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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•TRF protects clock mutant mice from obesity without changes in activity or calories•TRF restores rhythms in feeding-fasting, metabolic, and nutrient-sensing pathways•TRF prevents fatty liver, dyslipidemia, and glucose intolerance in clock mutant mice•TRF transcriptional program activates cellular homeostasis maintenance pathways
Chaix et al. show that time-restricted feeding (TRF; 10 hr access to food during the active phase) can improve metabolic health in mice with a compromised circadian clock. Their results point to metabolic dysfunction as secondary to disrupted behavioral rhythms (e.g., feeding-fasting), and which can be redressed by TRF.
Diurnal gene expression patterns underlie time-of-the-day-specific functional specialization of tissues. However, available circadian gene expression atlases of a few organs are largely from ...nocturnal vertebrates. We report the diurnal transcriptome of 64 tissues, including 22 brain regions, sampled every 2 hours over 24 hours, from the primate
(baboon). Genomic transcription was highly rhythmic, with up to 81.7% of protein-coding genes showing daily rhythms in expression. In addition to tissue-specific gene expression, the rhythmic transcriptome imparts another layer of functional specialization. Most ubiquitously expressed genes that participate in essential cellular functions exhibit rhythmic expression in a tissue-specific manner. The peak phases of rhythmic gene expression clustered around dawn and dusk, with a "quiescent period" during early night. Our findings also unveil a different temporal organization of central and peripheral tissues between diurnal and nocturnal animals.
Circadian clocks orchestrate periods of rest or activity and feeding or fasting over the course of a 24-hour day and maintain homeostasis. To assess whether a consolidated 24-hour cycle of feeding ...and fasting can sustain health, we explored the effect of time-restricted feeding (TRF; food access limited to daytime 12 hours every day) on neural, peripheral, and cardiovascular physiology in Drosophila melanogaster. We detected improved sleep, prevention of body weight gain, and deceleration of cardiac aging under TRF, even when caloric intake and activity were unchanged. We used temporal gene expression profiling and validation through classical genetics to identify the TCP-1 ring complex (TRiC) chaperonin, the mitochondrial electron transport chain complexes, and the circadian clock as pathways mediating the benefits of TRF.
In mammals, the circadian oscillator generates approximately 24-h rhythms in feeding behavior, even under constant environmental conditions. Livers of mice held under constant darkness exhibit ...circadian rhythm in abundance in up to 15% of expressed transcripts. Therefore, oscillations in hepatic transcripts could be driven by rhythmic food intake or sustained by the hepatic circadian oscillator, or a combination of both. To address this question, we used distinct feeding and fasting paradigms on wild-type (WT) and circadian clock-deficient mice. We monitored temporal patterns of feeding and hepatic transcription. Both food availability and the temporal pattern of feeding determined the repertoire, phase, and amplitude of the circadian transcriptome in WT liver. In the absence of feeding, only a small subset of transcripts continued to express circadian patterns. Conversely, temporally restricted feeding restored rhythmic transcription of hundreds of genes in oscillator-deficient mouse liver. Our findings show that both temporal pattern of food intake and the circadian clock drive rhythmic transcription, thereby highlighting temporal regulation of hepatic transcription as an emergent property of the circadian system.
Obesity caused by genetic and environmental factors can lead to compromised skeletal muscle function. Time-restricted feeding (TRF) has been shown to prevent muscle function decline from obesogenic ...challenges; however, its mechanism remains unclear. Here we demonstrate that TRF upregulates genes involved in glycine production (Sardh and CG5955) and utilization (Gnmt), while Dgat2, involved in triglyceride synthesis is downregulated in Drosophila models of diet- and genetic-induced obesity. Muscle-specific knockdown of Gnmt, Sardh, and CG5955 lead to muscle dysfunction, ectopic lipid accumulation, and loss of TRF-mediated benefits, while knockdown of Dgat2 retains muscle function during aging and reduces ectopic lipid accumulation. Further analyses demonstrate that TRF upregulates the purine cycle in a diet-induced obesity model and AMPK signaling-associated pathways in a genetic-induced obesity model. Overall, our data suggest that TRF improves muscle function through modulations of common and distinct pathways under different obesogenic challenges and provides potential targets for obesity treatments.
Pathological obesity can result from genetic predisposition, obesogenic diet, and circadian rhythm disruption. Obesity compromises function of muscle, which accounts for a majority of body mass. ...Behavioral intervention that can counteract obesity arising from genetic, diet or circadian disruption and can improve muscle function holds untapped potential to combat the obesity epidemic. Here we show that Drosophila melanogaster (fruit fly) subject to obesogenic challenges exhibits metabolic disease phenotypes in skeletal muscle; sarcomere disorganization, mitochondrial deformation, upregulation of Phospho-AKT level, aberrant intramuscular lipid infiltration, and insulin resistance. Imposing time-restricted feeding (TRF) paradigm in which flies were fed for 12 h during the day counteracts obesity-induced dysmetabolism and improves muscle performance by suppressing intramuscular fat deposits, Phospho-AKT level, mitochondrial aberrations, and markers of insulin resistance. Importantly, TRF was effective even in an irregular lighting schedule mimicking shiftwork. Hence, TRF is an effective dietary intervention for combating metabolic dysfunction arising from multiple causes.
In animals, circadian oscillators are based on a transcription-translation circuit that revolves around the transcription factors CLOCK and BMAL1. We found that the JumonjiC (JmjC) and ARID ...domain—containing histone lysine demethylase 1a (JARID1a) formed a complex with CLOCK-BMAL1, which was recruited to the Per2 promoter. JARID1a increased histone acetylation by inhibiting histone deacetylase 1 function and enhanced transcription by CLOCK-BMAL1 in a demethylase-independent manner. Depletion of JARID1a in mammalian cells reduced Per promoter histone acetylation, dampened expression of canonical circadian genes, and shortened the period of circadian rhythms. Drosophila lines with reduced expression of the Jarid1a homolog, lid, had lowered Per expression and similarly altered circadian rhythms. JARID1a thus has a nonredundant role in circadian oscillator function.
The mechanisms by which feeding and fasting drive rhythmic gene expression for physiological adaptation to daily rhythm in nutrient availability are not well understood. Here we show that, upon ...feeding, the RNA-binding protein NONO accumulates within speckle-like structures in liver cell nuclei. Combining RNA-immunoprecipitation and sequencing (RIP-seq), we find that an increased number of RNAs are bound by NONO after feeding. We further show that NONO binds and regulates the rhythmicity of genes involved in nutrient metabolism post-transcriptionally. Finally, we show that disrupted rhythmicity of NONO target genes has profound metabolic impact. Indeed, NONO-deficient mice exhibit impaired glucose tolerance and lower hepatic glycogen and lipids. Accordingly, these mice shift from glucose storage to fat oxidation, and therefore remain lean throughout adulthood. In conclusion, our study demonstrates that NONO post-transcriptionally coordinates circadian mRNA expression of metabolic genes with the feeding/fasting cycle, thereby playing a critical role in energy homeostasis.
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•Upon feeding, NONO-containing speckle-like structures increase in liver cell nuclei•The number of target RNAs bound by NONO increases upon feeding•NONO binds and regulates the rhythmicity of metabolic genes post-transcriptionally•NONO is required for normal glucose and lipid homeostasis in mice
Benegiamo et al. identify a metabolic role for the nuclear RNA-binding protein NONO. Upon feeding, NONO binds to pre-mRNAs of genes involved in glucose and fat metabolism in the liver, regulating their rhythmic expression post-transcriptionally. NONO-deficient mice exhibit disruptions in this temporal regulation and shift from glucose storage to fat oxidation.
Objective
Time‐restricted eating (TRE) restores circadian rhythms in mice, but the evidence to support this in humans is limited. The objective of this study was to investigate the effects of TRE on ...24‐hour profiles of plasma metabolites, glucoregulatory hormones, and the subcutaneous adipose tissue (SAT) transcriptome in humans.
Methods
Men (n = 15, age = 63 4 years, BMI 30.5 2.4 kg/m2) were recruited. A 35‐hour metabolic ward stay was conducted at baseline and after 8 weeks of 10‐hour TRE. Assessment included 24‐hour profiles of plasma glucose, nonesterified fatty acid (NEFA), triglyceride, glucoregulatory hormones, and the SAT transcriptome. Dim light melatonin onset and cortisol area under the curve were calculated.
Results
TRE did not alter dim light melatonin onset but reduced morning cortisol area under the curve. TRE altered 24‐hour profiles of insulin, NEFA, triglyceride, and glucose‐dependent insulinotropic peptide and increased transcripts of circadian locomotor output cycles protein kaput (CLOCK) and nuclear receptor subfamily 1 group D member 2 (NR1D2) and decreased period circadian regulator 1 (PER1) and nuclear receptor subfamily 1 group D member 1 (NR1D1) at 12:00 am. The rhythmicity of 450 genes was altered by TRE, which enriched in transcripts for transcription corepressor activity, DNA‐binding transcription factor binding, regulation of chromatin organization, and small GTPase binding pathways. Weighted gene coexpression network analysis revealed eigengenes that were correlated with BMI, insulin, and NEFA.
Conclusions
TRE restored 24‐hour profiles in hormones, metabolites, and genes controlling transcriptional regulation in SAT, which could underpin its metabolic health benefit.
The hypothalamic suprachiasmatic nucleus (SCN) is composed of heterogenous populations of neurons that express signaling peptides such as vasoactive intestinal polypeptide (VIP) and arginine ...vasopressin (AVP) and regulate circadian rhythms in behavior and physiology. SCN neurons acquire functional and morphological specializations from waves of transcription factors (TFs) that are expressed during neurogenesis. However, the in vitro generation of SCN neurons has never been achieved. Here we supplemented a highly efficient neuronal conversion protocol with TFs that are expressed during SCN neurogenesis, namely Six3, Six6, Dlx2, and Lhx1. Neurons induced from mouse and human fibroblasts predominantly exhibited neuronal properties such as bipolar or multipolar morphologies, GABAergic neurons with expression of VIP. Our study reveals a critical contribution of these TFs to the development of vasoactive intestinal peptide (Vip) expressing neurons in the SCN, suggesting the regenerative potential of neuronal subtypes contained in the SCN for future SCN regeneration and in vitro disease remodeling.
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•Induced neurons were generated with SCN-related transcription factors (iN-SCNTF)•The iN-SCNTF was GABAergic, vasoactive intestinal peptide (Vip) positive neurons•The iN-SCNTF were capable of exhibiting robust circadian rhythms in neuron firing•The iN-SCNTF may represent Vip-expressing neuronal subtypes in the SCN
Molecular biology; Neuroscience; Cell biology
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