Abstract
Introduction
Leptin is known to regulate pathways of energy metabolism, reproduction, and control appetite. Whether plasma leptin levels reflect changes in metabolites of these pathways is unknown.
Objectives
We aimed to find whether there is an association between leptin levels and levels of metabolites of energy and hormone metabolism.
Methods
We performed an untargeted metabolomics analysis of plasma from 110 healthy adults (men: women = 1:1; aged 18–40 years), using liquid chromatography-tandem mass spectrometry. Blood samples were collected from all the study subjects in the fasting state. Clinical features and markers of obesity and Type 2 diabetes mellitus (T2DM) were assessed in all. The association between levels of metabolites and clinical and biochemical parameters was identified using the multivariable-adjusted linear regression model and PLS-DA analysis.
Results
The leptin level was found to have a significant association with a substantial number of metabolites in women and men. Leptin level was positively associated with glycocholic acid and arachidic acid, metabolites related to energy metabolisms, pregnanediol-3-glucuronide, a metabolite of progesterone metabolism, and quercetin 3′-sulfate, a diet-derived metabolite. Leptin level was negatively associated with ponasteroside A and barringtogenol C levels. Leptin level was positively correlated with adiponectin and negatively with total calorie intake and levels of triglyceride and very-low-density lipoprotein. Leptin levels were associated with lipid and sex hormone metabolism in women, while metabolites involved in amino acid metabolism were correlated to leptin in men.
Conclusion
Our study indicates that leptin level reflects metabolome alterations and hence could be a useful marker to detect early changes in energy and hormone metabolisms.
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Data availability
The metabolomics data is available at MetaboLights (Study ID: MTBLS743).
Abbreviations
- T2DM:
-
Type 2 diabetes mellitus
- WAT:
-
White adipose tissue
- RPLC:
-
Reversed-phase liquid chromatography
- HILIC:
-
Hydrophilic interaction chromatography
- QC-RLSC:
-
Quality control-robust loess signal correction
- KNN:
-
K-nearest neighbor
- VLSFA:
-
Very long-chain saturated fatty acid
- PAI-1:
-
Plasminogen activator inhibitor-1
- GLP-1:
-
Glucagon like polypeptide-1
- HOMA-IR:
-
Homeostasis model of insulin resistance
References
Ardisson Korat, A. V., Malik, V. S., Furtado, J. D., Sacks, F., Rosner, B., Rexrode, K. M., et al. (2019). Circulating very-long-chain SFA concentrations are inversely associated with incident Type 2 diabetes in US men and women. The Journal of Nutrition. https://doi.org/10.1093/jn/nxz240.
Arthur, A., Garay, J., Guarda, B., Sieswerda, L., & Stevens, A. (2010). Redevelopment and evaluation of EpiData: A practical software tool for use in the public health field. International Journal of Infectious Diseases, 14, e428. https://doi.org/10.1016/j.ijid.2010.02.571.
Asao, K., Marekan, A. S., VanCleave, J., & Rothber, A. E. (2016). Leptin level and skipping breakfast: The national health and nutrition examination survey III (NHANES III). Nutrients. https://doi.org/10.3390/nu8030115.
Askari, H., Tykodi, G., Liu, J., & Dagogo-Jack, S. (2010). Fasting plasma leptin level is a surrogate measure of insulin sensitivity. Journal of Clinical Endocrinology and Metabolism, 95(8), 3836–3843. https://doi.org/10.1210/jc.2010-0296.
Baek, H. S., Choi, J. H., Oh, J. W., & Lee, H. B. (2013). Leptin and urinary leukotriene E4 and 9α,11β- prostaglandin F2 release after exercise challenge. Annals of Allergy, Asthma and Immunology, 111(2), 112–117. https://doi.org/10.1016/j.anai.2013.05.019.
Benomar, Y., Gertler, A., De Lacy, P., Crépin, D., Hamouda, H. O., Riffault, L., et al. (2013). Central resistin overexposure induces insulin resistance through toll-like receptor 4. Diabetes, 62(1), 102–144. https://doi.org/10.2337/db12-0237.
Cariou, B., Van Harmelen, K., Duran-Sandoval, D., Van Dijk, T. H., Grefhorst, A., Abdelkarim, M., et al. (2006). The farnesoid X receptor modulates adiposity and peripheral insulin sensitivity in mice. Journal of Biological Chemistry. https://doi.org/10.1074/jbc.M510258200.
Chan, J. L., & Mantzoros, C. S. (2005). Role of leptin in energy-deprivation states: Normal human physiology and clinical implications for hypothalamic amenorrhoea and anorexia nervosa. Lancet. https://doi.org/10.1016/S0140-6736(05)66830-4.
Chirumbolo, S. (2012). Hypothesis: The role of quercetin in adipokine biology. Nutrition, 28(7–8), 727–730. https://doi.org/10.1016/j.nut.2011.10.018.
Chong, J., Soufan, O., Li, C., Caraus, I., Li, S., Bourque, G., et al. (2018). MetaboAnalyst 4.0: Towards more transparent and integrative metabolomics analysis. Nucleic Acids Research, 46(W1), W486–W494. https://doi.org/10.1093/nar/gky310.
Chou, S. H., Chamberland, J. P., Liu, X., Matarese, G., Gao, C., Stefanakis, R., et al. (2011). Leptin is an effective treatment for hypothalamic amenorrhea. Proceedings of the National Academy of Sciences of the United States of America, 108(16), 6585–6590. https://doi.org/10.1073/pnas.1015674108.
Chou, S. H., & Mantzoros, C. (2014). Role of leptin in human reproductive disorders. Journal of Endocrinology. https://doi.org/10.1530/JOE-14-0245.
Considine, R. V., Sinha, M. K., Heiman, M. L., Kriauciunas, A., Stephens, T. W., Nyce, M. R., et al. (1996). Serum immunoreactive-leptin concentrations in normal-weight and obese humans. New England Journal of Medicine, 334(5), 292–295. https://doi.org/10.1056/NEJM199602013340503.
Couillard, C., Mauriege, P., Prud'Homme, D., Nadeau, A., Tremblay, A., Bouchard, C., et al. (1997). Plasma leptin concentrations: Gender differences and associations with metabolic risk factors for cardiovascular disease. Diabetologia, 40(10), 1178–1184. https://doi.org/10.1007/s001250050804.
Cui, H., López, M., & Rahmouni, K. (2017). The cellular and molecular bases of leptin and ghrelin resistance in obesity. Nature Reviews Endocrinology. https://doi.org/10.1038/nrendo.2016.222.
Dunn, W. B., Broadhurst, D., Begley, P., Zelena, E., Francis-Mcintyre, S., Anderson, N., et al. (2011). Procedures for large-scale metabolic profiling of serum and plasma using gas chromatography and liquid chromatography coupled to mass spectrometry. Nature Protocols, 6(7), 1060–1083. https://doi.org/10.1038/nprot.2011.335.
El-Haschimi, K., Pierroz, D. D., Hileman, S. M., Bjørbæk, C., & Flier, J. S. (2000). Two defects contribute to hypothalamic leptin resistance in mice with diet-induced obesity. Journal of Clinical Investigation, 105(12), 1827–1832. https://doi.org/10.1172/JCI9842.
Enriori, P. J., Evans, A. E., Sinnayah, P., Jobst, E. E., Tonelli-Lemos, L., Billes, S. K., et al. (2007). Diet-induced obesity causes severe but reversible leptin resistance in arcuate melanocortin neurons. Cell Metabolism, 5(3), 181–194. https://doi.org/10.1016/j.cmet.2007.02.004.
Forouhi, N. G., Koulman, A., Sharp, S. J., Imamura, F., Kröger, J., Schulze, M. B., et al. (2014). Differences in the prospective association between individual plasma phospholipid saturated fatty acids and incident type 2 diabetes: The EPIC-InterAct case-cohort study. The Lancet Diabetes and Endocrinology, 2(10), 810–818. https://doi.org/10.1016/S2213-8587(14)70146-9.
Fretts, A. M., Imamura, F., Marklund, M., Micha, R., Wu, J. H. Y., Murphy, R. A., et al. (2019). Associations of circulating very-long-chain saturated fatty acids and incident type 2 diabetes: A pooled analysis of prospective cohort studies. American Journal of Clinical Nutrition, 109(4), 1216–1223. https://doi.org/10.1093/ajcn/nqz005.
Giesbertz, P., Padberg, I., Rein, D., Ecker, J., Höfle, A. S., Spanier, B., et al. (2015). Metabolite profiling in plasma and tissues of ob/ob and db/db mice identifies novel markers of obesity and type 2 diabetes. Diabetologia, 58(9), 2133–2143. https://doi.org/10.1007/s00125-015-3656-y.
Gipson, G. T., Tatsuoka, K. S., Ball, R. J., Sokhansanj, B. A., Hansen, M. K., Ryan, T. E., et al. (2008). Multi-platform investigation of the metabolome in a leptin receptor defective murine model of type 2 diabetes. Molecular BioSystems, 4(10), 1015–1023. https://doi.org/10.1039/b807332e.
Gopalan, C., RamaSastri, B. V., Balasubramanian, S. C., NarasingaRao, B. S., Deostale, Y. G., & Pant, K. C. (2000). Nutritional value of Indian foods. Hyderabad: National Institute of Nutrition.
Hellström, L., Wahrenberg, H., Hruska, K., Reynisdottir, S., & Arner, P. (2000). Mechanisms behind gender differences in circulating leptin levels. Journal of Internal Medicine, 247(4), 457–462. https://doi.org/10.1046/j.1365-2796.2000.00678.x.
Hollman, P. C. H., & Katan, M. B. (1999). Health effects and bioavailability of dietary flavonols. Free Radical Research. https://doi.org/10.1080/10715769900301351.
Hsu, C. L., & Yen, G. C. (2006). Induction of cell apoptosis in 3T3-L1 pre-adipocytes by flavonoids is associated with their antioxidant activity. Molecular Nutrition and Food Research, 50(11), 1072–1079. https://doi.org/10.1002/mnfr.200600040.
Huang, W., Metlakunta, A., Dedousis, N., Ortmeyer, H. K., Stefanovic-Racic, M., & O’Doherty, R. M. (2009). Leptin augments the acute suppressive effects of insulin on hepatic very low-density lipoprotein production in rats. Endocrinology, 150(5), 2169–2174. https://doi.org/10.1210/en.2008-1271.
Izadi, V., Saraf-Bank, S., & Azadbakht, L. (2014). Dietary intakes and leptin concentrations. ARYA Atherosclerosis, 10, 266.
Kennedy, A., Gettys, T. W., Watson, P., Wallace, P., Ganaway, E., Pan, Q., et al. (1997). The metabolic significance of leptin in humans: Gender-based differences in relationship to adiposity, insulin sensitivity, and energy expenditure. Journal of Clinical Endocrinology and Metabolism, 82(4), 1293–1300. https://doi.org/10.1210/jc.82.4.1293.
Kihara, A. (2012). Very long-chain fatty acids: Elongation, physiology and related disorders. Journal of Biochemistry. https://doi.org/10.1093/jb/mvs105.
Kirchberg, F. F., Brandt, S., Moß, A., Peissner, W., Koenig, W., Rothenbacher, D., et al. (2017). Metabolomics reveals an entanglement of fasting leptin concentrations with fatty acid oxidation and gluconeogenesis in healthy children. PLoS ONE. https://doi.org/10.1371/journal.pone.0183185.
Kuiper, G. G. J. M., Lemmen, J. G., Carlsson, B., Corton, J. C., Safe, S. H., Van Der Saag, P. T., et al. (1998). Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor β. Endocrinology, 139(10), 4252–4263. https://doi.org/10.1210/endo.139.10.6216.
Kumar, A. A., Satheesh, G., Vijayakumar, G., Chandran, M., Prabhu, P. R., Simon, L., et al. (2020). Postprandial metabolism is impaired in overweight normoglycemic young adults without family history of diabetes. Scientific Reports, 10(1), 353. https://doi.org/10.1038/s41598-019-57257-2.
Kuppusamy, U. R., & Das, N. P. (1992). Effects of flavonoids on cyclic AMP phosphodiesterase and lipid mobilization in rat adipocytes. Biochemical Pharmacology, 44(7), 1307–1315. https://doi.org/10.1016/0006-2952(92)90531-M.
Lefebvre, P., Cariou, B., Lien, F., Kuipers, F., & Staels, B. (2009). Role of bile acids and bile acid receptors in metabolic regulation. Physiological Reviews. https://doi.org/10.1152/physrev.00010.2008.
Leung, R. Y. H., Li, G. H. Y., Cheung, B. M. Y., Tan, K. C. B., Kung, A. W. C., & Cheung, C. L. (2019). Serum metabolomic profiling and its association with 25-hydroxyvitamin D. Clinical Nutrition. https://doi.org/10.1016/j.clnu.2019.04.035.
Lipworth, B. J. (1999). Leukotriene-receptor antagonists. Lancet. https://doi.org/10.1016/S0140-6736(98)09019-9.
Liu, J., Dong, H., Zhang, Y., Cao, M., Song, L., Pan, Q., et al. (2015). Bilirubin increases insulin sensitivity by regulating cholesterol metabolism, adipokines and PPAR 3 Levels. Scientific Reports. https://doi.org/10.1038/srep09886.
Lubkowska, A., Radecka, A., Bryczkowska, I., Rotter, I., Laszczyńska, M., & Dudzińska, W. (2015). Serum adiponectin and leptin concentrations in relation to body fat distribution, hematological indices and lipid profile in humans. International Journal of Environmental Research and Public Health, 12(9), 11528–11548. https://doi.org/10.3390/ijerph120911528.
Malik, V. S., Chiuve, S. E., Campos, H., Rimm, E. B., Mozaffarian, D., Hu, F. B., et al. (2015). Circulating very-long-chain saturated fatty acids and incident coronary heart disease in US men and women. Circulation. https://doi.org/10.1161/CIRCULATIONAHA.114.014911.
Marco-Ramell, A., Tulipani, S., Palau-Rodriguez, M., Gonzalez-Dominguez, R., Miñarro, A., Jauregui, O., et al. (2018). Untargeted profiling of concordant/discordant phenotypes of high insulin resistance and obesity to predict the risk of developing diabetes. Journal of Proteome Research, 17(7), 2307–2317. https://doi.org/10.1021/acs.jproteome.7b00855.
Martins do, M. C., Faleiro, L. L., & Fonseca, A. (2012). Relationship between leptin and body mass and metabolic syndrome in an adult population. Revista Portuguesa de Cardiologia (English Edition), 31(11), 711–719. https://doi.org/10.1016/j.repc.2012.08.002.
Maya-Monteiro, C. M., Almeida, P. E., D’Ávila, H., Martins, A. S., Rezende, A. P., Castro-Faria-Neto, H., et al. (2008). Leptin induces macrophage lipid body formation by a phosphatidylinositol 3-kinase- and mammalian target of rapamycin-dependent mechanism. Journal of Biological Chemistry, 283(4), 2203–2210. https://doi.org/10.1074/jbc.M706706200.
Moon, H. S., Matarese, G., Brennan, A. M., Chamberland, J. P., Liu, X., Fiorenza, C. G., et al. (2011). Efficacy of metreleptin in obese patients with type 2 diabetes: Cellular and molecular pathways underlying leptin tolerance. Diabetes, 60(6), 1647–1656. https://doi.org/10.2337/db10-1791.
Myers, M. G., Cowley, M. A., & Münzberg, H. (2008). Mechanisms of leptin action and leptin resistance. Annual Review of Physiology, 70(1), 537–556. https://doi.org/10.1146/annurev.physiol.70.113006.100707.
Myers, M. G., Leibel, R. L., Seeley, R. J., & Schwartz, M. W. (2010). Obesity and leptin resistance: Distinguishing cause from effect. Trends in Endocrinology and Metabolism. https://doi.org/10.1016/j.tem.2010.08.002.
Ohnaka, K., Kono, S., Inoguchi, T., Yin, G., Morita, M., Adachi, M., et al. (2010). Inverse associations of serum bilirubin with high sensitivity C-reactive protein, glycated hemoglobin, and prevalence of type 2 diabetes in middle-aged and elderly Japanese men and women. Diabetes Research and Clinical Practice, 88(1), 103–110. https://doi.org/10.1016/j.diabres.2009.12.022.
Pan, W. W., & Myers, M. G. (2018). Leptin and the maintenance of elevated body weight. Nature Reviews Neuroscience. https://doi.org/10.1038/nrn.2017.168.
Patti, M. E., Houten, S. M., Bianco, A. C., Bernier, R., Larsen, P. R., Holst, J. J., et al. (2009). Serum bile acids are higher in humans with prior gastric bypass: Potential contribution to improved glucose and lipid metabolism. Obesity, 17(9), 1671–1677. https://doi.org/10.1038/oby.2009.102.
Pérez-Pérez, A., Vilariño-García, T., Fernández-Riejos, P., Martín-González, J., Segura-Egea, J. J., & Sánchez-Margalet, V. (2017). Role of leptin as a link between metabolism and the immune system. Cytokine and Growth Factor Reviews. https://doi.org/10.1016/j.cytogfr.2017.03.001.
R Core Team. (2018). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. Retrieved April 26, 2018, from https://www.R-project.org.
Saad, M. F., Damani, S., Gingerich, R. L., Riad-Gabriel, M. G., Khan, A., Boyadjian, R., et al. (1997). Sexual dimorphism in plasma leptin concentration. Journal of Clinical Endocrinology and Metabolism, 82(2), 579–584. https://doi.org/10.1210/jc.82.2.579.
Saad, M. F., Riad-Gabriel, M. G., Khan, A., Sharma, A., Michael, R., Jinagouda, S. D., et al. (1998). Diurnal and ultradian rhythmicity of plasma leptin: Effects of gender and adiposity. Journal of Clinical Endocrinology and Metabolism, 83(2), 453–459. https://doi.org/10.1210/jc.83.2.453.
Salek, R. M., Steinbeck, C., Viant, M. R., Goodacre, R., & Dunn, W. B. (2013). The role of reporting standards for metabolite annotation and identification in metabolomic studies. GigaScience. https://doi.org/10.1186/2047-217X-2-13.
Seridi, L., Leo, G. C., Lynis Dohm, G., Pories, W. J., & Lenhard, J. (2018). Time course metabolome of Roux-en-Y gastric bypass confirms correlation between leptin, body weight and the microbiome. PLoS ONE. https://doi.org/10.1371/journal.pone.0198156.
Stingl, H., Raffesberg, W., Nowotny, P., Waldhäusl, W., & Roden, M. (2002). Reduction of plasma leptin concentrations by arginine but not lipid infusion in humans. Obesity Research, 10(11), 1111–1119. https://doi.org/10.1038/oby.2002.151.
Tabung, F. K., Liang, L., Huang, T., Balasubramanian, R., Zhao, Y., Chandler, P. D., et al. (2019). Identifying metabolomic profiles of inflammatory diets in postmenopausal women. Clinical Nutrition. https://doi.org/10.1016/j.clnu.2019.06.010.
Takei, R., Inoue, T., Sonoda, N., Kohjima, M., Okamoto, M., Sakamoto, R., et al. (2019). Bilirubin reduces visceral obesity and insulin resistance by suppression of inflammatory cytokines. PLoS ONE. https://doi.org/10.1371/journal.pone.0223302.
Vejrazkova, D., Lischkova, O., Vankova, M., Stanicka, S., Vrbikova, J., Lukasova, P., et al. (2017). Distinct response of fat and gastrointestinal tissue to glucose in gestational diabetes mellitus and polycystic ovary syndrome. Physiological Research, 66(2), 283–292.
Wang, B., Chandrasekera, P., & Pippin, J. (2014). Leptin- and leptin receptor-deficient rodent models: Relevance for human Type 2 diabetes. Current Diabetes Reviews, 10(2), 131–145. https://doi.org/10.2174/1573399810666140508121012.
Wang, J., Obici, S., Morgan, K., Barzilai, N., Feng, Z., & Rossetti, L. (2001). Overfeeding rapidly induces leptin and insulin resistance. Diabetes, 50(12), 2786–2791. https://doi.org/10.2337/diabetes.50.12.2786.
Wen, B., Mei, Z., Zeng, C., & Liu, S. (2017). metaX: A flexible and comprehensive software for processing metabolomics data. BMC Bioinformatics. https://doi.org/10.1186/s12859-017-1579-y.
Wewer Albrechtsen, N. J., Kuhre, R. E., Pedersen, J., Knop, F. K., & Holst, J. J. (2016). The biology of glucagon and the consequences of hyperglucagonemia. Biomarkers in Medicine. https://doi.org/10.2217/bmm-2016-0090.
Won, E. Y., Yoon, M. K., Kim, S. W., Jung, Y., Bae, H. W., Lee, D., et al. (2013). Gender-specific metabolomic profiling of obesity in leptin-deficient ob/ob mice by 1H NMR spectroscopy. PLoS ONE. https://doi.org/10.1371/journal.pone.0075998.
Yang, J. Y., Della-Fera, M. A., Rayalam, S., Ambati, S., Hartzell, D. L., Park, H. J., et al. (2008). Enhanced inhibition of adipogenesis and induction of apoptosis in 3T3-L1 adipocytes with combinations of resveratrol and quercetin. Life Sciences, 82(19–20), 1032–1039. https://doi.org/10.1016/j.lfs.2008.03.003.
Yildizhan, R., Ilhan, G. A., Yildizhan, B., Kolusari, A., Adali, E., & Bugdayci, G. (2011). Serum retinol-binding protein 4, leptin, and plasma asymmetric dimethylarginine levels in obese and nonobese young women with polycystic ovary syndrome. Fertility and Sterility, 96(1), 246–250. https://doi.org/10.1016/j.fertnstert.2011.04.073.
Zhang, J., Yang, W., Li, S., Yao, S., Qi, P., Yang, Z., et al. (2016). An intelligentized strategy for endogenous small molecules characterization and quality evaluation of earthworm from two geographic origins by ultra-high performance HILIC/QTOF MSE and Progenesis QI. Analytical and Bioanalytical Chemistry, 408(14), 3881–3890. https://doi.org/10.1007/s00216-016-9482-3.
Zhong, H., Fang, C., Fan, Y., Lu, Y., Wen, B., Ren, H., et al. (2017). Lipidomic profiling reveals distinct differences in plasma lipid composition in healthy, prediabetic, and type 2 diabetic individuals. GigaScience. https://doi.org/10.1093/gigascience/gix036.
Acknowledgements
The authors wish to thank our participants in this study. This work was supported by Department of Biotechnology, Government of India.
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Funding was provided by Department of Biotechnology, Ministry of Science and Technology (Grant No. BT/PR8444/MED/30/1021/2013).
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AKA conducted the experiments and wrote the manuscript. AKA and GS analyzed the data. MCVR performed the metabolomics experiments. PRP performed Bio-Plex Pro Human Diabetes Assay. GV and CCK designed the study. VRK performed statistical analysis. CCK revised and finalized the manuscript. AJ is the principal investigator, designed this study and has full access to all data.
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Kumar, A.A., Satheesh, G., Vijayakumar, G. et al. Plasma leptin level mirrors metabolome alterations in young adults. Metabolomics 16, 87 (2020). https://doi.org/10.1007/s11306-020-01708-9
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DOI: https://doi.org/10.1007/s11306-020-01708-9