Misaligned feeding uncouples daily rhythms within brown adipose tissue and between peripheral clocks
Ontology highlight
ABSTRACT: Extended consumption of food into the rest period perturbs the phase relationship between circadian clocks in the periphery and the brain and has deleterious effects on health through mechanisms that remain incompletely understood. Beyond the liver, how other metabolic organs respond to hypocaloric diet (amount and timing) is largely unexplored. We investigated how feeding time impacts circadian gene expression in white (eWAT) and brown (BAT) adipose tissues in comparison to liver and hypothalamus. With automated feeders, we restricted food to either daytime or nighttime in C57BL/6J male mice, with or without caloric restriction. We found tissue-specific changes in the phase and amplitude of genome-wide mRNA expression patterns induced by daytime feeding in liver and eWAT, whereas BAT exhibited resilience and remained predominately entrained to the light-dark cycle, similar to hypothalamus. We uncovered an internal split within the BAT in response to conflicting environmental cues, displaying inverted oscillations on a subset of metabolic genes without modifying its local core circadian machinery. Integrating intra- and inter-tissue disruptions in circadian clock-controlled transcriptional networks with metabolic outcomes may help elucidate the mechanism underlying the health burden of eating at the wrong time of the day.
Project description:Circadian clocks in peripheral organs are entrained by feeding. Eating in the right time is crucial to maintain metabolic health, whereas eating in the wrong time increases the susceptibility to metabolic diseases. It is unknown how change of mealtime impacts circadian transcriptomes in peripheral organs and brain, such as liver, heart, kidney and visceral adipose tissue. Here, we presented global circadian transcript profile of mouse tissues (i.e. kidney, anterior hypothalamus) entrained by inverted feeding to compile an atlas for mechanistic insights into how feed-fast cycle regulates circadian biology.
Project description:Circadian desynchrony induced by shiftwork or jetlag is detrimental to metabolic health, but how synchronous or desynchronous signals are transmitted among tissues is unknown. We report that liver molecular clock dysfunction is signaled to the brain through the hepatic vagal afferent nerve (HVAN), leading to altered food intake patterns that are corrected by ablation of the HVAN. Hepatic branch vagotomy also prevents food intake disruptions induced by high-fat diet feeding and reduces body weight gain. Our findings reveal a homeostatic feedback signal that relies on communication between the liver and the brain to control circadian food intake patterns. This identifies the hepatic vagus nerve as a potential therapeutic target for obesity in the setting of chrono-disruption.
Project description:The cerebellum harbors a circadian clock that can be shifted by scheduled mealtime and participates in behavioral anticipation of food access. To determine which cerebellar proteins are modified by time-of-day and/or feeding time, we determined day-night variations of proteome in the cerebellum of mice fed either ad libitum or only during daytime (from noon to lights off). Two-dimensional differences in gel electrophoresis (2D-DIGE) combined with two-way analyses of variance reveals that a majority of cerebellar proteins are significantly regulated by feeding conditions (food availability). Levels of few other cerebellar proteins were modulated exclusively by daily (or circadian) cues, independent of meal time, and others due to combined influence of meal time and time-of-day. Changes reflect behavioral anticipation of mealtime and/or feeding-induced shift in the circadian clock of the cerebellum.
Project description:a circadian proteome atlas of eight organs, namely suprachiasmatic nucleus (SCN), hypothalamus (HPOA), liver (LIV), gall bladder (GBD), brown adipose tissue (BAT), kidney (KDN), heart (HEA) and muscle (MUS), from wild-type (WT) and Per1-/-/Per2-/- (DKO) mice housed under constant darkness and ad libitum feeding, collected every two hours for deep proteomic analysis over two days
Project description:Circadian clocks in peripheral organs are entrained by feeding. Eating in the right time is crucial to maintain metabolic health, whereas eating in the wrong time increases the susceptibility to metabolic diseases. It is unknown how change of mealtime impacts circadian transcriptomes in peripheral organs and brain, such as liver, heart, kidney and visceral adipose tissue. Here, we presented global circadian transcript profile of mouse liver entrained by inverted feeding to compile an atlas for mechanistic insights into how feed-fast cycle regulates circadian biology.
Project description:Circadian clocks in peripheral organs are entrained by feeding. Eating in the right time is crucial to maintain metabolic health, whereas eating in the wrong time increases the susceptibility to metabolic diseases. It is unknown how change of mealtime impacts circadian transcriptomes in peripheral organs and brain, such as liver, heart, kidney and visceral adipose tissue. Here, we presented global circadian transcript profile of mouse heart entrained by inverted feeding to compile an atlas for mechanistic insights into how feed-fast cycle regulates circadian biology.
Project description:Circadian clocks in peripheral organs are entrained by feeding. Eating in the right time is crucial to maintain metabolic health, whereas eating in the wrong time increases the susceptibility to metabolic diseases. It is unknown how change of mealtime impacts circadian transcriptomes in peripheral organs and brain, such as liver, heart, kidney and visceral adipose tissue. Here, we presented global circadian transcript profile of mouse kidney entrained by inverted feeding to compile an atlas for mechanistic insights into how feed-fast cycle regulates circadian biology.
Project description:Circadian clocks in peripheral organs are entrained by feeding. Eating in the right time is crucial to maintain metabolic health, whereas eating in the wrong time increases the susceptibility to metabolic diseases. It is unknown how change of mealtime impacts circadian transcriptomes in peripheral organs and brain, such as liver, heart, kidney and visceral adipose tissue. Here, we presented global circadian transcript profile of mouse visceral adipose tissue entrained by inverted feeding to compile an atlas for mechanistic insights into how feed-fast cycle regulates circadian biology.
Project description:Daily biological rhythms are orchestrated by a combination of the intrinsic circadian clock and external food/feeding-related signals which influence metabolism in health and disease. Understanding how and to which extent both circadian and fasting/feeding rhythms contribute to regulating daily physiology and metabolism is therefore an important ongoing effort. We generated a comprehensive proteomics dataset performing large scale time-series analysis of mouse liver obtained from feeding restricted mice over 2 full days with 16 time points in total, including as a first, a shorter post-feeding sampling-rate focus. Using our label-free absolute quantitative proteomics platform we obtained timelines with very few missing values (>99% data completeness) for over 4000 mouse liver proteoforms using 1D-LC-MS analysis of all time points and replicates (48 samples in total) allowing for robust statistical testing, as well as over 8000 mouse liver proteoforms using online 2D-LC-MS analysis of pooled replicates, providing additional depth of detection. Together our dataset provides an important resource recapitulating and extending current datasets. Our extra focus on post-feeding time points revealed a highly dynamic third metabolic period not previously observed with respect to more classic diurnal rhythmicity, providing an important addition to current knowledge.
Project description:Virtually every mammalian tissue exhibits rhythmic expression in thousands of genes, which activate tissue-specific processes at appropriate times of the day. Much of this rhythmic expression is thought to be driven cell-autonomously by molecular circadian clocks present throughout the body. However, increasing evidence suggests that systemic signals, and more specifically rhythmic food intake (RFI), can regulate rhythmic gene expression independently of the circadian clock. To determine the relative contribution of cell autonomous clocks versus RFI in the regulation of rhythmic gene expression, we developed a system that allows long-term manipulation of the daily rhythm of food intake in the mouse, and analyzed liver gene expression by RNA-Seq in mice fed ad libitum, only at night, or arrhythmically (mouse eating 1/8th of their daily food intake every 3 hours). We show that 70% of the cycling mouse liver transcriptome loses rhythmicity under arrhythmic feeding. Remarkably, this loss of rhythmic gene expression under arrhythmic feeding is independent of the liver circadian clock, which continues to exhibit normal oscillations in core clock gene expression. Many genes that lose rhythmicity participate in the regulation of metabolic processes such as lipogenesis and glycogenesis, likely contributing to an increased sensitivity to insulin that was observed in arrhythmically-fed mice. We also show that night-restricted feeding significantly increases the number of rhythmically expressed genes as well as the amplitude of the rhythms. Together, these results indicate that metabolic transcription factors control a large fraction of the rhythmic mouse liver transcriptome, and demonstrate that systemic signals driven by rhythmic food intake play a more important role than the cell-autonomous circadian clock in driving rhythms in liver gene expression and metabolic functions.