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Metabolite profiling of 5′-AMP induced hypometabolism


We have previously demonstrated that 5′-adenosine monophosphate (5′-AMP) can be used to induce deep hypometabolism in mice and other non-hibernating mammals. This reversible 5′-AMP induced hypometabolism (AIHM) allows mice to maintain a body temperature about 1 °C above the ambient temperature for several hours before spontaneous reversal to euthermia. Our biochemical and gene expression studies suggested that the molecular processes involved in AIHM behavior most likely occur at the metabolic interconversion level, rather than the gene or protein expression level. To understand the metabolic processes involved in AIHM behavior, we conducted a non-targeted comparative metabolomics investigation at multiple stages of AIHM in the plasma, liver and brain of animals that underwent AIHM. Dozens of metabolites representing many important metabolic pathways were detected and measured using a metabolite profiling platform combining both liquid-chromatography–mass spectrometry and gas-chromatography–mass spectrometry. Our findings indicate that there is a widespread suppression of energy generating metabolic pathways but lipid metabolism appears to be minimally altered. Regulation of carbohydrate metabolites appears to be the major way the animal utilizes energy in AIHM and during the following recovery process. The 5′-AMP administered has largely been catabolized by the time the animals have entered AIHM. During AIHM, the urea cycle appears to be functional, helping to avoid ammonia toxicity. Of all tissues studied, brain’s metabolite flux is the least affected by AIHM.

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  • Ames, B. N., Cathcart, R., Schwiers, E., & Hochstein, P. (1981). Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis. [Online]. Proceedings of the National Academy of Sciences of the United States of America, 78, 6858–6862.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Becker, B. F. (1993). Towards the physiological function of uric acid. Free Radical Biology and Medicine, 14, 615–631.

    CAS  Article  PubMed  Google Scholar 

  • Cravatt, B. F., Prospero-Garcia, O., Siuzdak, G., Gilula, N. B., Henriksen, S. J., Boger, D. L., et al. (1995). Chemical characterization of a family of brain lipids that induce sleep. Science, 268, 1506–1509.

    CAS  Article  PubMed  Google Scholar 

  • Daniels, I. S., Zhang, J., O’Brien, W. G., Tao, Z., Miki, T., Zhao, Z., et al. (2010). A role of erythrocytes in adenosine monophosphate initiation of hypometabolism in mammals. The Journal of biological chemistry, 285, 20716–20723.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Dello, S. A., Neis, E. P., de Jong, M. C., van Eijk, H. M., Kicken, C. H., Olde Damink, S. W., et al. (2013). Systematic review of ophthalmate as a novel biomarker of hepatic glutathione depletion. Clinical Nutrition, 32(3), 325–330.

  • Dungan, K. M. (2008). 1,5-anhydroglucitol (GlycoMark) as a marker of short-term glycemic control and glycemic excursions. Expert Review of Molecular Diagnostics, 8, 9–19.

    CAS  Article  PubMed  Google Scholar 

  • Epperson, L. E., Karimpour-Fard, A., Hunter, L. E., & Martin, S. L. (2011). Metabolic cycles in a circannual hibernator. Physiological Genomics, 43, 799–807.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Evans, A. M., DeHaven, C. D., Barrett, T., Mitchell, M., & Milgram, E. (2009). Integrated, nontargeted ultrahigh performance liquid chromatography/electrospray ionization tandem mass spectrometry platform for the identification and relative quantification of the small-molecule complement of biological systems. Analytical Chemistry, 81(16), 6656–6667.

    CAS  Article  PubMed  Google Scholar 

  • Fedorova, I., Hashimoto, A., Fecik, R. A., Hedrick, M. P., Hanus, L. O., Boger, D. L., et al. (2001). Behavioral evidence for the interaction of oleamide with multiple neurotransmitter systems. The Journal of pharmacology and experimental therapeutics, 299, 332–342.

    CAS  PubMed  Google Scholar 

  • Gonzalez-Correa, J. A., De La Cruz, J. P., Martin-Aurioles, E., Lopez-Egea, M. A., Ortiz, P., & De La Cuesta, F. S. (1997). Effects of S-adenosyl-l-methionine on hepatic and renal oxidative stress in an experimental model of acute biliary obstruction in rats. Hepatology, 26, 121–127.

    CAS  PubMed  Google Scholar 

  • Heldmaier, G., Klingenspor, M., Werneyer, M., Lampi, B. J., Brooks, S. P., & Storey, K. B. (1999). Metabolic adjustments during daily torpor in the Djungarian hamster. American Journal of Physiology, 276(5 Pt 1), E896–E906.

    CAS  PubMed  Google Scholar 

  • Hiley, C. R., & Hoi, P. M. (2007). Oleamide: a fatty acid amide signaling molecule in the cardiovascular system? Cardiovascular Drug Reviews, 25, 46–60.

    CAS  Article  PubMed  Google Scholar 

  • Iliff, B. W., & Swoap, S. J. (2012). Central adenosine receptor signaling is necessary for daily torpor in mice. American Journal of Physiology: Regulatory, Integrative and Comparative Physiology, 303, R477–R484.

    CAS  PubMed  Google Scholar 

  • Kolodziejczyk, J., Saluk-Juszczak, J., & Wachowicz, B. (2011). In vitro study of the antioxidative properties of the glucose derivatives against oxidation of plasma components. Journal of physiology and biochemistry, 67, 175–183.

    CAS  Article  PubMed  Google Scholar 

  • Lee, C. C. (2008). Is human hibernation possible? Annual Review of Medicine, 59, 177–186.

    CAS  Article  PubMed  Google Scholar 

  • Nelson, C. J., Otis, J. P., & Carey, H. V. (2010). Global analysis of circulating metabolites in hibernating ground squirrels. Comparative Biochemistry and Physiology Part D: Genomics and Proteomics, 5, 265–273.

    Google Scholar 

  • Nelson, C. J., Otis, J. P., Martin, S. L., & Carey, H. V. (2009). Analysis of the hibernation cycle using LC-MS-based metabolomics in ground squirrel liver. Physiological Genomics, 37, 43–51.

    CAS  Article  PubMed  Google Scholar 

  • Patti, G. J., Yanes, O., & Siuzdak, G. (2012). Innovation: metabolomics: the apogee of the omics trilogy. Nature Reviews Molecular Cell Biology, 13, 263–269.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Saluk-Juszczak, J. (2010). A comparative study of antioxidative activity of calcium-d-glucarate, sodium-d-gluconate and d-glucono-1,4-lactone in a human blood platelet model. Platelets, 21, 632–640.

    CAS  Article  PubMed  Google Scholar 

  • Serkova, N. J., Rose, J. C., Epperson, L. E., Carey, H. V., & Martin, S. L. (2007). Quantitative analysis of liver metabolites in three stages of the circannual hibernation cycle in 13-lined ground squirrels by NMR. Physiological Genomics, 31, 15–24.

    CAS  Article  PubMed  Google Scholar 

  • Swoap, S. J., Rathvon, M., & Gutilla, M. (2007). AMP does not induce torpor. American Journal of Physiology, 293, R468–R473.

    CAS  Article  PubMed  Google Scholar 

  • Tøien, Ø., Drew, K. L., Chao, M. L., & Rice, M. E. (2001). Ascorbate dynamics and oxygen consumption during arousal from hibernation in Arctic ground squirrels. American Journal of Physiology: Regulatory, Integrative and Comparative Physiology, 281(2), R572–R583.

    PubMed  Google Scholar 

  • Zhang, J., Kaasik, K., Blackburn, M. R., & Lee, C. C. (2006). Constant darkness is a circadian metabolic signal in mammals. Nature, 439(7074), 340–343.

    CAS  Article  PubMed  Google Scholar 

  • Zhao, Z., Miki, T., Van Oort-Jansen, A., Matsumoto, T., Loose, D. S., & Lee, C. C. (2011). Hepatic gene expression profiling of 5′-AMP-induced hypometabolism in mice. Physiological Genomics, 43, 325–345.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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We thank Julia Lever for her review and critiques on the manuscript. We thank Metabolon Inc. for their high quality service product and responsive technical support. Specifically, we would direct our thanks to Mike Milburn, Kirk Beebe, Danny Alexander, Mignon Keaton and Lining Guo. This study is supported by NIH Director’s Pioneer Award (5 DP1 OD000895).

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The authors declare no competing financial interests. The manuscript has been seen and approved by all authors.

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Correspondence to Zhaoyang Zhao.

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Zhao, Z., Van Oort, A., Tao, Z. et al. Metabolite profiling of 5′-AMP induced hypometabolism. Metabolomics 10, 63–76 (2014).

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  • Metabolomics
  • Hypometabolism
  • 5′-AMP
  • Non-targeted
  • Plasma
  • Liver