title: Oxalic acid and diacylglycerol 36:3 are cross-species markers of sleep debt.
abstract: Sleep is an essential biological process that is thought to have a critical role in metabolic regulation. In humans, reduced sleep duration has been associated with risk for metabolic disorders, including weight gain, diabetes, obesity, and cardiovascular disease. However, our understanding of the molecular mechanisms underlying effects of sleep loss is only in its nascent stages. In this study we used rat and human models to simulate modern-day conditions of restricted sleep and addressed cross-species consequences via comprehensive metabolite profiling. Serum from sleep-restricted rats was analyzed using polar and nonpolar methods in two independent datasets (n = 10 per study, 3,380 measured features, 407 identified). A total of 38 features were changed across independent experiments, with the majority classified as lipids (18 from 28 identified). In a parallel human study, 92 metabolites were identified as potentially significant, with the majority also classified as lipids (32 of 37 identified). Intriguingly, two metabolites, oxalic acid and diacylglycerol 36:3, were robustly and quantitatively reduced in both species following sleep restriction, and recovered to near baseline levels after sleep restriction (P < 0.05, false-discovery rate < 0.2). Elevated phospholipids were also noted after sleep restriction in both species, as well as metabolites associated with an oxidizing environment. In addition, polar metabolites reflective of neurotransmitters, vitamin B3, and gut metabolism were elevated in sleep-restricted humans. These results are consistent with induction of peroxisome proliferator-activated receptors and disruptions of the circadian clock. The findings provide a potential link between known pathologies of reduced sleep duration and metabolic dysfunction, and potential biomarkers for sleep loss.
authors: Department of Pharmacology, amita@mail.med.upenn.edu aalim@upenn.edu.
authors: Aalim M
authors: AM
authors: Weljie
authors: Center for Behavior and Neurosciences, University of Groningen, 9747 AG Groningen, The Netherlands.
authors: Peter
authors: P
authors: Meerlo
authors: Department of Psychiatry, Center for Sleep and Circadian Neurobiology.
authors: Namni
authors: N
authors: Goel
authors: Department of Pharmacology.
authors: Arjun
authors: A
authors: Sengupta
authors: Department of Psychiatry, Center for Sleep and Circadian Neurobiology.
authors: Matthew S
authors: MS
authors: Kayser
authors: Department of Biology, University of Pennsylvania School of Arts and Science, and.
authors: Ted
authors: T
authors: Abel
authors: The Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania Perelman School of Medicine.
authors: Morris J
authors: MJ
authors: Birnbaum
authors: Department of Psychiatry, Center for Sleep and Circadian Neurobiology.
authors: David F
authors: DF
authors: Dinges
authors: Program in Chronobiology, Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia, PA 19104; and amita@mail.med.upenn.edu aalim@upenn.edu.
authors: Amita
authors: A
authors: Sehgal
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D002940:Circadian Rhythm; D004075:Diglycerides / Q000378:metabolism*; D004195:Disease Models, Animal; D004734:Energy Metabolism; D005260:Female; D041981:Gastrointestinal Tract / Q000382:microbiology; D006801:Humans; D008297:Male; D055442:Metabolome; D055432:Metabolomics; D064307:Microbiota; D008875:Middle Aged; D018377:Neurotransmitter Agents / Q000378:metabolism; D009536:Niacinamide / Q000378:metabolism; D019815:Oxalic Acid / Q000378:metabolism*; D018384:Oxidative Stress; D047495:PPAR gamma / Q000378:metabolism; D010641:Phenotype; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D012892:Sleep Deprivation / Q000097:blood / Q000378:metabolism*; D013045:Species Specificity; D013997:Time Factors; D055815:Young Adult
chemical_list: C011439:1,2-diacylglycerol; D015415:Biomarkers; D004075:Diglycerides; D018377:Neurotransmitter Agents; D047495:PPAR gamma; D009536:Niacinamide; D019815:Oxalic Acid
keywords: lipidomics; mass spectrometry; metabolomics; sleep deprivation; sleep restriction