An adipo-biliary-uridine axis that regulates energy homeostasis

Deng, Yingfeng; Wang, Zhao V.; Gordillo, Ruth; An, Yu; Zhang, Chen; Liang, Qiren; Yoshino, Jun; Cautivo, Kelly M.; Brabander, Jef De; Elmquist, Joel K.; Horton, Jay D.; Hill, Joseph A.; Klein, Samuel; Scherer, Philipp E.

doi:10.1126/science.aaf5375

Cited by 92 publications

(117 citation statements)

References 45 publications

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“…In the fasting condition, participants had to abstain from food from 22:00 h to 13:00 h the following day, meaning a period of 15 h. For uridine, the precursor of U, it has recently been shown by Deng et al . that plasma uridine levels are elevated during fasting state and show a rapid drop in a post‐prandial state , thus showing a similar pattern as U levels in our study. Adipose tissue dominates uridine biosynthetic activity in the fasted state, resulting in elevated plasma uridine levels, but after food intake, a rapid reduction of plasma uridine is seen, both caused by reduction of uridine synthesis in adipocytes and enhancement of its clearance through the bile .…”

Section: Discussionsupporting

confidence: 87%

“…that plasma uridine levels are elevated during fasting state and show a rapid drop in a post‐prandial state , thus showing a similar pattern as U levels in our study. Adipose tissue dominates uridine biosynthetic activity in the fasted state, resulting in elevated plasma uridine levels, but after food intake, a rapid reduction of plasma uridine is seen, both caused by reduction of uridine synthesis in adipocytes and enhancement of its clearance through the bile . Assuming that endogenous U plasma levels are largely dependent on uridine homeostasis and not on the intake of U by food, this phenomenon could be an explanation for the findings in our study.…”

Section: Discussionsupporting

confidence: 87%

“…When radioactively labelled 3 H-uridine was administered intraperitoneally to mice, 3 H-uridine was metabolized rapidly with a half-life of less than 2 min, and radioactive 3 H-uracil levels were detected in plasma already 5 min after administration [32]. For uridine present in food, it was shown that gut-derived uridine is not released in the systemic circulation, but subsequently circulates with bile within the enterohepatic circulation [31]. This is also in line with our findings that food intake did not result in an increase in U levels.…”

Section: Discussionmentioning

confidence: 99%

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Food‐effect study on uracil and dihydrouracil plasma levels as marker for dihydropyrimidine dehydrogenase activity in human volunteers

Henricks

Jacobs

Meulendijks

et al. 2018

Brit J Clinical Pharma

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AimsThis study aimed to determine the effect of food intake on uracil and dihydrouracil plasma levels. These levels are a promising marker for dihydropyrimidine dehydrogenase activity and for individualizing fluoropyrimidine anticancer therapy.MethodsA randomized, cross‐over study in 16 healthy volunteers was performed, in which subjects were examined in fasted and fed state on two separate days. In fed condition, a high‐fat, high‐caloric breakfast was consumed between 8:00 h and 8:30 h. Whole blood for determination of uracil, dihydrouracil and uridine plasma levels was drawn on both test days at predefined time points between 8:00 h and 13:00 h.ResultsUracil levels were statistically significantly different between fasting and fed state. At 13:00 h, the mean uracil level in fasting state was 12.6 ± 3.7 ng ml−1 and after a test meal 9.4 ± 2.6 ng ml−1 (P < 0.001). Dihydrouracil levels were influenced by food intake as well (mean dihydrouracil level at 13:00 h in fasting state 147.0 ± 36.4 ng ml−1 and in fed state 85.7 ± 22.1 ng ml−1, P < 0.001). Uridine plasma levels showed curves with similar patterns as for uracil.ConclusionsIt was shown that both uracil and dihydrouracil levels were higher in fasting state than in fed state. This is hypothesized to be an direct effect of uridine plasma levels, which were previously shown to be elevated in fasting state and reduced after intake of food. These findings show that, when assessing plasma uracil and dihydrouracil levels for adaptive fluoropyrimidine dosing in clinical practice, sampling should be done between 8:00 h and 9:00 h after overnight fasting to avoid bias caused by circadian rhythm and food effects.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

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Food‐effect study on uracil and dihydrouracil plasma levels as marker for dihydropyrimidine dehydrogenase activity in human volunteers

Henricks

Jacobs

Meulendijks

et al. 2018

Brit J Clinical Pharma

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“…Recent work shows that plasma uridine levels are influenced by adipocyte‐biliary clearance (Deng et al, 2017). Potentially, uridine levels could affect UDP/UTP levels, which is the case in the hypothalamus, where UDP acts on the P2Y 6 receptors of AgRP neurons and promotes feeding behaviour (Steculorum et al, 2015).…”

Section: P2y Receptors In Endocrine and Exocrine Functionmentioning

confidence: 99%

Update of P2Y receptor pharmacology: IUPHAR Review 27

Jacobson

Delicado

Gachet

et al. 2020

British J Pharmacology

156

163

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Eight G protein-coupled P2Y receptor subtypes respond to extracellular adenine and uracil mononucleotides and dinucleotides. P2Y receptors belong to the δ group of rhodopsin-like GPCRs and contain two structurally distinct subfamilies: P2Y 1 , P2Y 2 , P2Y 4 , P2Y 6 , and P2Y 11 (principally G q protein-coupled P2Y 1 -like) and P2Y 12-14 (principally G i protein-coupled P2Y 12 -like) receptors. Brain P2Y receptors occur in neurons, glial cells, and vasculature. Endothelial P2Y 1 , P2Y 2 , P2Y 4 , and P2Y 6 receptors induce vasodilation, while smooth muscle P2Y 2 , P2Y 4 , and P2Y 6 receptor activation leads to vasoconstriction. Pancreatic P2Y 1 and P2Y 6 receptors stimulate while P2Y 13 receptors inhibits insulin secretion. Antagonists of P2Y 12 receptors, and potentially P2Y 1 receptors, are anti-thrombotic agents, and a P2Y 2 /P2Y 4 receptor agonist treats dry eye syndrome in Asia. P2Y receptor agonists are generally pro-inflammatory, and antagonists may eventually treat inflammatory conditions. This article reviews recent developments in P2Y receptor pharmacology (using synthetic agonists and antagonists), structure and biophysical properties (using X-ray crystallography, mutagenesis and modelling), physiological and pathophysiological roles, and present and potentially future therapeutic targeting.Abbreviations: BMD, bone mineral density; DUSP, dual specificity protein phosphatase; ECL, extracellular loop; EPAC, exchange protein activated by cAMP; KO, knockout; MSD, musculoskeletal disorder; SNP, single nucleotide polymorphism; SS, Sjögren's syndrome; TM, transmembrane helix.

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“…31 Recent studies indicate that plasma uridine plays a key role in energy homeostasis and thermoregulation, modulating leptin signaling and potentially affecting glucose and insulin metabolism. 32 Given the involvement of obesity and diabetes in the development of AF, deeper understanding of the physiological role of uridine in cardiometabolic disorders is needed. In fact, prior epidemiologic and clinical evidence has shown beneficial associations with higher plasma uridine, with higher levels of uridine associated with reduced mortality in the ARIC cohort, 33 and reduced pulse wave velocity in the Twins UK Registry.…”

Section: Bile Acids and Afmentioning

confidence: 99%

Serum metabolomics and incidence of atrial fibrillation: the Atherosclerosis Risk in Communities (ARIC) Study

Alonso

Yu²,

Sun

et al. 2018

Preprint

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We have previously identified associations of two circulating secondary bile acids (glycocholenate and glycolithocolate sulfate) with atrial fibrillation (AF) risk among blacks. We aimed to replicate these findings in an independent sample including both whites and blacks, and performed a new metabolomic analysis in the combined sample. We studied 3,922 participants from the ARIC cohort followed between 1987 and 2013. Of these, 1,919 had been included in the prior analysis and 2,003 were new samples.Metabolomic profiling was done in baseline serum samples using gas and liquid chromatography mass spectrometry. AF was ascertained from electrocardiograms, hospitalizations, and death certificates. We used multivariable Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (95%CI) of AF by one standard deviation difference of metabolite levels. Over a mean follow-up of 20 years, 608 participants developed AF. Glycocholenate sulfate was associated with AF in the replication and combined samples (HR 1.10, 95%CI 1.00, 1.21 and HR 1.13, 95%CI 1.04, 1.22, respectively).Glycolithocolate sulfate was not related to AF risk in the replication sample (HR 1.02, 95%CI 0.92, 1.13).An analysis of 245 metabolites in the combined cohort identified three additional metabolites associated with AF after multiple-comparison correction: pseudouridine (HR 1.18, 95%CI 1.10, 1.28), uridine (HR 0.86, 95%CI 0.79, 0.93) and acisoga (HR 1.17, 95%CI 1.09, 1.26). To conclude, we replicated a prospective association between a previously identified secondary bile acid, glycocholenate sulfate, and AF incidence, and identified new metabolites involved in nucleoside and polyamine metabolism as markers of AF risk.

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An adipo-biliary-uridine axis that regulates energy homeostasis

Cited by 92 publications

References 45 publications

Food‐effect study on uracil and dihydrouracil plasma levels as marker for dihydropyrimidine dehydrogenase activity in human volunteers

Food‐effect study on uracil and dihydrouracil plasma levels as marker for dihydropyrimidine dehydrogenase activity in human volunteers

Update of P2Y receptor pharmacology: IUPHAR Review 27

Serum metabolomics and incidence of atrial fibrillation: the Atherosclerosis Risk in Communities (ARIC) Study

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