{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T11:13:02Z","timestamp":1784632382018,"version":"3.55.0"},"reference-count":37,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2016,6,27]],"date-time":"2016-06-27T00:00:00Z","timestamp":1466985600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,6,27]],"date-time":"2016-06-27T00:00:00Z","timestamp":1466985600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Increasing evidences support that metabolically healthy obese (MHO) is a transient state. However, little is known about the early markers associated with the development of metabolic abnormalities in MHO individuals. Serum free fatty acids (FFAs) profile is highlighted in its association with obesity-related insulin resistance, type 2 diabetes mellitus (T2DM) and cardiovascular diseases (CVD). To examine the association of endogenous fatty acid metabolism with future development of metabolic abnormalities in MHO individuals, we retrospectively analyzed 24 [product FFA]\/[precursor FFA] ratios in fasting sera and clinical data from 481 individuals who participated in three independent studies, including 131 metabolic healthy subjects who completed the 10-year longitudinal Shanghai Diabetes Study (SHDS), 312 subjects cross-sectionally sampled from the Shanghai Obesity Study (SHOS) and 38 subjects who completed an 8-week very low carbohydrate diet (VLCD) intervention study. Results showed that higher baseline level of oleic acid\/stearic acid (OA\/SA) and lower levels of stearic acid\/palmitic acid (SA\/PA) and arachidonic acid\/dihomo-\u03b3-linolenic acid (AA\/DGLA) ratios were associated with higher rate of MHO to MUO conversion in the longitudinal SHDS. Further, the finding was validated in the cross-sectional and interventional studies. This panel of FFA ratios could be used for identification and early intervention of at-risk obese individuals.<\/jats:p>","DOI":"10.1038\/srep28418","type":"journal-article","created":{"date-parts":[[2016,6,27]],"date-time":"2016-06-27T09:26:39Z","timestamp":1467019599000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":48,"title":["A panel of free fatty acid ratios to predict the development of metabolic abnormalities in healthy obese individuals"],"prefix":"10.1038","volume":"6","author":[{"given":"Linjing","family":"Zhao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Ni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaojing","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aihua","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuqian","family":"Bao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiajian","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianlu","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoxiang","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Panee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingming","family":"Su","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Herbert","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Congrong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiping","family":"Jia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Jia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,6,27]]},"reference":[{"key":"BFsrep28418_CR1","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1001\/jama.289.1.76","volume":"289","author":"AH Mokdad","year":"2003","unstructured":"Mokdad, A. H. et al. Prevalence of obesity, diabetes and obesity-related health risk factors, 2001. JAMA 289, 76\u201379 (2003).","journal-title":"JAMA"},{"key":"BFsrep28418_CR2","doi-asserted-by":"publisher","first-page":"2569","DOI":"10.1210\/jc.2004-0165","volume":"89","author":"AD Karelis","year":"2004","unstructured":"Karelis, A. D., St-Pierre, D. H., Conus, F., Rabasa-Lhoret, R. & Poehlman, E. T. Metabolic and body composition factors in subgroups of obesity: what do we know? J Clin Endocrinol Metab 89, 2569\u20132575 (2004).","journal-title":"J Clin Endocrinol Metab"},{"key":"BFsrep28418_CR3","first-page":"1020","volume":"86","author":"M Brochu","year":"2001","unstructured":"Brochu, M. et al. What are the physical characteristics associated with a normal metabolic profile despite a high level of obesity in postmenopausal women? J Clin Endocrinol Metab 86, 1020\u20131025 (2001).","journal-title":"J Clin Endocrinol Metab"},{"key":"BFsrep28418_CR4","doi-asserted-by":"publisher","first-page":"2388","DOI":"10.2337\/dc12-1971","volume":"36","author":"SL Appleton","year":"2013","unstructured":"Appleton, S. L. et al. Diabetes and cardiovascular disease outcomes in the metabolically healthy obese phenotype a cohort study. Diabetes Care 36, 2388\u20132394 (2013).","journal-title":"Diabetes Care"},{"key":"BFsrep28418_CR5","doi-asserted-by":"publisher","first-page":"2906","DOI":"10.1210\/jc.2006-0594","volume":"91","author":"JB Meigs","year":"2006","unstructured":"Meigs, J. B. et al. Body mass index, metabolic syndrome and risk of type 2 diabetes or cardiovascular disease. J Clin Endocrinol Metab 91, 2906\u20132912 (2006).","journal-title":"J Clin Endocrinol Metab"},{"key":"BFsrep28418_CR6","doi-asserted-by":"publisher","first-page":"210","DOI":"10.2337\/dc10-0665","volume":"34","author":"G Calori","year":"2011","unstructured":"Calori, G. et al. Prevalence, metabolic features and prognosis of metabolically healthy obese Italian individuals: the Cremona Study. Diabetes Care 34, 210\u2013215 (2011).","journal-title":"Diabetes Care"},{"key":"BFsrep28418_CR7","doi-asserted-by":"publisher","first-page":"651","DOI":"10.1038\/oby.2011.243","volume":"20","author":"AD Ogorodnikova","year":"2012","unstructured":"Ogorodnikova, A. D. et al. Incident cardiovascular disease events in metabolically benign obese individuals. Obesity 20, 651\u2013659 (2012).","journal-title":"Obesity"},{"key":"BFsrep28418_CR8","doi-asserted-by":"publisher","first-page":"2989","DOI":"10.2337\/dc14-0869","volume":"37","author":"G Twig","year":"2014","unstructured":"Twig, G. et al. Diabetes risk among overweight and obese metabolically healthy young adults. Diabetes Care 37, 2989\u20132995 (2014).","journal-title":"Diabetes Care"},{"key":"BFsrep28418_CR9","doi-asserted-by":"publisher","first-page":"514","DOI":"10.1038\/ijo.2014.176","volume":"39","author":"R Eshtiaghi","year":"2014","unstructured":"Eshtiaghi, R., Keihani, S., Hosseinpanah, F., Barzin, M. & Azizi, F. Natural course of metabolically healthy abdominal obese adults after 10 years of follow-up: the Tehran Lipid and Glucose Study. Int J Obes 39, 514\u2013519 (2014).","journal-title":"Int J Obes"},{"key":"BFsrep28418_CR10","doi-asserted-by":"publisher","first-page":"2297","DOI":"10.2337\/dc09-0574","volume":"32","author":"JL Kuk","year":"2009","unstructured":"Kuk, J. L. & Ardern, C. I. Are metabolically normal but obese individuals at lower risk for all-cause mortality? Diabetes Care 32, 2297\u20132299 (2009).","journal-title":"Diabetes Care"},{"key":"BFsrep28418_CR11","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1097\/MED.0b013e3283444b09","volume":"18","author":"G Boden","year":"2011","unstructured":"Boden, G. Obesity, insulin resistance and free fatty acids. Curr Opin Endocrinol Diabetes Obes 18, 139\u2013143 (2011).","journal-title":"Curr Opin Endocrinol Diabetes Obes"},{"key":"BFsrep28418_CR12","doi-asserted-by":"publisher","first-page":"1612","DOI":"10.2337\/diabetes.50.7.1612","volume":"50","author":"G Boden","year":"2001","unstructured":"Boden, G., Lebed, B., Schatz, M., Homko, C. & Lemieux, S. Effects of acute changes of plasma free fatty acids on intramyocellular fat content and insulin resistance in healthy subjects. Diabetes 50, 1612\u20131617 (2001).","journal-title":"Diabetes"},{"key":"BFsrep28418_CR13","doi-asserted-by":"publisher","first-page":"3458","DOI":"10.2337\/diabetes.54.12.3458","volume":"54","author":"G Boden","year":"2005","unstructured":"Boden, G. et al. Free fatty acids produce insulin resistance and activate the proinflammatory nuclear factor-\u03baB pathway in rat liver. Diabetes 54, 3458\u20133465 (2005).","journal-title":"Diabetes"},{"key":"BFsrep28418_CR14","doi-asserted-by":"publisher","first-page":"1752","DOI":"10.1172\/JCI21625","volume":"114","author":"S Furukawa","year":"2004","unstructured":"Furukawa, S. et al. Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest 114, 1752\u20131761 (2004).","journal-title":"J Clin Invest"},{"key":"BFsrep28418_CR15","doi-asserted-by":"publisher","first-page":"E275","DOI":"10.1152\/ajpendo.00644.2005","volume":"291","author":"Y Wei","year":"2006","unstructured":"Wei, Y., Wang, D., Topczewski, F. & Pagliassotti, M. J. Saturated fatty acids induce endoplasmic reticulum stress and apoptosis independently of ceramide in liver cells. Am J Physiol Endocrinol Metab 291, E275\u2013E281 (2006).","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"BFsrep28418_CR16","doi-asserted-by":"publisher","first-page":"1513","DOI":"10.1016\/j.ebiom.2015.09.004","volume":"2","author":"Y Ni","year":"2015","unstructured":"Ni, Y. et al. Circulating unsaturated fatty acids delineate the metabolic status of obese individuals. EBioMedicine 2, 1513\u20131522 (2015).","journal-title":"EBioMedicine"},{"key":"BFsrep28418_CR17","doi-asserted-by":"publisher","first-page":"286","DOI":"10.1007\/s00125-006-0503-1","volume":"50","author":"W Jia","year":"2007","unstructured":"Jia, W. et al. Epidemiological characteristics of diabetes mellitus and impaired glucose regulation in a Chinese adult population: the Shanghai Diabetes Studies, a cross-sectional 3-year follow-up study in Shanghai urban communities. Diabetologia 50, 286\u2013292 (2007).","journal-title":"Diabetologia"},{"key":"BFsrep28418_CR18","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1210\/jc.2012-2906","volume":"98","author":"Y Bao","year":"2012","unstructured":"Bao, Y. et al. Inverse relationship between serum osteocalcin levels and visceral fat area in Chinese men. J Clin Endocrinol Metab 98, 345\u2013351 (2012).","journal-title":"J Clin Endocrinol Metab"},{"key":"BFsrep28418_CR19","doi-asserted-by":"publisher","first-page":"760804","DOI":"10.1155\/2013\/760804","volume":"2013","author":"Y Gu","year":"2013","unstructured":"Gu, Y. et al. Beneficial effects of an 8-week, very low carbohydrate diet intervention on obese subjects. Evid Based Complement Alternat Med 2013, 760804, 10.1155\/2013\/760804 (2013).","journal-title":"Evid Based Complement Alternat Med"},{"key":"BFsrep28418_CR20","doi-asserted-by":"publisher","first-page":"2318","DOI":"10.1210\/jc.2012-4253","volume":"98","author":"F Soriguer","year":"2013","unstructured":"Soriguer, F. et al. Metabolically healthy but obese, a matter of time? Findings from the prospective Pizarra study. J Clin Endocrinol Metab 98, 2318\u20132325 (2013).","journal-title":"J Clin Endocrinol Metab"},{"key":"BFsrep28418_CR21","doi-asserted-by":"publisher","first-page":"1365","DOI":"10.1038\/ijo.2015.75","volume":"39","author":"Y Hwang","year":"2015","unstructured":"Hwang, Y. et al. Visceral abdominal fat accumulation predicts the conversion of metabolically healthy obese subjects to an unhealthy phenotype. Int J Obes 39, 1365\u20131370 (2015).","journal-title":"Int J Obes"},{"key":"BFsrep28418_CR22","doi-asserted-by":"publisher","first-page":"758","DOI":"10.7326\/0003-4819-159-11-201312030-00008","volume":"159","author":"CK Kramer","year":"2013","unstructured":"Kramer, C. K., Zinman, B. & Retnakaran, R. Are metabolically healthy overweight and obesity benign conditions?: A systematic review and meta-analysis. Ann Intern Med 159, 758\u2013769 (2013).","journal-title":"Ann Intern Med"},{"key":"BFsrep28418_CR23","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1016\/S2213-8587(13)70062-7","volume":"1","author":"N Stefan","year":"2013","unstructured":"Stefan, N., H\u00e4ring, H.-U., Hu, F. B. & Schulze, M. B. Metabolically healthy obesity: epidemiology, mechanisms and clinical implications. Lancet Diabetes Endocrinol 1, 152\u2013162 (2013).","journal-title":"Lancet Diabetes Endocrinol"},{"key":"BFsrep28418_CR24","doi-asserted-by":"publisher","first-page":"971","DOI":"10.1038\/ijo.2010.216","volume":"35","author":"V Primeau","year":"2011","unstructured":"Primeau, V. et al. Characterizing the profile of obese patients who are metabolically healthy. Int J Obes (Lond) 35, 971\u2013981 (2011).","journal-title":"Int J Obes (Lond)"},{"key":"BFsrep28418_CR25","doi-asserted-by":"publisher","first-page":"4075","DOI":"10.1210\/jc.2007-2724","volume":"93","author":"CA Aguilar-Salinas","year":"2008","unstructured":"Aguilar-Salinas, C. A. et al. High adiponectin concentrations are associated with the metabolically healthy obese phenotype. J Clin Endocrinol Metab 93, 4075\u20134079 (2008).","journal-title":"J Clin Endocrinol Metab"},{"key":"BFsrep28418_CR26","doi-asserted-by":"publisher","first-page":"934","DOI":"10.1210\/jc.2014-3885","volume":"100","author":"CH Jung","year":"2015","unstructured":"Jung, C. H. et al. The risk of incident type 2 diabetes in a Korean metabolically healthy obese population: The role of systemic inflammation. J Clin Endocrinol Metab 100, 934\u2013941 (2015).","journal-title":"J Clin Endocrinol Metab"},{"key":"BFsrep28418_CR27","doi-asserted-by":"publisher","first-page":"462","DOI":"10.1210\/jc.2013-2832","volume":"99","author":"K Aung","year":"2014","unstructured":"Aung, K., Lorenzo, C., Hinojosa, M. A. & Haffner, S. M. Risk of developing diabetes and cardiovascular disease in metabolically unhealthy normal-weight and metabolically healthy obese individuals. J Clin Endocrinol Metab 99, 462\u2013468 (2014).","journal-title":"J Clin Endocrinol Metab"},{"key":"BFsrep28418_CR28","doi-asserted-by":"publisher","first-page":"2859","DOI":"10.1172\/JCI118742","volume":"97","author":"M Roden","year":"1996","unstructured":"Roden, M. et al. Mechanism of free fatty acid-induced insulin resistance in humans. J Clin Invest 97, 2859\u20132865 (1996).","journal-title":"J Clin Invest"},{"key":"BFsrep28418_CR29","doi-asserted-by":"publisher","first-page":"10878","DOI":"10.1073\/pnas.91.23.10878","volume":"91","author":"Y Lee","year":"1994","unstructured":"Lee, Y. et al. Beta-cell lipotoxicity in the pathogenesis of non-insulin-dependent diabetes mellitus of obese rats: impairment in adipocyte-beta-cell relationships. Proc Natl Acad Sci USA 91, 10878\u201310882 (1994).","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFsrep28418_CR30","doi-asserted-by":"publisher","first-page":"1609","DOI":"10.1001\/archinte.168.15.1609","volume":"168","author":"N Stefan","year":"2008","unstructured":"Stefan, N. et al. Identification and characterization of metabolically benign obesity in humans. Arch Intern Med 168, 1609\u20131616 (2008).","journal-title":"Arch Intern Med"},{"key":"BFsrep28418_CR31","doi-asserted-by":"publisher","first-page":"1881","DOI":"10.1038\/oby.2008.308","volume":"16","author":"E Succurro","year":"2008","unstructured":"Succurro, E. et al. Insulin secretion in metabolically obese, but normal weight and in metabolically healthy but obese individuals. Obesity 16, 1881\u20131886 (2008).","journal-title":"Obesity"},{"key":"BFsrep28418_CR32","doi-asserted-by":"publisher","first-page":"348","DOI":"10.1016\/j.plipres.2008.03.003","volume":"47","author":"L Hodson","year":"2008","unstructured":"Hodson, L., Skeaff, C. M. & Fielding, B. A. Fatty acid composition of adipose tissue and blood in humans and its use as a biomarker of dietary intake. Prog Lipid Res 47, 348\u2013380 (2008).","journal-title":"Prog Lipid Res"},{"key":"BFsrep28418_CR33","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1093\/clinchem\/39.5.825","volume":"39","author":"M P\u00fcttmann","year":"1993","unstructured":"P\u00fcttmann, M., Krug, H., von Ochsenstein, E. & Kattermann, R. Fast HPLC determination of serum free fatty acids in the picomole range. Clin Chem 39, 825\u2013832 (1993).","journal-title":"Clin Chem"},{"key":"BFsrep28418_CR34","doi-asserted-by":"publisher","first-page":"1752","DOI":"10.1007\/s00125-008-1038-4","volume":"51","author":"A Karelis","year":"2008","unstructured":"Karelis, A., Messier, V., Brochu, M. & Rabasa-Lhoret, R. Metabolically healthy but obese women: effect of an energy-restricted diet. Diabetologia 51, 1752\u20131754 (2008).","journal-title":"Diabetologia"},{"key":"BFsrep28418_CR35","first-page":"245","volume":"15","author":"B Zhou","year":"2002","unstructured":"Zhou, B. Effect of body mass index on all-cause mortality and incidence of cardiovascular diseases\u2013report for meta-analysis of prospective studies open optimal cut-off points of body mass index in Chinese adults. Biomed Environ Sci 15, 245\u2013252 (2002).","journal-title":"Biomed Environ Sci"},{"key":"BFsrep28418_CR36","doi-asserted-by":"publisher","first-page":"e97928","DOI":"10.1371\/journal.pone.0097928","volume":"9","author":"C Pang","year":"2014","unstructured":"Pang, C. et al. The significance of screening for microvascular diseases in Chinese community-based subjects with various metabolic abnormalities. PLoS One 9, e97928, 10.1371\/journal.pone.0097928 (2014).","journal-title":"PLoS One"},{"key":"BFsrep28418_CR37","doi-asserted-by":"publisher","first-page":"1462","DOI":"10.2337\/diacare.22.9.1462","volume":"22","author":"M Matsuda","year":"1999","unstructured":"Matsuda, M. & DeFronzo, R. A. Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care 22, 1462\u20131470 (1999).","journal-title":"Diabetes Care"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep28418","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep28418.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep28418.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T17:08:23Z","timestamp":1672852103000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep28418"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,6,27]]},"references-count":37,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,9,13]]}},"alternative-id":["BFsrep28418"],"URL":"https:\/\/doi.org\/10.1038\/srep28418","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,6,27]]},"assertion":[{"value":"3 February 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"31 May 2016","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 June 2016","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"28418"}}