{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T03:03:03Z","timestamp":1760151783815,"version":"build-2065373602"},"reference-count":55,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2022,9,12]],"date-time":"2022-09-12T00:00:00Z","timestamp":1662940800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004700","name":"Taipei Medical University","doi-asserted-by":"publisher","award":["DP2-111-21121-01-O-07-02","110TMU-TMUH-17"],"award-info":[{"award-number":["DP2-111-21121-01-O-07-02","110TMU-TMUH-17"]}],"id":[{"id":"10.13039\/501100004700","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Taipei Medical University Hospital","award":["DP2-111-21121-01-O-07-02","110TMU-TMUH-17"],"award-info":[{"award-number":["DP2-111-21121-01-O-07-02","110TMU-TMUH-17"]}]},{"name":"Taipei Medical University","award":["DP2-111-21121-01-O-07-02","110TMU-TMUH-17"],"award-info":[{"award-number":["DP2-111-21121-01-O-07-02","110TMU-TMUH-17"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>High fructose intake has been implicated in obesity and metabolic syndrome, which are related to increased cardiovascular mortality. However, few studies have experimentally examined the role of renin\u2013angiotensin system blockers and calcium channel blockers (CCB) in obesity. We investigated the effects of valsartan (an angiotensin II receptor blocker) and amlodipine (a CCB) on lipolysis through the potential mechanism of PU.1 inhibition. We observed that high fructose concentrations significantly increased adipose size and triglyceride, monoacylglycerol lipase, adipose triglyceride lipase, and stearoyl-CoA desaturase-1 (SCD1), activating transcription factor 3 and PU.1 levels in adipocytes in vitro. Subsequently, PU.1 inhibitor treatment was able to reduce triglyceride, SCD1, and PU.1 levels. In addition, elevated levels of triglyceride and PU.1, stimulated by a high fructose concentration, decreased with valsartan and amlodipine treatment. Overall, these findings suggest that high fructose concentrations cause triacylglycerol storage in adipocytes through PU.1-mediated activation. Furthermore, valsartan and amlodipine treatment reduced triacylglycerol storage in adipocytes by inhibiting PU.1 activation in high fructose concentrations in vitro. Thus, the benefits of valsartan and amlodipine in lipolysis may be through PU.1 inhibition in fructose-induced adiposity, and PU.1 inhibition might have a potential therapeutic role in lipolysis in fructose-induced obesity.<\/jats:p>","DOI":"10.3390\/nu14183759","type":"journal-article","created":{"date-parts":[[2022,9,13]],"date-time":"2022-09-13T04:05:41Z","timestamp":1663041941000},"page":"3759","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Benefits of Valsartan and Amlodipine in Lipolysis through PU.1 Inhibition in Fructose-Induced Adiposity"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9695-1067","authenticated-orcid":false,"given":"Chu-Lin","family":"Chou","sequence":"first","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"},{"name":"TMU Research Center of Urology and Kidney, Taipei Medical University, Taipei 110, Taiwan"},{"name":"Division of Nephrology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City 235, Taiwan"},{"name":"Division of Nephrology, Department of Internal Medicine, Hsin Kuo Min Hospital, Taipei Medical University, Taoyuan City 320, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ching-Hao","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"},{"name":"Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5577-9280","authenticated-orcid":false,"given":"Te-Chao","family":"Fang","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"},{"name":"TMU Research Center of Urology and Kidney, Taipei Medical University, Taipei 110, Taiwan"},{"name":"Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"},{"name":"Division of Nephrology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei Medical University, Taipei 110, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1161\/01.HYP.10.5.512","article-title":"Fructose-induced insulin resistance and hypertension in rats","volume":"10","author":"Hwang","year":"1987","journal-title":"Hypertension"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2163","DOI":"10.1046\/j.1523-1755.2003.00313.x","article-title":"Insulin receptors and renal sodium handling in hypertensive fructose-fed rats","volume":"64","author":"Catena","year":"2003","journal-title":"Kidney Int."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"882","DOI":"10.5114\/aoms.2011.25566","article-title":"Aliskiren prevents and ameliorates metabolic syndrome in fructose-fed rats","volume":"7","author":"Chou","year":"2011","journal-title":"Arch. Med. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1038\/hr.2012.124","article-title":"Direct renin inhibitor prevents and ameliorates insulin resistance, aortic endothelial dysfunction and vascular remodeling in fructose-fed hypertensive rats","volume":"36","author":"Chou","year":"2013","journal-title":"Hypertens. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1186\/1476-511X-10-20","article-title":"Fructose impairs glucose-induced hepatic triglyceride synthesis","volume":"10","author":"Huang","year":"2011","journal-title":"Lipids Health Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/1743-7075-2-5","article-title":"Fructose, insulin resistance, and metabolic dyslipidemia","volume":"2","author":"Basciano","year":"2005","journal-title":"Nutr. Metab."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"S13","DOI":"10.1301\/nr.2007.jun.S13-S23","article-title":"Fructose and the metabolic syndrome: Pathophysiology and molecular mechanisms","volume":"65","author":"Rutledge","year":"2007","journal-title":"Nutr. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Taskinen, M.R., Packard, C.J., and Boren, J. (2019). Dietary Fructose and the Metabolic Syndrome. Nutrients, 11.","DOI":"10.3390\/nu11091987"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Merino, B., Fernandez-Diaz, C.M., Cozar-Castellano, I., and Perdomo, G. (2019). Intestinal Fructose and Glucose Metabolism in Health and Disease. Nutrients, 12.","DOI":"10.3390\/nu12010094"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1038\/leu.2010.104","article-title":"The role of PU.1 and GATA-1 transcription factors during normal and leukemogenic hematopoiesis","volume":"24","author":"Burda","year":"2010","journal-title":"Leukemia"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"E1550","DOI":"10.1152\/ajpendo.00462.2011","article-title":"Adipocyte expression of PU.1 transcription factor causes insulin resistance through upregulation of inflammatory cytokine gene expression and ROS production","volume":"302","author":"Lin","year":"2012","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"14779","DOI":"10.1038\/s41598-019-51196-8","article-title":"Adipocyte PU.1 knockout promotes insulin sensitivity in HFD-fed obese mice","volume":"9","author":"Lackey","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/s11658-016-0032-y","article-title":"MITF and PU.1 inhibit adipogenesis of ovine primary preadipocytes by restraining C\/EBPbeta","volume":"22","author":"Ruan","year":"2017","journal-title":"Cell. Mol. Biol. Lett."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1210\/jc.2006-1268","article-title":"Review: Peroxisome proliferator-activated receptor gamma and adipose tissue--understanding obesity-related changes in regulation of lipid and glucose metabolism","volume":"92","author":"Sharma","year":"2007","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1007\/s00109-009-0520-x","article-title":"ATF3 transcription factor and its emerging roles in immunity and cancer","volume":"87","author":"Thompson","year":"2009","journal-title":"J. Mol. Med."},{"key":"ref_16","first-page":"321","article-title":"ATF3 and stress responses","volume":"7","author":"Hai","year":"1999","journal-title":"Gene Expr."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1038\/s41440-018-0058-9","article-title":"Role of activating transcription factor 3 in fructose-induced metabolic syndrome in mice","volume":"41","author":"Chou","year":"2018","journal-title":"Hypertens. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3949","DOI":"10.1128\/MCB.00429-12","article-title":"Activating transcription factor 3 regulates immune and metabolic homeostasis","volume":"32","author":"Rynes","year":"2012","journal-title":"Mol. Cell. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Lambadiari, V., Korakas, E., and Tsimihodimos, V. (2020). The Impact of Dietary Glycemic Index and Glycemic Load on Postprandial Lipid Kinetics, Dyslipidemia and Cardiovascular Risk. Nutrients, 12.","DOI":"10.3390\/nu12082204"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1172\/JCI96702","article-title":"Fructose metabolism and metabolic disease","volume":"128","author":"Hannou","year":"2018","journal-title":"J. Clin. Investig."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"E28","DOI":"10.1152\/ajpendo.90897.2008","article-title":"Biochemical and physiological function of stearoyl-CoA desaturase","volume":"297","author":"Paton","year":"2009","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/j.plipres.2009.05.001","article-title":"Lipolysis and lipid mobilization in human adipose tissue","volume":"48","author":"Lafontan","year":"2009","journal-title":"Prog. Lipid Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1016\/j.biocel.2009.12.009","article-title":"Lipolysis in adipocytes","volume":"42","author":"Ahmadian","year":"2010","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1016\/S1262-3636(07)70121-0","article-title":"Metabolism of lipids in human white adipocyte","volume":"30","author":"Large","year":"2004","journal-title":"Diabetes Metab."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1097\/MOL.0b013e3282f2b24a","article-title":"Fructose consumption: Potential mechanisms for its effects to increase visceral adiposity and induce dyslipidemia and insulin resistance","volume":"19","author":"Stanhope","year":"2008","journal-title":"Curr. Opin. Lipidol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1210\/jc.2011-2525","article-title":"Clinical review: Regulation of food intake, energy balance, and body fat mass: Implications for the pathogenesis and treatment of obesity","volume":"97","author":"Guyenet","year":"2012","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"R77","DOI":"10.1530\/JOE-16-0211","article-title":"Adipose tissue in control of metabolism","volume":"231","author":"Luo","year":"2016","journal-title":"J. Endocrinol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Chou, C.L., Lin, H., Chen, J.S., and Fang, T.C. (2017). Renin inhibition improves metabolic syndrome, and reduces angiotensin II levels and oxidative stress in visceral fat tissues in fructose-fed rats. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0180712"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1038\/ajh.2010.198","article-title":"Nifedipine, a calcium-channel blocker, attenuated glucose intolerance and white adipose tissue dysfunction in type 2 diabetic KK-A(y) mice","volume":"24","author":"Iwai","year":"2011","journal-title":"Am. J. Hypertens."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.ab.2012.03.005","article-title":"Protocol for effective differentiation of 3T3-L1 cells to adipocytes","volume":"425","author":"Zebisch","year":"2012","journal-title":"Anal. Biochem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13395-016-0118-2","article-title":"A novel method for the quantification of fatty infiltration in skeletal muscle","volume":"7","author":"Biltz","year":"2017","journal-title":"Skelet. Muscle"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1080\/21623945.2016.1240137","article-title":"Quantitative assessment of adipocyte differentiation in cell culture","volume":"5","author":"Kraus","year":"2016","journal-title":"Adipocyte"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"122","DOI":"10.4103\/CJP.CJP_3_20","article-title":"Resveratrol enhances therapeutic effect on pancreatic regeneration in diabetes mellitus rats receiving autologous transplantation of adipose-derived stem cells","volume":"63","author":"Chen","year":"2020","journal-title":"Chin. J. Physiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1038\/s42003-019-0624-y","article-title":"Adipocyte browning and resistance to obesity in mice is induced by expression of ATF3","volume":"2","author":"Cheng","year":"2019","journal-title":"Commun. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"286","DOI":"10.4103\/CJP.CJP_51_20","article-title":"Glucocorticoid transiently upregulates mitochondrial biogenesis in the osteoblast","volume":"63","author":"Hsu","year":"2020","journal-title":"Chin. J. Physiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"9299","DOI":"10.1038\/s41598-019-45803-x","article-title":"Identification of the fructose transporter GLUT5 (SLC2A5) as a novel target of nuclear receptor LXR","volume":"9","author":"Zwarts","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1161\/CIRCRESAHA.109.196261","article-title":"Activating transcription factor 3 constitutes a negative feedback mechanism that attenuates saturated Fatty acid\/toll-like receptor 4 signaling and macrophage activation in obese adipose tissue","volume":"105","author":"Suganami","year":"2009","journal-title":"Circ. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.3389\/fphys.2018.01125","article-title":"Serum and Adipose Tissue mRNA Levels of ATF3 and FNDC5\/Irisin in Colorectal Cancer Patients With or Without Obesity","volume":"9","author":"Zhu","year":"2018","journal-title":"Front. Physiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.bbrc.2012.03.104","article-title":"ATF3 inhibits adipocyte differentiation of 3T3-L1 cells","volume":"421","author":"Jang","year":"2012","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"848","DOI":"10.1038\/s12276-021-00616-9","article-title":"Alternative regulatory mechanism for the maintenance of bone homeostasis via STAT5-mediated regulation of the differentiation of BMSCs into adipocytes","volume":"53","author":"Seong","year":"2021","journal-title":"Exp. Mol. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1007\/BF02255999","article-title":"Effects of the calcium channel blocker amlodipine on serum and aortic cholesterol, lipid peroxidation, antioxidant status and aortic histology in cholesterol-fed rabbits","volume":"10","author":"Turgan","year":"2003","journal-title":"J. Biomed. Sci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.pathophys.2010.05.003","article-title":"Amlodipine treatment decreases plasma and carotid artery tissue levels of endothelin-1 in atherosclerotic rabbits","volume":"18","author":"Rashidi","year":"2011","journal-title":"Pathophysiology"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1248\/bpb.23.766","article-title":"Antioxidant effects of calcium antagonists in rat brain homogenates","volume":"23","author":"Yao","year":"2000","journal-title":"Biol. Pharm. Bull."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/0026-0495(95)90160-4","article-title":"Improvement of insulin sensitivity for glucose metabolism with the long-acting Ca-channel blocker amlodipine in essential hypertensive subjects","volume":"44","author":"Harano","year":"1995","journal-title":"Metabolism"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1161\/HYPERTENSIONAHA.109.148049","article-title":"Valsartan protects pancreatic islets and adipose tissue from the inflammatory and metabolic consequences of a high-fat diet in mice","volume":"55","author":"Cole","year":"2010","journal-title":"Hypertension"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1038\/ajh.2007.50","article-title":"Blockade of AT1 receptor improves adipocyte differentiation in atherosclerotic and diabetic models","volume":"21","author":"Tomono","year":"2008","journal-title":"Am. J. Hypertens."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"E355","DOI":"10.1152\/ajpendo.00632.2006","article-title":"Angiotensin II-mediated oxidative stress promotes myocardial tissue remodeling in the transgenic (mRen2) 27 Ren2 rat","volume":"293","author":"Govindarajan","year":"2007","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/j.diabres.2006.04.015","article-title":"Effect of valsartan, an angiotensin II receptor blocker, on markers of oxidation and glycation in Japanese type 2 diabetic subjects: Blood pressure-independent effect of valsartan","volume":"74","author":"Saisho","year":"2006","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1097\/00005344-200207000-00004","article-title":"Valsartan therapy has additive anti-oxidative effect to that of fluvastatin therapy against low-density lipoprotein oxidation: Studies in hypercholesterolemic and hypertensive patients","volume":"40","author":"Hussein","year":"2002","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.scr.2017.10.022","article-title":"Local angiotensin II promotes adipogenic differentiation of human adipose tissue mesenchymal stem cells through type 2 angiotensin receptor","volume":"25","author":"Sysoeva","year":"2017","journal-title":"Stem Cell Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"8481","DOI":"10.1038\/s41598-019-44834-8","article-title":"Angiotensin II Increases Endoplasmic Reticulum Stress in Adipose Tissue and Adipocytes","volume":"9","author":"Menikdiwela","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1717","DOI":"10.1038\/sj.ki.5001810","article-title":"Blockade of Angiotensin II type-1 receptor reduces oxidative stress in adipose tissue and ameliorates adipocytokine dysregulation","volume":"70","author":"Kurata","year":"2006","journal-title":"Kidney Int."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2409","DOI":"10.1097\/HJH.0b013e3283310e1b","article-title":"Long-term treatment with an angiotensin II receptor blocker decreases adipocyte size and improves insulin signaling in obese Zucker rats","volume":"27","author":"Munoz","year":"2009","journal-title":"J. Hypertens."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1186\/1476-511X-12-108","article-title":"Effects of angiotensin II type 1 receptor blocker and adiponectin on adipocyte dysfunction in stroke-prone spontaneously hypertensive rats","volume":"12","author":"Takemori","year":"2013","journal-title":"Lipids Health Dis."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1977","DOI":"10.1097\/00004872-200410000-00021","article-title":"Blockade of the renin-angiotensin system decreases adipocyte size with improvement in insulin sensitivity","volume":"22","author":"Furuhashi","year":"2004","journal-title":"J. Hypertens."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/14\/18\/3759\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:29:39Z","timestamp":1760142579000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/14\/18\/3759"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,12]]},"references-count":55,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2022,9]]}},"alternative-id":["nu14183759"],"URL":"https:\/\/doi.org\/10.3390\/nu14183759","relation":{},"ISSN":["2072-6643"],"issn-type":[{"type":"electronic","value":"2072-6643"}],"subject":[],"published":{"date-parts":[[2022,9,12]]}}}