{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T23:10:52Z","timestamp":1790118652444,"version":"4.0.1"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,3,9]],"date-time":"2021-03-09T00:00:00Z","timestamp":1615248000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Pre-clinical research studies have shown that Madecassoside (MA) has favorable therapeutic effects on arthritis, acne, vitiligo and other diseases. However, the effects of MA on obesity have not yet been studied. This study mainly aimed to investigate the effects of MA in protecting against obesity and its underlying mechanism in reducing obesity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Obese diabetic KKay\/TaJcl mice model was adopted to the study. The body weight of all animals was recorded daily, and the blood glucose, blood lipid, and serum aminotransferase levels were examined, respectively. The expression of P-AMPK, SIRT1, P-LKB1, P-ACC, and P-HSL in abdominal fat, mesenteric fat, and epididymal fat was measured by western blotting, and the levels of PPAR\u03b1, CPT1a, PGC-1\u03b1, UCP-1, Cidea, Cox7a1, and Cox8b were examined by real-time quantitative PCR (RT-qPCR).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The results revealed that the body weight of the mice in MA group was significantly reduced, and the body mass index (BMI) showed significant difference between the two groups after 8 weeks of MA treatment. Further research revealed that it affected the mesenteric fat and epididymis fat by activating SIRT1\/AMPK signaling pathway, and then promoted fatty acid oxidation of epididymal fat (PPAR\u03b1 \u2191, CPT1a\u2191, and PGC-1\u03b1\u2191). Last but not the least, it also promoted the expression of UCP-1 and stimulated thermoregulatory genes (Cidea, Cox7a1, and Cox8b) in brown fat and mesenteric fat.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Taken together, these findings suggest that MA can inhibit the weight gain in obese diabetic mice, and reduce triglyceride levels, inhibit lipogenesis of mesenteric fat, promote epididymal fat lipolysis and fatty acid oxidation. Furthermore, MA treatment might promote mesenteric fat browning and activate mitochondrial function in brown fat as well as mesenteric fat.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2021.627950","type":"journal-article","created":{"date-parts":[[2021,3,9]],"date-time":"2021-03-09T07:00:09Z","timestamp":1615273209000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":17,"title":["Madecassoside Inhibits Body Weight Gain via Modulating SIRT1-AMPK Signaling Pathway and Activating Genes Related to Thermogenesis"],"prefix":"10.3389","volume":"12","author":[{"given":"Boju","family":"Sun","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Misa","family":"Hayashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maya","family":"Kudo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lili","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingling","family":"Qin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tonghua","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,3,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1016\/j.metabol.2018.10.011","article-title":"Obesity and cardiovascular disease: revisiting an old relationship","volume":"92","author":"Koliaki","year":"2019","journal-title":"Metabolism"},{"key":"B2","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1038\/s41467-019-14080-7","article-title":"Genetic deletion of mast cell serotonin synthesis prevents the development of obesity and insulin resistance","volume":"11","author":"Yabut","year":"2020","journal-title":"Nat Commun"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1111\/j.1467-789X.2005.00221.x","article-title":"Diagnosis and management of the metabolic syndrome in obesity","volume":"6","author":"Liberopoulos","year":"2005","journal-title":"Obes Rev"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2008-1585","article-title":"Role of body fat distribution and the metabolic complications of obesity","volume":"93","author":"Jensen","year":"2008","journal-title":"J Clin Endocrinol Metab"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.117.030501","article-title":"Effect of Distinct Lifestyle Interventions on Mobilization of Fat Storage Pools: CENTRAL Magnetic Resonance Imaging Randomized Controlled Trial","volume":"137","author":"Gepner","year":"2018","journal-title":"Circulation"},{"key":"B6","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1080\/17512433.2020.1698291","article-title":"Pharmacotherapy in obesity: a systematic review and meta-analysis of randomized controlled trials of anti-obesity drugs","volume":"13","author":"Singh","year":"2020","journal-title":"Expert Rev Clin Pharmacol"},{"key":"B7","first-page":"1","article-title":"Bariatric surgery for people with diabetes and morbid obesity: an evidence-based analysis","volume":"9","year":"2009","journal-title":"Ont Health Technol Assess Ser"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1007\/s13300-020-00816-y","article-title":"Drug Therapy in Obesity: A Review of Current and Emerging Treatments","volume":"11","author":"Williams","year":"2020","journal-title":"Diabetes Ther"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.5582\/ddt.2019.01052","article-title":"Centella asiatica (L.) extract attenuates inflammation and improve insulin sensitivity in a coculture of lipopolysaccharide (LPS)-induced 3T3-L1 adipocytes and RAW 264.7 macrophages","volume":"13","author":"Kusumastuti","year":"2019","journal-title":"Drug Discovery Ther"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.jep.2016.01.001","article-title":"Metabolic alteration in obese diabetes rats upon treatment with Centella asiatica extract","volume":"180","author":"Maulidiani","year":"2016","journal-title":"J Ethnopharmacol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1055\/s-0042-122344","article-title":"Pharmacokinetics of a Standardized Extract of Centella asiatica ECa 233 in Rats","volume":"83","author":"Anukunwithaya","year":"2017","journal-title":"Planta Med"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.jep.2013.09.004","article-title":"In vivo disposition and metabolism of madecassoside, a major bioactive constituent in Centella asiatica (L.) Urb","volume":"150","author":"Leng","year":"2013","journal-title":"J Ethnopharmacol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1055\/s-2008-1074533","article-title":"Madecassoside isolated from Centella asiatica herbs facilitates burn wound healing in mice","volume":"74","author":"Liu","year":"2008","journal-title":"Planta Med"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1111\/bph.13421","article-title":"Madecassoside ameliorates bleomycin-induced pulmonary fibrosis in mice through promoting the generation of hepatocyte growth factor via PPAR-gamma in colon","volume":"173","author":"Xia","year":"2016","journal-title":"Br J Pharmacol"},{"key":"B15","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1016\/j.intimp.2016.01.027","article-title":"Madecassoside suppresses proliferation and invasiveness of HGF-induced human hepatocellular carcinoma cells via PKC-cMET-ERK1\/2-COX-2-PGE2 pathway","volume":"33","author":"Li","year":"2016","journal-title":"Int Immunopharmacol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2019.134386","article-title":"Madecassoside ameliorates lipopolysaccharide-induced neurotoxicity in rats by activating the Nrf2-HO-1 pathway","volume":"709","author":"Liu","year":"2019","journal-title":"Neurosci Lett"},{"key":"B17","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1080\/14786419.2019.1696794","article-title":"Effect of madecassoside and catalpol in amelioration of insulin sensitivity in pancreatic (INS-1E) \u03b2\u2013cell line","volume":"4","author":"Elhassan","year":"2019","journal-title":"Nat Prod Res"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1155\/2020\/7540197","article-title":"Rat Chondrocyte Inflammation and Osteoarthritis Are Ameliorated by Madecassoside","volume":"2020","author":"Moqbel","year":"2020","journal-title":"Oxid Med Cell Longev"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M800533200","article-title":"Hepatic overexpression of hormone-sensitive lipase and adipose triglyceride lipase promotes fatty acid oxidation, stimulates direct release of free fatty acids, and ameliorates steatosis","volume":"283","author":"Reid","year":"2008","journal-title":"J Biol Chem"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M115.636852","article-title":"Insulin Resistance Prevents AMPK-induced Tau Dephosphorylation through Akt-mediated Increase in AMPKSer-485 Phosphorylation","volume":"290","author":"Kim","year":"2015","journal-title":"J Biol Chem"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1093\/jn\/105.10.1253","article-title":"Induction of fatty liver by ethanol drinking in KK and KK-Ay mice","volume":"105","author":"Furuno","year":"1975","journal-title":"J Nutr"},{"key":"B22","doi-asserted-by":"publisher","first-page":"2866","DOI":"10.3390\/nu11122866","article-title":"The Effect of n-3 PUFA Binding Phosphatidylglycerol on Metabolic Syndrome-Related Parameters and n-3 PUFA Accretion in Diabetic\/Obese KK-A(y) Mice","volume":"11","author":"Chen","year":"2019","journal-title":"Nutrients"},{"key":"B23","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1507\/endocrj1954.35.83","article-title":"Thermogenesis in brown adipose tissue of genetically obese, diabetic (KKAY) mice","volume":"35","author":"Ohta","year":"1988","journal-title":"Endocrinol Jpn"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2020.02.009","article-title":"Epigenetic Transgenerational Inheritance of Obesity Susceptibility","volume":"31","author":"King","year":"2020","journal-title":"Trends Endocrinol Metab"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1042\/CS20190128","article-title":"Adipocyte dedifferentiation in health and diseases","volume":"133","author":"Song","year":"2019","journal-title":"Clin Sci (Lond)"},{"key":"B26","doi-asserted-by":"publisher","first-page":"4415","DOI":"10.3390\/ijms21124415","article-title":"A New Selective PPAR\u03b3 Modulator Inhibits Triglycerides Accumulation during Murine Adipocytes\u2019 and Human Adipose-Derived Mesenchymal Stem Cells Differentiation","volume":"21","author":"Al Haj","year":"2020","journal-title":"Int J Mol Sci"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1002\/ptr.6779","article-title":"Triptolide enhances lipolysis of adipocytes by enhancing ATGL transcription via upregulation of p53","volume":"34","author":"Wang","year":"2020","journal-title":"Phytother Res"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.2174\/1381612826666200701211422","article-title":"Role of Dietary Polyphenols in Adipose Tissue Browning: A Narrative Review","volume":"26","author":"Salazar","year":"2020","journal-title":"Curr Pharm Des"},{"key":"B29","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1093\/abbs\/gms108","article-title":"SIRT1 and energy metabolism","volume":"45","author":"Li","year":"2013","journal-title":"Acta Biochim Biophys Sin (Shanghai)"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.06.027","article-title":"Brown remodeling of white adipose tissue by SirT1-dependent deacetylation of Ppar\u03b3","volume":"150","author":"Qiang","year":"2012","journal-title":"Cell"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0610615104","article-title":"Myogenic gene expression signature establishes that brown and white adipocytes originate from distinct cell lineages","volume":"104","author":"Timmons","year":"2007","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B32","doi-asserted-by":"publisher","first-page":"231","DOI":"10.21037\/atm.2020.01.31","article-title":"A traditional Chinese herbal formula, ameliorates diet-induced obesity and hepatic steatosis by activating the AMPK\/SREBP-1 and the AMPK\/ACC\/CPT1A pathways","volume":"8","author":"Yao","year":"2020","journal-title":"Ann Transl Med"},{"key":"B33","doi-asserted-by":"publisher","first-page":"1133","DOI":"10.3390\/nu12041133","article-title":"Shikonin Attenuates Hepatic Steatosis by Enhancing Beta Oxidation and Energy Expenditure via AMPK Activation","volume":"12","author":"Gwon","year":"2020","journal-title":"Nutrients"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2020.103943","article-title":"Design, synthesis and biological evaluation of novel chroman derivatives as non-selective acetyl-CoA carboxylase inhibitors","volume":"101","author":"Wei","year":"2020","journal-title":"Bioorg Chem"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00259.2003","article-title":"Resistance to high-fat diet-induced obesity and altered expression of adipose-specific genes in HSL-deficient mice","volume":"285","author":"Harada","year":"2003","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1155\/2020\/4179852","article-title":"The Effects of New Selective PPAR\u03b1 Agonist CP775146 on Systematic Lipid Metabolism in Obese Mice and Its Potential Mechanism","volume":"2020","author":"Tang","year":"2020","journal-title":"J Diabetes Res"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.119.043319","article-title":"Increasing Fatty Acid Oxidation Prevents High-Fat Diet-Induced Cardiomyopathy Through Regulating Parkin-Mediated Mitophagy","volume":"142","author":"Shao","year":"2020","journal-title":"Circulation"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1007\/s11745-015-4016-x","article-title":"Rosiglitazone, but not epigallocatechin-3-gallate, attenuates the decrease in PGC-1\u03b1 protein levels in palmitate-induced insulin-resistant C2C12 cells","volume":"50","author":"Karimfar","year":"2015","journal-title":"Lipids"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1007\/s00204-018-2335-4","article-title":"Peroxisome proliferator-activated receptor \u03b1 attenuates high-cholesterol diet-induced toxicity and pro-thrombotic effects in mice","volume":"93","author":"Lu","year":"2019","journal-title":"Arch Toxicol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamem.2019.183094","article-title":"Role of membrane curvature on the activation\/deactivation of Carnitine Palmitoyltransferase 1A: A coarse grain molecular dynamic study","volume":"1862","author":"Frigini","year":"2020","journal-title":"Biochim Biophys Acta Biomembr"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2006.04.002","article-title":"Complementary action of the PGC-1 coactivators in mitochondrial biogenesis and brown fat differentiation","volume":"3","author":"Uldry","year":"2006","journal-title":"Cell Metab"},{"key":"B42","doi-asserted-by":"publisher","first-page":"E6241","DOI":"10.3390\/ijms21176241","article-title":"Induction of Adipose Tissue Browning as a Strategy to Combat Obesity","volume":"21","author":"Kury\u0142owicz","year":"2020","journal-title":"Int J Mol Sci"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.2000.278.2.R494","article-title":"Effect of NPY in the hypothalamic paraventricular nucleus on uncoupling proteins 1, 2, and 3 in the rat","volume":"278","author":"Kotz","year":"2000","journal-title":"Am J Physiol Regul Integr Comp Physiol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.53.9.2250","article-title":"Involvement of hypothalamic histamine H1 receptor in the regulation of feeding rhythm and obesity","volume":"53","author":"Masaki","year":"2004","journal-title":"Diabetes"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C300557200","article-title":"AMP-activated protein kinase plays a role in the control of food intake","volume":"279","author":"Andersson","year":"2004","journal-title":"J Biol Chem"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2015.07.003","article-title":"Regulation of brown fat by AMP-activated protein kinase","volume":"21","author":"van Dam","year":"2015","journal-title":"Trends Mol Med"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.4161\/21623945.2014.983752","article-title":"Hypothalamic GLP-1: the control of BAT thermogenesis and browning of white fat","volume":"4","author":"L\u00f3pez","year":"2015","journal-title":"Adipocyte"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.00299.2015","article-title":"Reduced cortical BACE1 content with one bout of exercise is accompanied by declines in AMPK, Akt, and MAPK signaling in obese, glucose-intolerant mice","volume":"119","author":"MacPherson","year":"2015","journal-title":"J Appl Physiol (1985)"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.2337\/db17-1538","article-title":"SF1-Specific AMPK\u03b11 Deletion Protects Against Diet-Induced Obesity","volume":"67","author":"Seoane-Collazo","year":"2018","journal-title":"Diabetes"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2020.568032","article-title":"Therapeutic Potential of Centella asiatica and Its Triterpenes: A Review","volume":"11","author":"Sun","year":"2020","journal-title":"Front Pharmacol"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2018.02.115","article-title":"Centella asiatica ameliorates diabetes-induced stress in rat tissues via influences on antioxidants and inflammatory cytokines","volume":"101","author":"Masola","year":"2018","journal-title":"BioMed Pharmacother"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2021.627950\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,3,9]],"date-time":"2021-03-09T07:00:12Z","timestamp":1615273212000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2021.627950\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,9]]},"references-count":51,"alternative-id":["10.3389\/fendo.2021.627950"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2021.627950","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,9]]},"article-number":"627950"}}