{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T20:21:46Z","timestamp":1790626906367,"version":"4.1.0"},"reference-count":52,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2021,7,21]],"date-time":"2021-07-21T00:00:00Z","timestamp":1626825600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004462","name":"Consiglio Nazionale delle Ricerche","doi-asserted-by":"publisher","award":["DSB.AD003.061"],"award-info":[{"award-number":["DSB.AD003.061"]}],"id":[{"id":"10.13039\/501100004462","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010677","name":"H2020 Health","doi-asserted-by":"publisher","award":["634413"],"award-info":[{"award-number":["634413"]}],"id":[{"id":"10.13039\/100010677","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010665","name":"H2020 Marie Sk\u0142odowska-Curie Actions","doi-asserted-by":"publisher","award":["722619"],"award-info":[{"award-number":["722619"]}],"id":[{"id":"10.13039\/100010665","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010665","name":"H2020 Marie Sk\u0142odowska-Curie Actions","doi-asserted-by":"publisher","award":["734719"],"award-info":[{"award-number":["734719"]}],"id":[{"id":"10.13039\/100010665","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007723","name":"Takeda Pharmaceuticals U.S.A.","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007723","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000097","name":"National Center for Research Resources","doi-asserted-by":"publisher","award":["MO1\u2010RR\u201001346"],"award-info":[{"award-number":["MO1\u2010RR\u201001346"]}],"id":[{"id":"10.13039\/100000097","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Liver International"],"published-print":{"date-parts":[[2021,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background and Aims<\/jats:title><jats:p>Peroxisome proliferator\u2010activated receptor (PPAR)\u2010\u03b3 agonists decrease hepatic\/visceral fat (VF) and improve necroinflammation despite subcutaneous (SC) fat weight\u2010gain. Understanding the impact of changes in VF, VF\u2010to\u2010SC fat distribution (VF\/SC) and adiponectin (ADPN) levels in relation to histological improvement after weight\u2010loss or pioglitazone is relevant as novel PPAR\u2010\u03b3 agonists are being developed for treating non\u2010alcoholic steatohepatitis (NASH).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Fifty\u2010five patients with NASH received a \u2212500\u00a0kcal\/d hypocaloric diet and were randomized (double\u2010blind) to pioglitazone (45\u00a0mg\/d) or placebo for 6\u2010months. Before and after treatment patients underwent a liver biopsy and measurement of hepatic\/peripheral glucose fluxes, hepatic\/adipose tissue\u2010IR and, in 35 patients, hepatic and VF\/SC\u2010fat was measured by magnetic resonance spectroscopy\/imaging. Data were examined by multivariable statistical analyses combined with machine\u2010learning techniques (partial least square discriminant analysis [PLS\u2010DA]).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Both pioglitazone (despite weight\u2010gain) and placebo (if weight\u2010loss) reduced steatosis but only pioglitazone ameliorated necroinflammation. Using machine\u2010learning PLS\u2010DA showed that the treatment differences induced by a PPAR\u2010\u03b3 agonist vs placebo on metabolic variables and liver histology could be best explained by the increase in ADPN and a decrease in VF\/SC, and to a lesser degree, improvement in oral glucose tolerance test\u2010glucose concentrations and ALT. Decrease in steatosis and disease activity score (ballooning plus lobular inflammation) kept a close relationship with an increase in ADPN (<jats:italic>r<\/jats:italic>\u00a0=\u00a0\u2212.71 and <jats:italic>r<\/jats:italic>\u00a0=\u00a0\u2212.44, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a0.007, respectively) and reduction in VF\/SC fat (<jats:italic>r<\/jats:italic>\u00a0=\u00a0.41 and <jats:italic>r<\/jats:italic>\u00a0=\u00a0.37, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a0.03 respectively).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Reduction in VF and improved VF\/SC\u2010distribution, combined with an increase in ADPN, mediate the histological benefits of PPAR\u2010\u03b3 action, highlighting the central role of fat metabolism and its distribution on steatohepatitis disease activity in patients with NASH.<\/jats:p><\/jats:sec>","DOI":"10.1111\/liv.15005","type":"journal-article","created":{"date-parts":[[2021,7,5]],"date-time":"2021-07-05T07:30:48Z","timestamp":1625470248000},"page":"2659-2670","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":95,"title":["PPAR\u2010\u03b3\u2010induced changes in visceral fat and adiponectin levels are associated with improvement of steatohepatitis in patients with NASH"],"prefix":"10.1111","volume":"41","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2594-1651","authenticated-orcid":false,"given":"Amalia","family":"Gastaldelli","sequence":"first","affiliation":[{"name":"Diabetes Division The University of Texas Health Science Center at San Antonio San Antonio TX USA"},{"name":"Institute of Clinical Physiology National Research Council CNR Pisa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3251-4412","authenticated-orcid":false,"given":"Silvia","family":"Sabatini","sequence":"additional","affiliation":[{"name":"Institute of Clinical Physiology National Research Council CNR Pisa Italy"},{"name":"Universit\u00e0 degli Studi di Siena Siena Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2540-1110","authenticated-orcid":false,"given":"Fabrizia","family":"Carli","sequence":"additional","affiliation":[{"name":"Institute of Clinical Physiology National Research Council CNR Pisa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6311-502X","authenticated-orcid":false,"given":"Melania","family":"Gaggini","sequence":"additional","affiliation":[{"name":"Institute of Clinical Physiology National Research Council CNR Pisa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5570-4396","authenticated-orcid":false,"given":"Fernando","family":"Bril","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes and Metabolism University of Florida Gainesville FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4357-0447","authenticated-orcid":false,"given":"Renata","family":"Belfort\u2010DeAguiar","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Endocrinology Yale University School of Medicine New Haven CT USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6955-9572","authenticated-orcid":false,"given":"Vincenzo","family":"Positano","sequence":"additional","affiliation":[{"name":"Fondazione Toscana Gabriele Monasterio Pisa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5208-6828","authenticated-orcid":false,"given":"Diana","family":"Barb","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes and Metabolism University of Florida Gainesville FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sushma","family":"Kadiyala","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes and Metabolism University of Florida Gainesville FL USA"},{"name":"Division of Endocrinology, Diabetes and Metabolism Malcom Randall Veteran Administration Medical Center at Gainesville Gainesville FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8285-2204","authenticated-orcid":false,"given":"Stephen","family":"Harrison","sequence":"additional","affiliation":[{"name":"Pinnacle Clinical Research Group San Antonio TX USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8629-418X","authenticated-orcid":false,"given":"Kenneth","family":"Cusi","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes and Metabolism University of Florida Gainesville FL USA"},{"name":"Division of Endocrinology, Diabetes and Metabolism Malcom Randall Veteran Administration Medical Center at Gainesville Gainesville FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,7,21]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.28431"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1160\/TH13-04-0285"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-8587(19)30084-1"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-8587(16)00082-6"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2019.12.054"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.2183\/pjab.86.131"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cgh.2017.04.045"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-005-1682-x"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2007.04.068"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0904944106"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.22350"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2003-031941"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1210\/jcem.87.6.8567"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/oby.2007.568"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.3390\/nu5051544"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.28985"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.25539"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2019.06.031"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.2337\/db16-1167"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-020-05281-7"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2008.06.047"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa060326"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0907929"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.clpt.6100034"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.23116"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.25805"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.90960.2008"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.2337\/dc05-2445"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2005-1159"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamainternmed.2016.9607"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.7326\/M15-1774"},{"key":"e_1_2_9_33_1","unstructured":"RindD HansenR GuzauskasG et al.Obeticholic acid for the treatment of nonalcoholic steatohepatitis with fibrosis: effectiveness and value.ICER: Institute for Clinical and Economic Review;2020. July 21 2020.https:\/\/icer\u2010review.org\/material\/nash\u2010evidence\u2010report\/. Accessed January 10 2021."},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.25762"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2015.11.004"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.aohep.2020.09.006"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-020-00366-5"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1002\/cem.2609"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.20701"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cld.2015.10.008"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-005-1891-3"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/0026-0495(89)90129-7"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.25889"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2012.02.003"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1177\/193229680700100521"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2012.11.038"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1111\/eci.13017"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2028395"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2004-2240"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.53.8.2169"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2003-031315"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.2337\/dc14-2775"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1055\/a-1129-6785"}],"container-title":["Liver International"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/liv.15005","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/liv.15005","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/liv.15005","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,24]],"date-time":"2023-08-24T11:44:35Z","timestamp":1692877475000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/liv.15005"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,21]]},"references-count":52,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2021,11]]}},"alternative-id":["10.1111\/liv.15005"],"URL":"https:\/\/doi.org\/10.1111\/liv.15005","archive":["Portico"],"relation":{},"ISSN":["1478-3223","1478-3231"],"issn-type":[{"value":"1478-3223","type":"print"},{"value":"1478-3231","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,21]]},"assertion":[{"value":"2021-04-17","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-06-24","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-07-21","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}