{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T10:31:29Z","timestamp":1770978689846,"version":"3.50.1"},"reference-count":45,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,4,15]],"date-time":"2021-04-15T00:00:00Z","timestamp":1618444800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007637","name":"Departamento Administrativo de Ciencia, Tecnolog\u00eda e Innovaci\u00f3n (COLCIENCIAS)","doi-asserted-by":"publisher","award":["111577756880"],"award-info":[{"award-number":["111577756880"]}],"id":[{"id":"10.13039\/100007637","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Obesity has a strong relationship to insulin resistance and diabetes mellitus, a chronic metabolic disease that alters many physiological functions. Naturally derived drugs have aroused great interest in treating obesity, and triterpenoids are natural compounds with multiple biological activities and antidiabetic mechanisms. Here, we evaluated the bioactivity of ursolic acid lactone (UAL), a lesser-known triterpenoid, obtained from Eucalyptus tereticornis. We used different cell lines to show for the first time that this molecule exhibits anti-inflammatory properties in a macrophage model, increases glucose uptake in insulin-resistant muscle cells, and reduces triglyceride content in hepatocytes and adipocytes. In 3T3-L1 adipocytes, UAL inhibited the expression of genes involved in adipogenesis and lipogenesis, enhanced the expression of genes involved in fat oxidation, and increased AMP-activated protein kinase phosphorylation. The range of biological activities demonstrated in vitro indicates that UAL is a promising molecule for fighting diabetes.<\/jats:p>","DOI":"10.3390\/molecules26082282","type":"journal-article","created":{"date-parts":[[2021,4,15]],"date-time":"2021-04-15T12:11:00Z","timestamp":1618488660000},"page":"2282","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Ursolic Acid Lactone Obtained from Eucalyptus tereticornis Increases Glucose Uptake and Reduces Inflammatory Activity and Intracellular Neutral Fat: An In Vitro Study"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1860-1176","authenticated-orcid":false,"given":"Norman","family":"Balcazar","sequence":"first","affiliation":[{"name":"GENMOL Group, Sede de Investigaci\u00f3n Universitaria, University of Antioquia, Medell\u00edn 050010, Antioquia, Colombia"},{"name":"Department of Physiology and Biochemistry, Faculty of Medicine, University of Antioquia, Medell\u00edn 050010, Antioquia, Colombia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6062-6775","authenticated-orcid":false,"given":"Laura I.","family":"Betancur","sequence":"additional","affiliation":[{"name":"GENMOL Group, Sede de Investigaci\u00f3n Universitaria, University of Antioquia, Medell\u00edn 050010, Antioquia, Colombia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diana L.","family":"Mu\u00f1oz","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biochemistry, Faculty of Medicine, University of Antioquia, Medell\u00edn 050010, Antioquia, Colombia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frankly J.","family":"Cabrera","sequence":"additional","affiliation":[{"name":"GENMOL Group, Sede de Investigaci\u00f3n Universitaria, University of Antioquia, Medell\u00edn 050010, Antioquia, Colombia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adriana","family":"Casta\u00f1o","sequence":"additional","affiliation":[{"name":"QOPN Group, Faculty of Exact and Natural Sciences, Sede de Investigaci\u00f3n Universitaria, University of Antioquia, Medell\u00edn 050010, Antioquia, Colombia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9530-8395","authenticated-orcid":false,"given":"Luis F.","family":"Echeverri","sequence":"additional","affiliation":[{"name":"QOPN Group, Faculty of Exact and Natural Sciences, Sede de Investigaci\u00f3n Universitaria, University of Antioquia, Medell\u00edn 050010, Antioquia, Colombia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7335-2865","authenticated-orcid":false,"given":"Sergio","family":"Acin","sequence":"additional","affiliation":[{"name":"GENMOL Group, Sede de Investigaci\u00f3n Universitaria, University of Antioquia, Medell\u00edn 050010, Antioquia, Colombia"},{"name":"Department of Physiology and Biochemistry, Faculty of Medicine, University of Antioquia, Medell\u00edn 050010, Antioquia, Colombia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,15]]},"reference":[{"key":"ref_1","first-page":"2050","article-title":"Medicinal plants for the treatment of obesity: Ethnopharmacological approach and chemical and biological studies","volume":"9","year":"2017","journal-title":"Am. J. Transl. Res."},{"key":"ref_2","unstructured":"International Diabetes Federation (2019). IDF Diabetes Atla, International Diabetes Federation. [9th ed.]."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Schnurr, T.M., Jakupovi\u0107, H., Carrasquilla, G.D., \u00c4ngquist, L., Grarup, N., S\u00f8rensen, T.I.A., Tj\u00f8nneland, A., Overvad, K., Pedersen, O., and Hansen, T. (2020). Obesity, unfavourable lifestyle and genetic risk of type 2 diabetes: A case-cohort study. Diabetologia.","DOI":"10.1007\/s00125-020-05140-5"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Smith, U., and Kahn, B.B. (2016). Adipose tissue regulates insulin sensitivity: Role of adipogenesis, de novo lipogenesis and novel lipids. J. Intern. Med.","DOI":"10.1111\/joim.12540"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1055\/s-0035-1546131","article-title":"Natural products for the treatment of type 2 diabetes mellitus","volume":"81","author":"Francini","year":"2015","journal-title":"Planta Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1016\/j.phrs.2018.01.015","article-title":"Natural products for the treatment of type 2 diabetes mellitus: Pharmacology and mechanisms","volume":"130","author":"Xu","year":"2018","journal-title":"Pharmacol. Res."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Alqahtani, A., Hamid, K., Kam, A., Wong, K.H., Abdelhak, Z., Razmovski-Naumovski, V., Chan, K., Li, K.M., Groundwater, P.W., and Li, G.Q. (2013). The pentacyclic triterpenoids in herbal medicines and their pharmacological activities in diabetes and diabetic complications. Curr. Med. Chem.","DOI":"10.2174\/0929867311320070007"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Furtado, N.A.J.C., Pirson, L., Edelberg, H., Miranda, L.M., Loira-Pastoriza, C., Preat, V., Larondelle, Y., and Andr\u00e9, C.M. (2017). Pentacyclic triterpene bioavailability: An overview of in vitro and in vivo studies. Molecules, 4.","DOI":"10.3390\/molecules22030400"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Dey, B., and Mitra, A. (2013). Chemo-profiling of eucalyptus and study of its hypoglycemic potential. World J. Diabetes.","DOI":"10.4239\/wjd.v4.i5.170"},{"key":"ref_10","first-page":"30","article-title":"A review on phytochemistry and pharmacological profile of Eucalyptus globulus","volume":"11","author":"Kumar","year":"2020","journal-title":"Int. J. Pharm. Res."},{"key":"ref_11","first-page":"418693","article-title":"Antihyperglycemic activity of eucalyptus tereticornis in insulin-resistant cells and a nutritional model of diabetic mice","volume":"2015","author":"Granados","year":"2015","journal-title":"Adv. Pharmacol. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Ceballos, S., Guil\u00ed En, A., Lorena, D., Noz, M., Cast\u00e3, A., Echeverri, L.F., Ac\u00edn, S., Bal, N., and Bal Azar, N. (2018). Immunometabolic regulation by triterpenes of Eucalyptus tereticornis in adipose tissue cell line models. Phytomedicine.","DOI":"10.1016\/j.phymed.2018.03.059"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Ac\u00edn, S., Mu\u00f1oz, D.L., Guillen, A., Soscue, D., Casta\u00f1o, A., Echeverri, F., and Balcazar, N. (2021). Triterpene-enriched fractions from Eucalyptus tereticornis ameliorate metabolic alterations in a mouse model of diet-induced obesity. J. Ethnopharmacol.","DOI":"10.1016\/j.jep.2020.113298"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"235","DOI":"10.4196\/kjpp.2018.22.3.235","article-title":"Ursolic acid in health and disease","volume":"22","author":"Seo","year":"2018","journal-title":"Korean J. Physiol. Pharmacol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Ram\u00edrez-Rodr\u00edguez, A.M., Gonz\u00e1lez-Ortiz, M., Mart\u00ednez-Abundis, E., and Acu\u00f1a Ortega, N. (2017). Effect of ursolic acid on metabolic syndrome, insulin sensitivity, and inflammation. J. Med. Food.","DOI":"10.1089\/jmf.2017.0003"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1791","DOI":"10.2337\/db12-1215","article-title":"Biochemical basis of the antidiabetic activity of oleanolic acid and related pentacyclic triterpenes","volume":"62","author":"Castellano","year":"2013","journal-title":"Diabetes"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Ayeleso, T.B., Matumba, M.G., and Mukwevho, E. (2017). Oleanolic acid and its derivatives: Biological activities and therapeutic potential in chronic diseases. Molecules, 22.","DOI":"10.3390\/molecules22111915"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1590\/S0103-50532012000300013","article-title":"Determination of ursolic acid and ursolic acid lactone in the leaves of eucalyptus tereticornis by hplc","volume":"23","author":"Maurya","year":"2012","journal-title":"J. Braz. Chem. Soc."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1607","DOI":"10.3389\/fphys.2019.01607","article-title":"Chronic adipose tissue inflammation linking obesity to insulin resistance and type 2 diabetes","volume":"10","author":"Zatterale","year":"2020","journal-title":"Front. Physiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"498","DOI":"10.3390\/nu5020498","article-title":"Fat depots, free fatty acids, and dyslipidemia","volume":"5","author":"Ebbert","year":"2013","journal-title":"Nutrients"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Marica Bakovic, N.H. (2015). Biologically active triterpenoids and their cardioprotective and anti- inflammatory effects. J. Bioanal. Biomed.","DOI":"10.4172\/1948-593X.S12-005"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Mlala, S., Oyedeji, A.O., Gondwe, M., and Oyedeji, O.O. (2019). Ursolic acid and its derivatives as bioactive agents. Molecules, 24.","DOI":"10.3390\/molecules24152751"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Bano, Z., Begum, S., Ali, S.S., Kiran, Z., Siddiqui, B.S., Ahmed, A., Khawaja, S., Fatima, F., and Jabeen, A. (2021). Phytochemicals from Carissa carandas with potent cytotoxic and anti-inflammatory activities. Nat. Prod. Res., 1\u20136.","DOI":"10.1080\/14786419.2021.1886101"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"He, Y., Li, Y., Zhao, T., Wang, Y., and Sun, C. (2013). Ursolic acid inhibits adipogenesis in 3T3-L1 adipocytes through LKB1\/AMPK pathway. PLoS ONE.","DOI":"10.1371\/journal.pone.0070135"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Zhu, Y., Li, X., Chen, J., Chen, T., Shi, Z., Lei, M., Zhang, Y., Bai, P., Li, Y., and Fei, X. (2016). The pentacyclic triterpene Lupeol switches M1 macrophages to M2 and ameliorates experimental inflammatory bowel disease. Int. Immunopharmacol.","DOI":"10.1016\/j.intimp.2015.11.031"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Zhao, J., Zheng, H., Sui, Z., Jing, F., Quan, X., Zhao, W., and Liu, G. (2019). Ursolic acid exhibits anti-inflammatory effects through blocking TLR4-MyD88 pathway mediated by autophagy. Cytokine.","DOI":"10.1016\/j.cyto.2019.05.013"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2428","DOI":"10.3390\/toxins2102428","article-title":"Targeting inflammatory pathways by triterpenoids for prevention and treatment of cancer","volume":"2","author":"Yadav","year":"2010","journal-title":"Toxins"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"14348","DOI":"10.3390\/molecules200814348","article-title":"Macrophage activation by ursolic and oleanolic acids during mycobacterial infection","volume":"20","year":"2015","journal-title":"Molecules"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Podder, B., Jang, W.S., Nam, K.W., Lee, B.E., and Song, H.Y. (2015). Ursolic acid activates intracellular killing effect of macrophages during mycobacterium tuberculosis infection. J. Microbiol. Biotechnol.","DOI":"10.4014\/jmb.1407.07020"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1196\/annals.1427.015","article-title":"The role of mitochondria in reactive oxygen species metabolism and signaling","volume":"1147","author":"Starkov","year":"2008","journal-title":"Proc. Ann. N. Y. Acad. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Gong, S., Peng, Y., Jiang, P., Wang, M., Fan, M., Wang, X., Zhou, H., Li, H., Yan, Q., and Huang, T. (2014). A deafness-associated tRNAHis mutation alters the mitochondrial function, ROS production and membrane potential. Nucleic Acids Res.","DOI":"10.1093\/nar\/gku466"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"R453","DOI":"10.1016\/j.cub.2014.03.034","article-title":"ROS function in redox signaling and oxidative stress","volume":"24","author":"Schieber","year":"2014","journal-title":"Curr. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/j.imbio.2018.11.010","article-title":"Reactive oxygen species (ROS) in macrophage activation and function in diabetes","volume":"224","author":"Rendra","year":"2019","journal-title":"Immunobiology"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Lee, M.S., and Thuong, P.T. (2010). Stimulation of glucose uptake by triterpenoids from Weigela subsessilis. Phyther. Res.","DOI":"10.1002\/ptr.2865"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Zhang, W., Hong, D., Zhou, Y., Zhang, Y., Shen, Q., Li, J.Y., Li, J.-Y., Hu, L.-H., and Li, J. (2006). Ursolic acid and its derivative inhibit protein tyrosine phosphatase 1B, enhancing insulin receptor phosphorylation and stimulating glucose uptake. Biochim. Biophys. Acta Gen. Subj.","DOI":"10.1016\/j.bbagen.2006.05.009"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"G697","DOI":"10.1152\/ajpgi.00426.2010","article-title":"Obesity, diabetes mellitus, and liver fibrosis","volume":"300","author":"Chiang","year":"2011","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/j.phymed.2018.09.011","article-title":"Pentacyclic triterpenes: New tools to fight metabolic syndrome","volume":"50","author":"Sharma","year":"2018","journal-title":"Phytomedicine"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Zorova, L.D., Popkov, V.A., Plotnikov, E.Y., Silachev, D.N., Pevzner, I.B., Jankauskas, S.S., Babenko, V.A., Zorov, S.D., Balakireva, A.V., and Juhaszova, M. (2018). Mitochondrial membrane potential. Anal. Biochem.","DOI":"10.1016\/j.ab.2017.07.009"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1016\/j.molcel.2017.05.032","article-title":"AMPK: Mechanisms of cellular energy sensing and restoration of metabolic balance","volume":"66","author":"Garcia","year":"2017","journal-title":"Mol. Cell"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Chen, C., Deng, Y., Hu, X., Ren, H., Zhu, J., Fu, S., Xie, J., and Peng, Y. (2018). miR-128-3p regulates 3T3-L1 adipogenesis and lipolysis by targeting Pparg and Sertad2. J. Physiol. Biochem.","DOI":"10.1007\/s13105-018-0625-1"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Kim, G.C., Kim, J.S., Kim, G.M., and Choi, S.Y. (2017). Anti-adipogenic effects of Tropaeolum majus (nasturtium) ethanol extract on 3T3-L1 cells. Food Nutr. Res.","DOI":"10.1080\/16546628.2017.1339555"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1369","DOI":"10.1194\/jlr.M400373-JLR200","article-title":"Adiponectin promotes adipocyte differentiation, insulin sensitivity, and lipid accumulation","volume":"46","author":"Fu","year":"2005","journal-title":"J. Lipid Res."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Barber\u00e1, M.J., Schl\u00fcter, A., Pedraza, N., Iglesias, R., Villarroya, F., and Giralt, M. (2001). Peroxisome proliferator-activated receptor \u03b1 activates transcription of the brown fat uncoupling protein-1 gene. A link between regulation of the thermogenic and lipid oxidation pathways in the brown fat cell. J. Biol. Chem.","DOI":"10.1074\/jbc.M006246200"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Corrales, P., Vidal-Puig, A., and Medina-G\u00f3mez, G. (2018). PPARS and metabolic disorders associated with challenged adipose tissue plasticity. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19072124"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"P\u00e9rez-P\u00e9rez, A., S\u00e1nchez-Jim\u00e9nez, F., Vilari\u00f1o-Garc\u00eda, T., and S\u00e1nchez-Margalet, V. (2020). Role of leptin in inflammation and vice versa. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21165887"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/8\/2282\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:48:15Z","timestamp":1760161695000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/8\/2282"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,15]]},"references-count":45,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2021,4]]}},"alternative-id":["molecules26082282"],"URL":"https:\/\/doi.org\/10.3390\/molecules26082282","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,15]]}}}