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Gut microbiota directs PPAR?-driven reprogramming of the liver circadian clock by nutritional challenge.

ABSTRACT: The liver circadian clock is reprogrammed by nutritional challenge through the rewiring of specific transcriptional pathways. As the gut microbiota is tightly connected to host metabolism, whose coordination is governed by the circadian clock, we explored whether gut microbes influence circadian homeostasis and how they distally control the peripheral clock in the liver. Using fecal transplant procedures we reveal that, in response to high-fat diet, the gut microbiota drives PPAR?-mediated activation of newly oscillatory transcriptional programs in the liver. Moreover, antibiotics treatment prevents PPAR?-driven transcription in the liver, underscoring the essential role of gut microbes in clock reprogramming and hepatic circadian homeostasis. Thus, a specific molecular signature characterizes the influence of the gut microbiome in the liver, leading to the transcriptional rewiring of hepatic metabolism.

SUBMITTER: Murakami M

PROVIDER: S-EPMC5007574 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Gut microbiota directs PPARγ-driven reprogramming of the liver circadian clock by nutritional challenge.

Murakami Mari M Tognini Paola P Liu Yu Y Eckel-Mahan Kristin L KL Baldi Pierre P Sassone-Corsi Paolo P

EMBO reports 20160714 9

The liver circadian clock is reprogrammed by nutritional challenge through the rewiring of specific transcriptional pathways. As the gut microbiota is tightly connected to host metabolism, whose coordination is governed by the circadian clock, we explored whether gut microbes influence circadian homeostasis and how they distally control the peripheral clock in the liver. Using fecal transplant procedures we reveal that, in response to high-fat diet, the gut microbiota drives PPARγ-mediated activ ...[more]

PMID: 27418314

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Gut microbiota directs PPARγ-driven reprogramming of the liver circadian clock by nutritional challenge

Project description:The liver circadian clock is reprogrammed by nutritional challenge through the rewiring of specific transcriptional pathways. As the gut microbiota is tightly connected to host metabolism, whose coordination is governed by the circadian clock, we explored whether gut microbes influence circadian homeostasis and how they distally control the peripheral clock in the liver. Using fecal transplant procedures we reveal that, in response to high fat diet, the gut microbiota drives PPARγ-mediated activation of newly oscillatory transcriptional programs in the liver. Moreover, antibiotics treatment prevents PPARγ-driven transcription in the liver, underscoring the essential role of gut microbes in clock reprogramming and hepatic circadian homeostasis. Thus, a specific molecular signature characterizes the influence of the gut microbiome in the liver, leading to the transcriptional rewiring of hepatic metabolism. We used microarray to quantify the tissue specific expression level of circadian genes in terms of total RNA.

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Reprogramming of the circadian clock by nutritional challenge.

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Physcion Protects Against Ethanol-Induced Liver Injury by Reprogramming of Circadian Clock.

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Project description:To fulfil the bioenergetic requirements for increased cell size and clonal expansion, activated T cells reprogramme their metabolic signatures from energetically quiescent to activated. However, the molecular mechanisms and essential components controlling metabolic reprogramming in T cells are not well understood. Here, we show that the mTORC1-PPAR? pathway is crucial for the fatty acid uptake programme in activated CD4+ T cells. This pathway is required for full activation and rapid proliferation of naive and memory CD4+ T cells. PPAR? directly binds and induces genes associated with fatty acid uptake in CD4+ T cells in both mice and humans. The PPAR?-dependent fatty acid uptake programme is critical for metabolic reprogramming. Thus, we provide important mechanistic insights into the metabolic reprogramming mechanisms that govern the expression of key enzymes, fatty acid metabolism and the acquisition of an activated phenotype during CD4+ T cell activation.

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Project description:PurposeA high-fat diet (HFD) increases the risk of developing many systemic diseases; however, the effects of high fat intake on lacrimal gland functions and the molecular mechanisms underlying these effects are unknown. We explored the effects of an HFD on the circadian rhythms of the extraorbital lacrimal glands (ELGs).MethodsMale C57BL/6J mice maintained on a 12/12-hour light/dark cycle were fed an ad libitum HFD or normal chow (NC) for 2 weeks. The ELGs were collected from euthanized animals every 3 hours throughout the circadian cycle (24 hours). Using high-throughput RNA-sequencing (RNA-Seq), we studied the circadian transcriptomic profile of the ELGs. Circadian oscillations in cell size, secretion response, lipid deposition, and immune cell trafficking of the ELGs were also analyzed.ResultsAn HFD modulated the circadian transcriptomic profile of the ELGs, including the composition, phase, and amplitude of cyclical transcript oscillations, and affected the associated signaling pathways at spatiotemporal levels. HFD feeding significantly altered the normal rhythmic oscillations of ELG cell size, immune cell trafficking, secretion response, and lipid deposition. After dietary reversal in HFD-fed animals, the activity, core temperature, and lipid accumulation in lacrimal glands recovered partially to the level of NC-fed animals. However, the average cell size of the ELGs, the recruitment of immune cells, and the rhythm of lacrimal secretion did not return to the levels of the NC-fed group.ConclusionsHFD perturbation interferes with the cyclical transcriptomic profile, cell size, immune cell trafficking, and secretion function of the ELGs with a strikingly high sensitivity.

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| S-EPMC10950852 | biostudies-literature

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