis. Mutation of the core clock protein REVERBα in these cells exacerbated the development of bleomycin-induced fibrosis, whereas mutation of REVERBα in club or myeloid cells had no effect on the bleomycin phenotype. Knockdown of REVERBα revealed regulation of the poorly described transcription factor TBPL1. Both REVERBα and TBPL1 altered integrinβ1 focal adhesion formation, resulting in increased myofibroblast activation. The translational importance of our findings was established through analysis of two human cohorts. In the UK Biobank circadian strain markers (sleep length, chronotype and shift work) are associated with pulmonary fibrosis making them novel risk factors. In a separate cohort REVERBα expression was increased in human idiopathic pulmonary fibrosis (IPF) lung tissue. Pharmacological targeting of REVERBα inhibited myofibroblast activation in IPF fibroblasts and collagen secretion in organotypic cultures from IPF patients, suggesting targeting REVERBα could be a viable therapeutic approach.SignificanceThe circadian clock plays an essential role in energy metabolism, and inflammation. In contrast the importance of the clock in the pathogenesis of fibrosis remains poorly explored. This study describes a striking alteration in circadian biology during pulmonary fibrosis where the relatively arrhythmic alveolar structures gain circadian but desynchronous rhythmicity due to infiltration by fibroblasts. Disruption of the clock in these cells, which are not widely implicated in circadian pathophysiology, results in a pro-fibrotic phenotype. Translation of these findings in humans revealed previously unrecognised important circadian risk factors for pulmonary fibrosis (sleep length, chronotype and shift work). In addition, targeting REVERBα repressed collagen secretion from human fibrotic lung tissue making this protein a promising therapeutic target.

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“…Indeed, neglecting our internal 24‐h timing system, which coordinates countless fundamental physiological processes, can exacerbate ill‐health conditions such as psychiatric disorders, obesity, diabetes, cardiovascular disease, and possibly even cancer . Unfortunately, most humans pay little attention to their internal clock and daily light exposure (a key cue for setting and regulating the clock) and too often push their bodies beyond their clocks’ capabilities .…”

mentioning

confidence: 99%

“…Long‐term consequences of circadian disruption may include psychiatric disorders, obesity, diabetes, cardiac disease, and cancers . It is now widely accepted in research that modern lifestyles cause insufficient or inappropriate light exposure on our circadian timing system, which likely contributes to the current epidemic of sleep deficiency in developed societies .…”

mentioning

confidence: 99%