title: Decreased body fat, elevated plasma transforming growth factor-β levels, and impaired BMP4-like signaling in biglycan-deficient mice.
abstract: Biglycan (BGN), a small leucine-rich proteoglycan, binds the pro-fibrotic cytokine transforming growth factor β (TGFβ) and inhibits its bioactivity in vitro. Nevertheless, it is controversial whether BGN plays an inhibitory role in vivo. Therefore, the purpose of this study was to evaluate the effect of BGN deficiency on TGFβ activity in vivo by studying 1-year-old Bgn null and wild-type (WT) mice on an Ldlr-null background. Phenotypic and metabolic characterization showed that the Bgn null mice had lower body weight, shorter body length, and shorter femur length (all p < 0.05). Surprisingly, the Bgn null mice also exhibited a striking reduction in percent body fat compared to WT mice (p == 0.006), but no changes were observed in plasma triglycerides, total cholesterol, or glycohemoglobin. Both total and bioactive TGFβ1 concentrations in plasma were markedly elevated in Bgn null mice compared to WT mice (4-fold and 11-fold increase, respectively, both p < 0.001), but no changes were found in hepatic levels of mRNA for Tgfβ1 or its receptors. Bgn null mice exhibited elevated expression of hepatic fibronectin protein (p = 0.034) without changes in hepatic or renal histology, and Bgn null mice had decreased urinary albumin/creatinine ratio (p = 0.01). Two key downstream targets of bone morphogenetic protein 4-like signaling, SMAD1/3/5 phosphorylation and Id2 gene expression, were found dramatically reduced in Bgn null livers (p = 0.034). Thus, BGN deficiency decreases body fat in this hyperlipidemic mouse model without changing liver or kidney histology. Overall, we propose that this unexpected phenotype arises from the effects of BGN deficiency in vivo to elevate TGFβ levels while decreasing bone morphogenetic protein 4-like signaling.
authors: Division of Endocrinology and Molecular Medicine, Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY 40536-0200, USA.
authors: Tao
authors: T
authors: Tang
authors: Joel C
authors: JC
authors: Thompson
authors: Patricia G
authors: PG
authors: Wilson
authors: Christina
authors: C
authors: Nelson
authors: Kevin Jon
authors: KJ
authors: Williams
authors: Lisa R
authors: LR
authors: Tannock
mesh_terms: D000273:Adipose Tissue / Q000473:pathology*; D050154:Adiposity / Q000502:physiology*; D000818:Animals; D058578:Biglycan / Q000172:deficiency*; D001823:Body Composition; D001835:Body Weight / Q000502:physiology; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006949:Hyperlipidemias / Q000097:blood / Q000235:genetics / Q000473:pathology*; D051797:Inhibitor of Differentiation Protein 2 / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000033:anatomy & histology / Q000378:metabolism; D007677:Kidney Function Tests; D008099:Liver / Q000033:anatomy & histology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009929:Organ Size; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000097:blood* / Q000235:genetics
chemical_list: C546885:Bgn protein, mouse; D058578:Biglycan; C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; C497452:Idb2 protein, mouse; D051797:Inhibitor of Differentiation Protein 2; D012333:RNA, Messenger; D051785:Smad Proteins; D016212:Transforming Growth Factor beta