transforming-growth-factor-beta and Lipodystrophy

In our routine review of Oral Submucous Fibrosis (OSMF) biopsies, we observed decreased adipose tissue even though most are from buccal mucosa. Pathogenesis of OSMF has demonstrated the role of Transforming Growth Factor β (TGF β), in causing fibrosis. This study aims to correlate the role of TGF β with loss of adipose tissue in OSMF.. From our archives, 84 OSMF cases (24 early and 60 advanced OSMF) were screened for adipose tissue. Immunoexpression of TGF β in these cases were investigated.. Adipose tissue was seen in 67% of early OSMF and in 13% of advanced cases. Early cases showed more intense TGF β staining of epithelium, fibroblast, macrophages and inflammatory cells than the advanced cases.. These findings suggest that TGF β plays a key role in causing lipodystrophy in OSMF and is secreted more during early course of the disease than in advanced stage.

Topics: Fibrosis; Humans; Immunohistochemistry; Lipodystrophy; Mouth Mucosa; Transforming Growth Factor beta

Adipocyte differentiation is an important component of obesity, but how hormonal cues mediate adipocyte differentiation remains elusive. BMP stimulates in vitro adipocyte differentiation, but the role of BMP in adipogenesis in vivo is unknown. Drosophila Schnurri (Shn) is required for the signaling of Decapentaplegic, a Drosophila BMP homolog, via interaction with the Mad/Medea transcription factors. Vertebrates have three Shn orthologs, Shn-1, -2, and -3. Here, we report that Shn-2(-/-) mice have reduced white adipose tissue and that Shn-2(-/-) mouse embryonic fibroblasts cannot efficiently differentiate into adipocytes in vitro. Shn-2 enters the nucleus upon BMP-2 stimulation and, in cooperation with Smad1/4 and C/EBPalpha, induces the expression of PPARgamma2, a key transcription factor for adipocyte differentiation. Shn-2 directly interacts with both Smad1/4 and C/EBPalpha on the PPARgamma2 promoter. These results indicate that Shn-2-mediated BMP signaling has a critical role in adipogenesis.

Topics: Adipogenesis; Adipose Tissue; Animals; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; CCAAT-Enhancer-Binding Protein-alpha; DNA-Binding Proteins; Gene Expression Regulation; In Vitro Techniques; Lipodystrophy; Male; Mice; PPAR gamma; Promoter Regions, Genetic; RNA, Messenger; Signal Transduction; Smad1 Protein; Smad4 Protein; Transforming Growth Factor beta

Transgenic mice overexpressing a constitutively active human TGF-beta1 under control of the rat phosphoenolpyruvate carboxykinase regulatory sequences developed fibrosis of the liver, kidney, and adipose tissue, and exhibited a severe reduction in body fat. Expression of the transgene in hepatocytes resulted in increased collagen deposition, altered lobular organization, increased hepatocyte turnover, and in extreme cases, hemorrhage and thrombosis. Renal expression of the transgene was localized to the proximal tubule epithelium, and was associated with tubulointerstitial fibrosis, characterized by excessive collagen deposition and increased fibronectin and plasminogen activator inhibitor-1 immunoreactivity. Pronounced glomerulosclerosis was evident, and hydronephrosis developed with low penetrance. Expression of TGF-beta1 in white and brown adipose tissue resulted in a lipodystrophy-like syndrome. All white fat depots and brown fat pads were severely reduced in size, and exhibited prominent fibroplasia. This reduction in WAT was due to impaired adipose accretion. Introduction of the transgene into the ob/ob background suppressed the obesity characteristic of this mutation; however, transgenic mutant mice developed severe hepato- and splenomegaly. These studies strengthen the link between TGF-beta1 expression and fibrotic disease, and demonstrate the potency of TGF-beta1 in modulating mesenchymal cell differentiation in vivo.

Topics: Adipose Tissue; Alanine Transaminase; Animals; Apoptosis; Aspartate Aminotransferases; Collagen; DNA; Female; Glomerulosclerosis, Focal Segmental; Humans; Kidney; Lipodystrophy; Liver; Liver Cirrhosis, Experimental; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Mice, Transgenic; Phosphoenolpyruvate Carboxykinase (GTP); Rats; Recombinant Fusion Proteins; Skin; Syndrome; Transforming Growth Factor beta