Circadian time signatures of fitness and disease Bass, Joseph; Lazar, Mitchell A.
Science (American Association for the Advancement of Science),
11/2016, Letnik:
354, Številka:
6315
Journal Article
Recenzirano
Biological clocks are autonomous anticipatory oscillators that play a critical role in the organization and information processing from genome to whole organisms. Transformative advances into the ...clock system have opened insight into fundamental mechanisms through which clocks program energy transfer from sunlight into organic matter and potential energy, in addition to cell development and genotoxic stress response. The identification of clocks in nearly every single cell of the body raises questions as to how this gives rise to rhythmic physiology in multicellular organisms and how environmental signals entrain clocks to geophysical time. Here, we consider advances in understanding how regulatory networks emergent in clocks give rise to cell type-specific functions within tissues to affect homeostasis.
Circadian Integration of Metabolism and Energetics Bass, Joseph; Takahashi, Joseph S
Science (American Association for the Advancement of Science),
12/2010, Letnik:
330, Številka:
6009
Journal Article
Recenzirano
Odprti dostop
Circadian clocks align behavioral and biochemical processes with the day/night cycle. Nearly all vertebrate cells possess self-sustained clocks that couple endogenous rhythms with changes in cellular ...environment. Genetic disruption of clock genes in mice perturbs metabolic functions of specific tissues at distinct phases of the sleep/wake cycle. Circadian desynchrony, a characteristic of shift work and sleep disruption in humans, also leads to metabolic pathologies. Here, we review advances in understanding the interrelationship among circadian disruption, sleep deprivation, obesity, and diabetes and implications for rational therapeutics for these conditions.
Muscle atrophy and sarcopenia (the term given to the age-related decline in muscle mass and function), influence an individuals risk of falls, frailty, functional decline, and, ultimately, impaired ...quality of life. Vitamin D deficiency (low serum levels of 25-hydroxyvitamin D (25(OH)D3)) has been reported to impair muscle strength and increase risk of sarcopenia. The mechanisms that underpin the link between low 25(OH)D3 and sarcopenia are yet to be fully understood but several lines of evidence have highlighted the importance of both genomic and non-genomic effects of active vitamin D (1,25-dihydroxyvitamin D (1,25(OH)2D3)) and its nuclear vitamin D receptor (VDR), in skeletal muscle functioning. Studies in vitro have demonstrated a key role for the vitamin D/VDR axis in regulating biological processes central to sarcopenic muscle atrophy, such as proteolysis, mitochondrial function, cellular senescence, and adiposity. The aim of this review is to provide a mechanistic overview of the proposed mechanisms for the vitamin D/VDR axis in sarcopenic muscle atrophy.
•Vitamin D deficiency is prevalent and it impacts musculoskeletal health negatively, therefore warranting future research.•This review synthesises how the vitamin D/VDR axis may impact systems biology within skeletal muscle.•We provide a working model of mechanistic links between the vitamin D/VDR axis and muscle biology.
Biological clocks are genetically encoded oscillators that allow organisms to anticipate changes in the light-dark environment that are tied to the rotation of Earth. Clocks enhance fitness and ...growth in prokaryotes, and they are expressed throughout the central nervous system and peripheral tissues of multicelled organisms in which they influence sleep, arousal, feeding and metabolism. Biological clocks capture the imagination because of their tie to geophysical time, and tools are now in hand to analyse their function in health and disease at the cellular and molecular level.
Joseph T. Bass discusses recent developments in circadian clock research and reflects on the future of the field and its potential applications to clinical medicine.
The discovery of an internal temporal clockwork that coordinates behavior and metabolism according to the rising and setting of the sun was first revealed in flies and plants. However, in the past ...decade, a molecular transcription–translation feedback loop with similar properties has also been identified in mammals. In mammals, this transcriptional oscillator programs 24-hour cycles in sleep, activity and feeding within the master pacemaker neurons of the suprachiasmatic nucleus of the hypothalamus. More recent studies have shown that the core transcription mechanism is also present in other locations within the brain, in addition to many peripheral tissues. Processes ranging from glucose transport to gluconeogenesis, lipolysis, adipogenesis and mitochondrial oxidative phosphorylation are controlled through overlapping transcription networks that are tied to the clock and are thus time sensitive. Because disruption of tissue timing occurs when food intake, activity and sleep are altered, understanding how these many tissue clocks are synchronized to tick at the same time each day, and determining how each tissue ‘senses time’ set by these molecular clocks might open new insight into human disease, including disorders of sleep, circadian disruption, diabetes and obesity.
Studies of body weight regulation have focused almost entirely on caloric intake and energy expenditure. However, a number of recent studies in animals linking energy regulation and the circadian ...clock at the molecular, physiological, and behavioral levels raise the possibility that the timing of food intake itself may play a significant role in weight gain. The present study focused on the role of the circadian phase of food consumption in weight gain. We provide evidence that nocturnal mice fed a high‐fat diet only during the 12‐h light phase gain significantly more weight than mice fed only during the 12‐h dark phase. A better understanding of the role of the circadian system for weight gain could have important implications for developing new therapeutic strategies for combating the obesity epidemic facing the human population today.
Disrupted sleep-wake and molecular circadian rhythms are a feature of aging associated with metabolic disease and reduced levels of NAD+, yet whether changes in nucleotide metabolism control ...circadian behavioral and genomic rhythms remains unknown. Here, we reveal that supplementation with the NAD+ precursor nicotinamide riboside (NR) markedly reprograms metabolic and stress-response pathways that decline with aging through inhibition of the clock repressor PER2. NR enhances BMAL1 chromatin binding genome-wide through PER2K680 deacetylation, which in turn primes PER2 phosphorylation within a domain that controls nuclear transport and stability and that is mutated in human advanced sleep phase syndrome. In old mice, dampened BMAL1 chromatin binding, transcriptional oscillations, mitochondrial respiration rhythms, and late evening activity are restored by NAD+ repletion to youthful levels with NR. These results reveal effects of NAD+ on metabolism and the circadian system with aging through the spatiotemporal control of the molecular clock.
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•NAD+ induces transcription of stress and metabolic genes through the circadian clock•BMAL1 is required for chromatin remodeling and HSF1 recruitment in response to NAD+•NAD+ regulates PER2 acetylation and localization to control feedback repression•NAD+ counters age-related decline in circadian function
Aging is associated with disrupted circadian rhythms through signals that remain unidentified. Levine et al. show that NAD+ controls global circadian transcription through post-translational modification of PER2 and feedback repression. Raising NAD+ restores youthful transcription and mitochondrial rhythms in old age, revealing that NAD+ governs both behavior and metabolic health.
Dietary protein is critical for the maintenance of musculoskeletal health, whereappropriate intake (i.e., source, dose, timing) can mitigate declines in muscle and bone mass and/orfunction. ...Animal-derived protein is a potent anabolic source due to rapid digestion and absorptionkinetics stimulating robust increases in muscle protein synthesis and promoting bone accretion andmaintenance. However, global concerns surrounding environmental sustainability has led to anincreasing interest in plant- and collagen-derived protein as alternative or adjunct dietary sources.This is despite the lower anabolic profile of plant and collagen protein due to the inferior essentialamino acid profile (e.g., lower leucine content) and subordinate digestibility (versus animal). Thisreview evaluates the efficacy of animal-, plant- and collagen-derived proteins in isolation, and asprotein blends, for augmenting muscle and bone metabolism and health in the context of ageing,exercise and energy restriction.
The molecular clock maintains energy constancy by producing circadian oscillations of rate-limiting enzymes involved in tissue metabolism across the day and night. During periods of feeding, ...pancreatic islets secrete insulin to maintain glucose homeostasis, and although rhythmic control of insulin release is recognized to be dysregulated in humans with diabetes, it is not known how the circadian clock may affect this process. Here we show that pancreatic islets possess self-sustained circadian gene and protein oscillations of the transcription factors CLOCK and BMAL1. The phase of oscillation of islet genes involved in growth, glucose metabolism and insulin signalling is delayed in circadian mutant mice, and both Clock and Bmal1 (also called Arntl) mutants show impaired glucose tolerance, reduced insulin secretion and defects in size and proliferation of pancreatic islets that worsen with age. Clock disruption leads to transcriptome-wide alterations in the expression of islet genes involved in growth, survival and synaptic vesicle assembly. Notably, conditional ablation of the pancreatic clock causes diabetes mellitus due to defective -cell function at the very latest stage of stimulus-secretion coupling. These results demonstrate a role for the -cell clock in coordinating insulin secretion with the sleep-wake cycle, and reveal that ablation of the pancreatic clock can trigger the onset of diabetes mellitus.
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