title: Reduction of obesity-associated white adipose tissue inflammation by rosiglitazone is associated with reduced non-alcoholic fatty liver disease in LDLr-deficient mice.
abstract: Obesity is associated with chronic low-grade inflammation that drives the development of metabolic diseases, including non-alcoholic fatty liver disease (NAFLD). We recently showed that white adipose tissue (WAT) constitutes an important source of inflammatory factors. Hence, interventions that attenuate WAT inflammation may reduce NAFLD development. Male LDLr-/- mice were fed a high-fat diet (HFD) for 9 weeks followed by 7 weeks of HFD with or without rosiglitazone. Effects on WAT inflammation and NAFLD development were analyzed using biochemical and (immuno)histochemical techniques, combined with gene expression analyses. Nine weeks of HFD feeding induced obesity and WAT inflammation, which progressed gradually until the end of the study. Rosiglitazone fully blocked progression of WAT inflammation and activated PPARγ significantly in WAT. Rosiglitazone intervention did not activate PPARγ in liver, but improved liver histology and counteracted the expression of genes associated with severe NAFLD in humans. Rosiglitazone reduced expression of pro-inflammatory factors in WAT (TNF-α, leptin) and increased expression of adiponectin, which was reflected in plasma. Furthermore, rosiglitazone lowered circulating levels of pro-inflammatory saturated fatty acids. Together, these observations provide a rationale for the observed indirect hepatoprotective effects and suggest that WAT represents a promising therapeutic target for the treatment of obesity-associated NAFLD.
authors.affiliation: Department of Metabolic Health Research, Netherlands Organization for Applied Scientific Research (TNO), Zernikedreef 9, 2333 CK Leiden, The Netherlands.|Department of Vascular Surgery, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.
authors.forename: Petra
authors.initials: P
authors.lastname: Mulder
authors.affiliation: Department of Metabolic Health Research, Netherlands Organization for Applied Scientific Research (TNO), Zernikedreef 9, 2333 CK Leiden, The Netherlands.
authors.forename: Martine C
authors.initials: MC
authors.lastname: Morrison
authors.affiliation: Department of Microbiology and Systems Biology, Netherlands Organization for Applied Scientific Research (TNO), 3704 HE, Zeist, The Netherlands.
authors.forename: Lars
authors.initials: L
authors.lastname: Verschuren
authors.affiliation: Department of Metabolic Health Research, Netherlands Organization for Applied Scientific Research (TNO), Zernikedreef 9, 2333 CK Leiden, The Netherlands.
authors.forename: Wen
authors.initials: W
authors.lastname: Liang
authors.affiliation: Department of Vascular Surgery, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.
authors.forename: J Hajo
authors.initials: JH
authors.lastname: van Bockel
authors.affiliation: Department of Metabolic Health Research, Netherlands Organization for Applied Scientific Research (TNO), Zernikedreef 9, 2333 CK Leiden, The Netherlands.
authors.forename: Teake
authors.initials: T
authors.lastname: Kooistra
authors.affiliation: Department of Metabolic Health Research, Netherlands Organization for Applied Scientific Research (TNO), Zernikedreef 9, 2333 CK Leiden, The Netherlands.
authors.forename: Peter Y
authors.initials: PY
authors.lastname: Wielinga
authors.affiliation: Department of Metabolic Health Research, Netherlands Organization for Applied Scientific Research (TNO), Zernikedreef 9, 2333 CK Leiden, The Netherlands.|Department of Vascular Surgery, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.
authors.forename: Robert
authors.initials: R
authors.lastname: Kleemann
mesh_terms: D052436:Adipose Tissue, White / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D007249:Inflammation / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009765:Obesity / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011973:Receptors, LDL / Q000172:deficiency*; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*
chemical_list: D011973:Receptors, LDL; D045162:Thiazolidinediones; D000077154:Rosiglitazone