Treatment with all-trans retinoic acid (ATRA), the carboxylic form of vitamin A, lowers body weight in rodents by promoting oxidative metabolism in multiple tissues including white and brown adipose tissues. We aimed to identify novel markers of the metabolic impact of ATRA through targeted blood metabolomics analyses, with a focus on acylcarnitines and amino acids. Blood was obtained from mice treated with a high ATRA dose (50 mg/kg body weight/day, subcutaneous injection) or placebo (controls) during the 4 days preceding collection. LC-MS/MS analyses with a focus on acylcarnitines and amino acids were conducted on plasma and PBMC. Main results showed that, relative to controls, ATRA-treated mice had in plasma: increased levels of carnitine, acetylcarnitine, and longer acylcarnitine species; decreased levels of citrulline, and increased global arginine bioavailability ratio for nitric oxide synthesis; increased levels of creatine, taurine and docosahexaenoic acid; and a decreased n-6/n-3 polyunsaturated fatty acids ratio. While some of these features likely reflect the stimulation of lipid mobilization and oxidation promoted by ATRA treatment systemically, other may also play a causal role underlying ATRA actions. The results connect ATRA to specific nutrition-modulated biochemical pathways, and suggest novel mechanisms of action of vitamin A-derived retinoic acid on metabolic health.

CIBER de Fisiopatología de la Obesidad y Nutrición 28029 Madrid Spain

Department of Adipose Tissue Biology Institute of Physiology of the Czech Academy of Sciences 14220 Prague 4 Czech Republic

Grup de Recerca Nutrigenòmica i Obesitat Laboratori de Biologia Molecular Nutrició i Biotecnologia Universitat de les Illes Balears 07122 Palma de Mallorca Spain

Institut d'Investigació Sanitària Illes Balears 07120 Palma de Mallorca Spain

See more in PubMed

Rauschert S., Uhl O., Koletzko B., Hellmuth C. Metabolomic biomarkers for obesity in humans: A short review. Ann. Nutr. Metab. 2014;64:314–324. doi: 10.1159/000365040. PubMed DOI

Reynés B., Priego T., Cifre M., Oliver P., Palou A. Peripheral Blood Cells, a Transcriptomic Tool in Nutrigenomic and Obesity Studies: Current State of the Art. Compr. Rev. Food Sci. Food Saf. 2018;17:1006–1020. doi: 10.1111/1541-4337.12363. PubMed DOI

Alvarez R., de Andres J., Yubero P., Vinas O., Mampel T., Iglesias R., Giralt M., Villarroya F. A novel regulatory pathway of brown fat thermogenesis. Retinoic acid is a transcriptional activator of the mitochondrial uncoupling protein gene. J. Biol. Chem. 1995;270:5666–5673. doi: 10.1074/jbc.270.10.5666. PubMed DOI

Puigserver P., Vazquez F., Bonet M.L., Pico C., Palou A. In vitro and in vivo induction of brown adipocyte uncoupling protein (thermogenin) by retinoic acid. Pt 3Biochem. J. 1996;317:827–833. doi: 10.1042/bj3170827. PubMed DOI PMC

Bonet M.L., Oliver J., Pico C., Felipe F., Ribot J., Cinti S., Palou A. Opposite effects of feeding a vitamin A-deficient diet and retinoic acid treatment on brown adipose tissue uncoupling protein 1 (UCP1), UCP2 and leptin expression. J. Endocrinol. 2000;166:511–517. doi: 10.1677/joe.0.1660511. PubMed DOI

Mercader J., Ribot J., Murano I., Felipe F., Cinti S., Bonet M.L., Palou A. Remodeling of white adipose tissue after retinoic acid administration in mice. Endocrinology. 2006;147:5325–5332. doi: 10.1210/en.2006-0760. PubMed DOI

Mercader J., Madsen L., Felipe F., Palou A., Kristiansen K., Bonet M.L. All-trans retinoic acid increases oxidative metabolism in mature adipocytes. Cell Physiol. Biochem. 2007;20:1061–1072. doi: 10.1159/000110717. PubMed DOI

Tourniaire F., Musinovic H., Gouranton E., Astier J., Marcotorchino J., Arreguin A., Bernot D., Palou A., Bonet M.L., Ribot J., et al. All-trans retinoic acid induces oxidative phosphorylation and mitochondria biogenesis in adipocytes. J. Lipid Res. 2015;56:1100–1109. doi: 10.1194/jlr.M053652. PubMed DOI PMC

Amengual J., Ribot J., Bonet M.L., Palou A. Retinoic acid treatment increases lipid oxidation capacity in skeletal muscle of mice. Obes. (Silver Spring) 2008;16:585–591. doi: 10.1038/oby.2007.104. PubMed DOI

Berry D.C., Noy N. All-trans-retinoic acid represses obesity and insulin resistance by activating both peroxisome proliferation-activated receptor beta/delta and retinoic acid receptor. Mol. Cell Biol. 2009;29:3286–3296. doi: 10.1128/MCB.01742-08. PubMed DOI PMC

Amengual J., Garcia-Carrizo F.J., Arreguin A., Musinovic H., Granados N., Palou A., Bonet M.L., Ribot J. Retinoic Acid Increases Fatty Acid Oxidation and Irisin Expression in Skeletal Muscle Cells and Impacts Irisin In Vivo. Cell Physiol. Biochem. 2018;46:187–202. doi: 10.1159/000488422. PubMed DOI

Amengual J., Ribot J., Bonet M.L., Palou A. Retinoic acid treatment enhances lipid oxidation and inhibits lipid biosynthesis capacities in the liver of mice. Cell Physiol. Biochem. 2010;25:657–666. doi: 10.1159/000315085. PubMed DOI

Amengual J., Petrov P., Bonet M.L., Ribot J., Palou A. Induction of carnitine palmitoyl transferase 1 and fatty acid oxidation by retinoic acid in HepG2 cells. Int. J. Biochem. Cell Biol. 2012;44:2019–2027. doi: 10.1016/j.biocel.2012.07.026. PubMed DOI

He Y., Gong L., Fang Y., Zhan Q., Liu H.X., Lu Y., Guo G.L., Lehman-McKeeman L., Fang J., Wan Y.J. The role of retinoic acid in hepatic lipid homeostasis defined by genomic binding and transcriptome profiling. BMC Genom. 2013;14:575. doi: 10.1186/1471-2164-14-575. PubMed DOI PMC

Tripathy S., Chapman J.D., Han C.Y., Hogarth C.A., Arnold S.L., Onken J., Kent T., Goodlett D.R., Isoherranen N. All-Trans-Retinoic Acid Enhances Mitochondrial Function in Models of Human Liver. Mol. Pharm. 2016;89:560–574. doi: 10.1124/mol.116.103697. PubMed DOI PMC

Ribot J., Felipe F., Bonet M.L., Palou A. Changes of adiposity in response to vitamin A status correlate with changes of PPAR gamma 2 expression. Obes. Res. 2001;9:500–509. doi: 10.1038/oby.2001.65. PubMed DOI

Guo H., Foncea R., O’Byrne S.M., Jiang H., Zhang Y., Deis J.A., Blaner W.S., Bernlohr D.A., Chen X. Lipocalin 2, a Regulator of Retinoid Homeostasis and Retinoid-mediated Thermogenic Activation in Adipose Tissue. J. Biol. Chem. 2016;291:11216–11229. doi: 10.1074/jbc.M115.711556. PubMed DOI PMC

Yang D., Vuckovic M.G., Smullin C.P., Kim M., Lo C.P., Devericks E., Yoo H.S., Tintcheva M., Deng Y., Napoli J.L. Modest Decreases in Endogenous All-trans-Retinoic Acid Produced by a Mouse Rdh10 Heterozygote Provoke Major Abnormalities in Adipogenesis and Lipid Metabolism. Diabetes. 2018;67:662–673. doi: 10.2337/db17-0946. PubMed DOI PMC

Krois C.R., Vuckovic M.G., Huang P., Zaversnik C., Liu C.S., Gibson C.E., Wheeler M.R., Obrochta K.M., Min J.H., Herber C.B., et al. RDH1 suppresses adiposity by promoting brown adipose adaptation to fasting and re-feeding. Cell Mol. Life Sci. 2019;76:2425–2447. doi: 10.1007/s00018-019-03046-z. PubMed DOI PMC

Yanagitani A., Yamada S., Yasui S., Shimomura T., Murai R., Murawaki Y., Hashiguchi K., Kanbe T., Saeki T., Ichiba M., et al. Retinoic acid receptor alpha dominant negative form causes steatohepatitis and liver tumors in transgenic mice. Hepatology. 2004;40:366–375. doi: 10.1002/hep.20335. PubMed DOI

Felipe F., Bonet M.L., Ribot J., Palou A. Modulation of resistin expression by retinoic acid and vitamin A status. Diabetes. 2004;53:882–889. doi: 10.2337/diabetes.53.4.882. PubMed DOI

Mercader J., Granados N., Bonet M.L., Palou A. All-trans retinoic acid decreases murine adipose retinol binding protein 4 production. Cell Physiol. Biochem. 2008;22:363–372. doi: 10.1159/000149815. PubMed DOI

Reuter S.E., Evans A.M. Carnitine and acylcarnitines: Pharmacokinetic, pharmacological and clinical aspects. Clin. Pharmacokinet. 2012;51:553–572. doi: 10.1007/BF03261931. PubMed DOI

Schooneman M.G., Vaz F.M., Houten S.M., Soeters M.R. Acylcarnitines: Reflecting or inflicting insulin resistance? Diabetes. 2013;62:1–8. doi: 10.2337/db12-0466. PubMed DOI PMC

Adams S.H., Hoppel C.L., Lok K.H., Zhao L., Wong S.W., Minkler P.E., Hwang D.H., Newman J.W., Garvey W.T. Plasma acylcarnitine profiles suggest incomplete long-chain fatty acid beta-oxidation and altered tricarboxylic acid cycle activity in type 2 diabetic African-American women. J. Nutr. 2009;139:1073–1081. doi: 10.3945/jn.108.103754. PubMed DOI PMC

Koves T.R., Ussher J.R., Noland R.C., Slentz D., Mosedale M., Ilkayeva O., Bain J., Stevens R., Dyck J.R., Newgard C.B., et al. Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. Cell Metab. 2008;7:45–56. doi: 10.1016/j.cmet.2007.10.013. PubMed DOI

Mihalik S.J., Goodpaster B.H., Kelley D.E., Chace D.H., Vockley J., Toledo F.G., DeLany J.P. Increased levels of plasma acylcarnitines in obesity and type 2 diabetes and identification of a marker of glucolipotoxicity. Obesity. 2010;18:1695–1700. doi: 10.1038/oby.2009.510. PubMed DOI PMC

Sampey B.P., Freemerman A.J., Zhang J., Kuan P.F., Galanko J.A., O’Connell T.M., Ilkayeva O.R., Muehlbauer M.J., Stevens R.D., Newgard C.B., et al. Metabolomic profiling reveals mitochondrial-derived lipid biomarkers that drive obesity-associated inflammation. PLoS ONE. 2012;7:e38812. doi: 10.1371/journal.pone.0038812. PubMed DOI PMC

Zhang X., Zhang C., Chen L., Han X., Ji L. Human serum acylcarnitine profiles in different glucose tolerance states. Diabetes Res. Clin. Pr. 2014;104:376–382. doi: 10.1016/j.diabres.2014.04.013. PubMed DOI

Gopalan V., Michael N., Ishino S., Lee S.S., Yang A.Y., Bhanu Prakash K.N., Yaligar J., Sadananthan S.A., Kaneko M., Zhou Z., et al. Effect of Exercise and Calorie Restriction on Tissue Acylcarnitines, Tissue Desaturase Indices, and Fat Accumulation in Diet-Induced Obese Rats. Sci. Rep. 2016;6:26445. doi: 10.1038/srep26445. PubMed DOI PMC

Redman L.M., Huffman K.M., Landerman L.R., Pieper C.F., Bain J.R., Muehlbauer M.J., Stevens R.D., Wenner B.R., Kraus V.B., Newgard C.B., et al. Effect of caloric restriction with and without exercise on metabolic intermediates in nonobese men and women. J. Clin. Endocrinol. Metab. 2011;96:E312–E321. doi: 10.1210/jc.2010-1971. PubMed DOI PMC

Schooneman M.G., Napolitano A., Houten S.M., Ambler G.K., Murgatroyd P.R., Miller S.R., Hollak C.E., Tan C.Y., Virtue S., Vidal-Puig A., et al. Assessment of plasma acylcarnitines before and after weight loss in obese subjects. Arch. Biochem. Biophys. 2016;606:73–80. doi: 10.1016/j.abb.2016.07.013. PubMed DOI

Wang T.J., Larson M.G., Vasan R.S., Cheng S., Rhee E.P., McCabe E., Lewis G.D., Fox C.S., Jacques P.F., Fernandez C., et al. Metabolite profiles and the risk of developing diabetes. Nat. Med. 2011;17:448–453. doi: 10.1038/nm.2307. PubMed DOI PMC

Yoon M.S. The Emerging Role of Branched-Chain Amino Acids in Insulin Resistance and Metabolism. Nutrients. 2016;8:405. doi: 10.3390/nu8070405. PubMed DOI PMC

Tang W.H., Wang Z., Cho L., Brennan D.M., Hazen S.L. Diminished global arginine bioavailability and increased arginine catabolism as metabolic profile of increased cardiovascular risk. J. Am. Coll Cardiol. 2009;53:2061–2067. doi: 10.1016/j.jacc.2009.02.036. PubMed DOI PMC

Tang W.H., Shrestha K., Wang Z., Troughton R.W., Klein A.L., Hazen S.L. Diminished global arginine bioavailability as a metabolic defect in chronic systolic heart failure. J. Card. Fail. 2013;19:87–93. doi: 10.1016/j.cardfail.2013.01.001. PubMed DOI PMC

Szabova L., Macejova D., Dvorcakova M., Mostbock S., Blazickova S., Zorad S., Walrand S., Cardinault N., Vasson M.P., Rock E., et al. Expression of nuclear retinoic acid receptor in peripheral blood mononuclear cells (PBMC) of healthy subjects. Life Sci. 2003;72:831–836. doi: 10.1016/S0024-3205(02)02307-X. PubMed DOI

Petrov P.D., Bonet M.L., Reynes B., Oliver P., Palou A., Ribot J. Whole Blood RNA as a Source of Transcript-Based Nutrition- and Metabolic Health-Related Biomarkers. PLoS ONE. 2016;11:e0155361. doi: 10.1371/journal.pone.0155361. PubMed DOI PMC

Ozpolat B., Mehta K., Lopez-Berestein G. Regulation of a highly specific retinoic acid-4-hydroxylase (CYP26A1) enzyme and all-trans-retinoic acid metabolism in human intestinal, liver, endothelial, and acute promyelocytic leukemia cells. Leuk. Lymphoma. 2005;46:1497–1506. doi: 10.1080/10428190500174737. PubMed DOI

Bonet M.L., Ribot J., Palou A. Lipid metabolism in mammalian tissues and its control by retinoic acid. Biochim. Biophys. Acta. 2012;1821:177–189. doi: 10.1016/j.bbalip.2011.06.001. PubMed DOI

Bonet M.L., Canas J.A., Ribot J., Palou A. Carotenoids and their conversion products in the control of adipocyte function, adiposity and obesity. Arch. Biochem. Biophys. 2015;572:112–125. doi: 10.1016/j.abb.2015.02.022. PubMed DOI

Liu Y., Chen H., Mu D., Fan J., Song J., Zhong Y., Li D., Xia M. Circulating Retinoic Acid Levels and the Development of Metabolic Syndrome. J. Clin. Endocrinol. Metab. 2016;101:1686–1692. doi: 10.1210/jc.2015-4038. PubMed DOI

Poirier Y., Antonenkov V.D., Glumoff T., Hiltunen J.K. Peroxisomal beta-oxidation--a metabolic pathway with multiple functions. Biochim. Biophys. Acta. 2006;1763:1413–1426. doi: 10.1016/j.bbamcr.2006.08.034. PubMed DOI

Ferdinandusse S., Denis S., Van Roermund C.W., Wanders R.J., Dacremont G. Identification of the peroxisomal beta-oxidation enzymes involved in the degradation of long-chain dicarboxylic acids. J. Lipid Res. 2004;45:1104–1111. doi: 10.1194/jlr.M300512-JLR200. PubMed DOI

Nguyen P., Leray V., Diez M., Serisier S., Le Bloc’h J., Siliart B., Dumon H. Liver lipid metabolism. J. Anim. Physiol. Anim. Nutr. 2008;92:272–283. doi: 10.1111/j.1439-0396.2007.00752.x. PubMed DOI

Ahn M.Y., Seo Y.J., Ji S.D., Han J.W., Hwang J.S., Yun E.Y. Fatty Acid Composition of Adipose Tissues in Obese Mice and SD Rats Fed with Isaria sinclairii Powder. Toxicol. Res. 2010;26:185–192. doi: 10.5487/TR.2010.26.3.185. PubMed DOI PMC

Schooneman M.G., Ten Have G.A., van Vlies N., Houten S.M., Deutz N.E., Soeters M.R. Transorgan fluxes in a porcine model reveal a central role for liver in acylcarnitine metabolism. Am. J. Physiol. Endocrinol. Metab. 2015;309:E256–E264. doi: 10.1152/ajpendo.00503.2014. PubMed DOI

Makrecka-Kuka M., Sevostjanovs E., Vilks K., Volska K., Antone U., Kuka J., Makarova E., Pugovics O., Dambrova M., Liepinsh E. Plasma acylcarnitine concentrations reflect the acylcarnitine profile in cardiac tissues. Sci. Rep. 2017;7:17528. doi: 10.1038/s41598-017-17797-x. PubMed DOI PMC

Sohlenius A.K., Wigren J., Backstrom K., Andersson K., DePierre J.W. Synergistic induction of acyl-CoA oxidase activity, an indicator of peroxisome proliferation, by arachidonic acid and retinoic acid in Morris hepatoma 7800C1 cells. Biochim. Biophys. Acta. 1995;1258:257–264. doi: 10.1016/0005-2760(95)00123-T. PubMed DOI

Ringseis R., Wege N., Wen G., Rauer C., Hirche F., Kluge H., Eder K. Carnitine synthesis and uptake into cells are stimulated by fasting in pigs as a model of nonproliferating species. J. Nutr. Biochem. 2009;20:840–847. doi: 10.1016/j.jnutbio.2008.07.012. PubMed DOI

McCoin C.S., Knotts T.A., Adams S.H. Acylcarnitines--old actors auditioning for new roles in metabolic physiology. Nat. Rev. Endocrinol. 2015;11:617–625. doi: 10.1038/nrendo.2015.129. PubMed DOI PMC

Seiler S.E., Martin O.J., Noland R.C., Slentz D.H., DeBalsi K.L., Ilkayeva O.R., An J., Newgard C.B., Koves T.R., Muoio D.M. Obesity and lipid stress inhibit carnitine acetyltransferase activity. J. Lipid Res. 2014;55:635–644. doi: 10.1194/jlr.M043448. PubMed DOI PMC

Wessels B., van den Broek N.M., Ciapaite J., Houten S.M., Wanders R.J., Nicolay K., Prompers J.J. Carnitine supplementation in high-fat diet-fed rats does not ameliorate lipid-induced skeletal muscle mitochondrial dysfunction in vivo. Am. J. Physiol. Endocrinol. Metab. 2015;309:E670–E678. doi: 10.1152/ajpendo.00144.2015. PubMed DOI

Noland R.C., Koves T.R., Seiler S.E., Lum H., Lust R.M., Ilkayeva O., Stevens R.D., Hegardt F.G., Muoio D.M. Carnitine insufficiency caused by aging and overnutrition compromises mitochondrial performance and metabolic control. J. Biol. Chem. 2009;284:22840–22852. doi: 10.1074/jbc.M109.032888. PubMed DOI PMC

Nicassio L., Fracasso F., Sirago G., Musicco C., Picca A., Marzetti E., Calvani R., Cantatore P., Gadaleta M.N., Pesce V. Dietary supplementation with acetyl-l-carnitine counteracts age-related alterations of mitochondrial biogenesis, dynamics and antioxidant defenses in brain of old rats. Exp. Gerontol. 2017;98:99–109. doi: 10.1016/j.exger.2017.08.017. PubMed DOI

Bene J., Hadzsiev K., Melegh B. Role of carnitine and its derivatives in the development and management of type 2 diabetes. Nutr. Diabetes. 2018;8:8. doi: 10.1038/s41387-018-0017-1. PubMed DOI PMC

Wyss M., Kaddurah-Daouk R. Creatine and creatinine metabolism. Physiol. Rev. 2000;80:1107–1213. doi: 10.1152/physrev.2000.80.3.1107. PubMed DOI

Kim G.S., Chevli K.D., Fitch C.D. Fasting modulates creatine entry into skeletal muscle in the mouse. Experientia. 1983;39:1360–1362. doi: 10.1007/BF01990104. PubMed DOI

Pandke K.E., Mullen K.L., Snook L.A., Bonen A., Dyck D.J. Decreasing intramuscular phosphagen content simultaneously increases plasma membrane FAT/CD36 and GLUT4 transporter abundance. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2008;295:R806–R813. doi: 10.1152/ajpregu.90540.2008. PubMed DOI

Campbell C., Grapov D., Fiehn O., Chandler C.J., Burnett D.J., Souza E.C., Casazza G.A., Gustafson M.B., Keim N.L., Newman J.W., et al. Improved metabolic health alters host metabolism in parallel with changes in systemic xeno-metabolites of gut origin. PLoS ONE. 2014;9:e84260. doi: 10.1371/journal.pone.0084260. PubMed DOI PMC

Simcox J., Geoghegan G., Maschek J.A., Bensard C.L., Pasquali M., Miao R., Lee S., Jiang L., Huck I., Kershaw E.E., et al. Global Analysis of Plasma Lipids Identifies Liver-Derived Acylcarnitines as a Fuel Source for Brown Fat Thermogenesis. Cell Metab. 2017;26:509–522.e506. doi: 10.1016/j.cmet.2017.08.006. PubMed DOI PMC

Kazak L., Chouchani E.T., Jedrychowski M.P., Erickson B.K., Shinoda K., Cohen P., Vetrivelan R., Lu G.Z., Laznik-Bogoslavski D., Hasenfuss S.C., et al. A creatine-driven substrate cycle enhances energy expenditure and thermogenesis in beige fat. Cell. 2015;163:643–655. doi: 10.1016/j.cell.2015.09.035. PubMed DOI PMC

Kazak L., Chouchani E.T., Lu G.Z., Jedrychowski M.P., Bare C.J., Mina A.I., Kumari M., Zhang S., Vuckovic I., Laznik-Bogoslavski D., et al. Genetic Depletion of Adipocyte Creatine Metabolism Inhibits Diet-Induced Thermogenesis and Drives Obesity. Cell Metab. 2017;26:660–671.e663. doi: 10.1016/j.cmet.2017.08.009. PubMed DOI PMC

Achan V., Tran C.T., Arrigoni F., Whitley G.S., Leiper J.M., Vallance P. all-trans-Retinoic acid increases nitric oxide synthesis by endothelial cells: A role for the induction of dimethylarginine dimethylaminohydrolase. Circ. Res. 2002;90:764–769. doi: 10.1161/01.RES.0000014450.40853.2B. PubMed DOI

Uruno A., Sugawara A., Kanatsuka H., Kagechika H., Saito A., Sato K., Kudo M., Takeuchi K., Ito S. Upregulation of nitric oxide production in vascular endothelial cells by all-trans retinoic acid through the phosphoinositide 3-kinase/Akt pathway. Circulation. 2005;112:727–736. doi: 10.1161/CIRCULATIONAHA.104.500959. PubMed DOI

Nisoli E., Tonello C., Briscini L., Carruba M.O. Inducible nitric oxide synthase in rat brown adipocytes: Implications for blood flow to brown adipose tissue. Endocrinology. 1997;138:676–682. doi: 10.1210/endo.138.2.4956. PubMed DOI

Nisoli E., Tonello C., Cardile A., Cozzi V., Bracale R., Tedesco L., Falcone S., Valerio A., Cantoni O., Clementi E., et al. Calorie restriction promotes mitochondrial biogenesis by inducing the expression of eNOS. Science. 2005;310:314–317. doi: 10.1126/science.1117728. PubMed DOI

Mitschke M.M., Hoffmann L.S., Gnad T., Scholz D., Kruithoff K., Mayer P., Haas B., Sassmann A., Pfeifer A., Kilic A. Increased cGMP promotes healthy expansion and browning of white adipose tissue. FASEB J. 2013;27:1621–1630. doi: 10.1096/fj.12-221580. PubMed DOI

Pacher P., Beckman J.S., Liaudet L. Nitric oxide and peroxynitrite in health and disease. Physiol. Rev. 2007;87:315–424. doi: 10.1152/physrev.00029.2006. PubMed DOI PMC

Litvinova L., Atochin D.N., Fattakhov N., Vasilenko M., Zatolokin P., Kirienkova E. Nitric oxide and mitochondria in metabolic syndrome. Front. Physiol. 2015;6:20. doi: 10.3389/fphys.2015.00020. PubMed DOI PMC

Sailer M., Dahlhoff C., Giesbertz P., Eidens M.K., de Wit N., Rubio-Aliaga I., Boekschoten M.V., Muller M., Daniel H. Increased plasma citrulline in mice marks diet-induced obesity and may predict the development of the metabolic syndrome. PLoS ONE. 2013;8:e63950. doi: 10.1371/journal.pone.0063950. PubMed DOI PMC

Erdely A., Kepka-Lenhart D., Salmen-Muniz R., Chapman R., Hulderman T., Kashon M., Simeonova P.P., Morris S.M., Jr. Arginase activities and global arginine bioavailability in wild-type and ApoE-deficient mice: Responses to high fat and high cholesterol diets. PLoS ONE. 2010;5:e15253. doi: 10.1371/journal.pone.0015253. PubMed DOI PMC

Tripolt N.J., Meinitzer A., Eder M., Wascher T.C., Pieber T.R., Sourij H. Multifactorial risk factor intervention in patients with Type 2 diabetes improves arginine bioavailability ratios. Diabet. Med. 2012;29:e365–e368. doi: 10.1111/j.1464-5491.2012.03743.x. PubMed DOI

Murakami S. Role of taurine in the pathogenesis of obesity. Mol Nutr Food Res. 2015;59:1353–1363. doi: 10.1002/mnfr.201500067. PubMed DOI

Wang W., Wu Z., Dai Z., Yang Y., Wang J., Wu G. Glycine metabolism in animals and humans: Implications for nutrition and health. Amino Acids. 2013;45:463–477. doi: 10.1007/s00726-013-1493-1. PubMed DOI

Tastesen H.S., Keenan A.H., Madsen L., Kristiansen K., Liaset B. Scallop protein with endogenous high taurine and glycine content prevents high-fat, high-sucrose-induced obesity and improves plasma lipid profile in male C57BL/6J mice. Amino Acids. 2014;46:1659–1671. doi: 10.1007/s00726-014-1715-1. PubMed DOI PMC

Tsuboyama-Kasaoka N., Shozawa C., Sano K., Kamei Y., Kasaoka S., Hosokawa Y., Ezaki O. Taurine (2-aminoethanesulfonic acid) deficiency creates a vicious circle promoting obesity. Endocrinology. 2006;147:3276–3284. doi: 10.1210/en.2005-1007. PubMed DOI

Cao P.J., Jin Y.J., Li M.E., Zhou R., Yang M.Z. PGC-1alpha may associated with the anti-obesity effect of taurine on rats induced by arcuate nucleus lesion. Nutr. Neurosci. 2016;19:86–93. doi: 10.1179/1476830514Y.0000000153. PubMed DOI

Yang F., He Y., Liu H.X., Tsuei J., Jiang X., Yang L., Wang Z.T., Wan Y.J. All-trans retinoic acid regulates hepatic bile acid homeostasis. Biochem. Pharm. 2014;91:483–489. doi: 10.1016/j.bcp.2014.08.018. PubMed DOI PMC

Chesney R.W., Han X. Differential regulation of TauT by calcitriol and retinoic acid via VDR/RXR in LLC-PK1 and MCF-7 cells. Adv. Exp. Med. Biol. 2013;776:291–305. doi: 10.1007/978-1-4614-6093-0_27. PubMed DOI

Kim J., Okla M., Erickson A., Carr T., Natarajan S.K., Chung S. Eicosapentaenoic Acid Potentiates Brown Thermogenesis through FFAR4-dependent Up-regulation of miR-30b and miR-378. J. Biol. Chem. 2016;291:20551–20562. doi: 10.1074/jbc.M116.721480. PubMed DOI PMC

Quesada-Lopez T., Cereijo R., Turatsinze J.V., Planavila A., Cairo M., Gavalda-Navarro A., Peyrou M., Moure R., Iglesias R., Giralt M., et al. The lipid sensor GPR120 promotes brown fat activation and FGF21 release from adipocytes. Nat. Commun. 2016;7:13479. doi: 10.1038/ncomms13479. PubMed DOI PMC

Guo X.F., Li X., Shi M., Li D. n-3 Polyunsaturated Fatty Acids and Metabolic Syndrome Risk: A Meta-Analysis. Nutrients. 2017;9:703. doi: 10.3390/nu9070703. PubMed DOI PMC

Fleckenstein-Elsen M., Dinnies D., Jelenik T., Roden M., Romacho T., Eckel J. Eicosapentaenoic acid and arachidonic acid differentially regulate adipogenesis, acquisition of a brite phenotype and mitochondrial function in primary human adipocytes. Mol. Nutr. Food Res. 2016;60:2065–2075. doi: 10.1002/mnfr.201500892. PubMed DOI

Simopoulos A.P. An Increase in the Omega-6/Omega-3 Fatty Acid Ratio Increases the Risk for Obesity. Nutrients. 2016;8:128. doi: 10.3390/nu8030128. PubMed DOI PMC

Qin X., Park H.G., Zhang J.Y., Lawrence P., Liu G., Subramanian N., Kothapalli K.S., Brenna J.T. Brown but not white adipose cells synthesize omega-3 docosahexaenoic acid in culture. Prostaglandins Leukot. Essent. Fatty Acids. 2016;104:19–24. doi: 10.1016/j.plefa.2015.11.001. PubMed DOI PMC

Kim H.I., Raffler J., Lu W., Lee J.J., Abbey D., Saleheen D., Rabinowitz J.D., Bennett M.J., Hand N.J., Brown C., et al. Fine Mapping and Functional Analysis Reveal a Role of SLC22A1 in Acylcarnitine Transport. Am. J. Hum. Genet. 2017;101:489–502. doi: 10.1016/j.ajhg.2017.08.008. PubMed DOI PMC

Erkelens M.N., Mebius R.E. Retinoic Acid and Immune Homeostasis: A Balancing Act. Trends Immunol. 2017;38:168–180. doi: 10.1016/j.it.2016.12.006. PubMed DOI

Escribese M.M., Conde E., Saenz-Morales D., Hordijk P.L., Garcia-Bermejo M.L. Mononuclear cell extravasation in an inflammatory response is abrogated by all-trans-retinoic acid through inhibiting the acquisition of an appropriate migratory phenotype. J. Pharm. Exp. 2008;324:454–462. doi: 10.1124/jpet.107.127225. PubMed DOI

Diaz-Rua R., Palou A., Oliver P. Cpt1a gene expression in peripheral blood mononuclear cells as an early biomarker of diet-related metabolic alterations. Food Nutr. Res. 2016;60:33554. doi: 10.3402/fnr.v60.33554. PubMed DOI PMC

Bajad S.U., Lu W., Kimball E.H., Yuan J., Peterson C., Rabinowitz J.D. Separation and quantitation of water soluble cellular metabolites by hydrophilic interaction chromatography-tandem mass spectrometry. J. Chromatogr. A. 2006;1125:76–88. doi: 10.1016/j.chroma.2006.05.019. PubMed DOI

Yuan M., Breitkopf S.B., Yang X., Asara J.M. A positive/negative ion-switching, targeted mass spectrometry-based metabolomics platform for bodily fluids, cells, and fresh and fixed tissue. Nat. Protoc. 2012;7:872–881. doi: 10.1038/nprot.2012.024. PubMed DOI PMC

Rombaldova M., Janovska P., Kopecky J., Kuda O. Omega-3 fatty acids promote fatty acid utilization and production of pro-resolving lipid mediators in alternatively activated adipose tissue macrophages. Biochem Biophys. Res. Commun. 2017;490:1080–1085. doi: 10.1016/j.bbrc.2017.06.170. PubMed DOI

Pfaffl M.W. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. 2001;29:e45. doi: 10.1093/nar/29.9.e45. PubMed DOI PMC