Dataset Information

Metabolic clock generates nutrient anticipation rhythms in mTOR signaling.

ABSTRACT: The mTOR signaling pathway modulates metabolic processes with respect to nutrient availability and other growth-related cues. According to the existing paradigm, mTOR complex 1 (mTORC1) activityin vivo is induced by food and gradually decreases during fasting. We found that mTORC1 activity is controlled by an internal clock mechanism different from the known light-entrainable circadian clock. We observed 24-hr rhythms in phosphorylation of mTORC1 downstream targets, which were entrained by food, persisted during fasting and could be uncoupled from oscillating expression of the canonical circadian clock genes. Furthermore, these rhythms were present in tissues of mice with disrupted light-entrainable circadian clock. We propose tissue-specific rhythms in the expression of tor and its negative regulator deptor as the molecular mechanism of the mTORC1 activity oscillation. Our data demonstrate the existence of at least two independent molecular circadian clocks: one providing metabolic adaptation to periodic light/darkness and the other - to feeding.

SUBMITTER: Khapre RV

PROVIDER: S-EPMC4169861 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Metabolic clock generates nutrient anticipation rhythms in mTOR signaling.

Khapre Rohini V RV Patel Sonal A SA Kondratova Anna A AA Chaudhary Amol A Velingkaar Nikkhil N Antoch Marina P MP Kondratov Roman V RV

Aging 20140801 8

The mTOR signaling pathway modulates metabolic processes with respect to nutrient availability and other growth-related cues. According to the existing paradigm, mTOR complex 1 (mTORC1) activityin vivo is induced by food and gradually decreases during fasting. We found that mTORC1 activity is controlled by an internal clock mechanism different from the known light-entrainable circadian clock. We observed 24-hr rhythms in phosphorylation of mTORC1 downstream targets, which were entrained by food, ...[more]

PMID: 25239872

Similar Datasets

Project description:We have used the Cambridge Protein Trap resource (CPTI) to screen for flies whose locomotor rhythms are rhythmic in constant light (LL) as a means of identifying circadian photoreception genes. From the screen of ∼150 CPTI lines, we obtained seven hits, two of which targeted the glutamate pathway, Got1 (Glutamate oxaloacetate transaminase 1) and Gs2 (Glutamine synthetase 2). We focused on these by employing available mutants and observed that variants of these genes also showed high levels of LL rhythmicity compared with controls. It was also clear that the genetic background was important with a strong interaction observed with the common and naturally occurring timeless (tim) polymorphisms, ls-tim and s-tim. The less circadian photosensitive ls-tim allele generated high levels of LL rhythmicity in combination with Got1 or Gs2, even though ls-tim and s-tim alleles do not, by themselves, generate the LL phenotype. The use of dsRNAi for both genes as well as for Gad (Glutamic acid decarboxylase) and the metabotropic glutamate receptor DmGluRA driven by clock gene promoters also revealed high levels of LL rhythmicity compared to controls. It is clear that the glutamate pathway is heavily implicated in circadian photoreception. TIM levels in Got1 and Gs2 mutants cycled and were more abundant than in controls under LL. Got1 but not Gs2 mutants showed diminished phase shifts to 10 min light pulses. Neurogenetic dissection of the LL rhythmic phenotype using the gal4/gal80 UAS bipartite system suggested that the more dorsal CRY-negative clock neurons, DNs and LNds were responsible for the LL phenotype. Immunocytochemistry using the CPTI YFP tagged insertions for the two genes revealed that the DN1s but not the DN2 and DN3s expressed Got1 and Gs2, but expression was also observed in the lateral neurons, the LNds and s-LNvs. Expression of both genes was also found in neuroglia. However, downregulation of glial Gs2 and Got1 using repo-gal4 did not generate high levels of LL rhythmicity, so it is unlikely that this phenotype is mediated by glial expression. Our results suggest a model whereby the DN1s and possibly CRY-negative LNds use glutamate signaling to supress the pacemaker s-LNvs in LL.

Project description:BackgroundWhile additional research is needed, a number of large epidemiological studies show an association between circadian disruption and metabolic disorders. Specifically, obesity, insulin resistance, cardiovascular disease, and other signs of metabolic syndrome all have been linked to circadian disruption in humans. Studies in other species support this association and generally reveal that feeding that is not in phase with the external light/dark cycle, as often occurs with night or rotating shift workers, is disadvantageous in terms of energy balance. As food is a strong driver of circadian rhythms in the periphery, understanding how nutrient metabolism drives clocks across the body is important for dissecting out why circadian misalignment may produce such metabolic effects. A number of circadian clock proteins as well as their accessory proteins (such as nuclear receptors) are highly sensitive to nutrient metabolism. Macronutrients and micronutrients can function as zeitgebers for the clock in a tissue-specific way and can thus impair synchrony between clocks across the body, or potentially restore synchrony in the case of circadian misalignment. Circadian nuclear receptors are particularly sensitive to nutrient metabolism and can alter tissue-specific rhythms in response to changes in the diet. Finally, SNPs in human clock genes appear to be correlated with diet-specific responses and along with chronotype eventually may provide valuable information from a clinical perspective on how to use diet and nutrition to treat metabolic disorders.Scope of reviewThis article presents a background of the circadian clock components and their interrelated metabolic and transcriptional feedback loops, followed by a review of some recent studies in humans and rodents that address the effects of nutrient metabolism on the circadian clock and vice versa. We focus on studies in which results suggest that nutrients provide an opportunity to restore or, alternatively, can destroy synchrony between peripheral clocks and the central pacemaker in the brain as well as between peripheral clocks themselves. In addition, we review several studies looking at clock gene SNPs in humans and the metabolic phenotypes or tendencies associated with particular clock gene mutations.Major conclusionsTargeted use of specific nutrients based on chronotype has the potential for immense clinical utility in the future. Macronutrients and micronutrients have the ability to function as zeitgebers for the clock by activating or modulating specific clock proteins or accessory proteins (such as nuclear receptors). Circadian clock control by nutrients can be tissue-specific. With a better understanding of the mechanisms that support nutrient-induced circadian control in specific tissues, human chronotype and SNP information might eventually be used to tailor nutritional regimens for metabolic disease treatment and thus be an important part of personalized medicine's future.

Dataset Information

Metabolic clock generates nutrient anticipation rhythms in mTOR signaling.

Publications

Metabolic clock generates nutrient anticipation rhythms in mTOR signaling.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets