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TGF-? mediates suppression of adipogenesis by estradiol through connective tissue growth factor induction.

ABSTRACT: In the bone marrow cavity, adipocyte numbers increase, whereas osteoblast progenitor numbers decrease with aging. Because adipocytes and osteoblasts share a common progenitor, it is possible that this shift is due to an increase in adipocyte-lineage cells at the expense of osteoblast-lineage commitment. Estrogens inhibit adipocyte differentiation, and in both men and women, circulating estrogens correlate with bone loss with aging. In bone cells, estrogens stimulate expression of TGF-? and suppress mesenchymal cell adipogenesis. Using a tripotential mesenchymal cell line, we have examined whether estradiol suppression of adipocyte differentiation is due to stimulation of TGF-? and the mechanism by which TGF-? suppresses adipogenesis. We observed that estradiol-mediated suppression of adipogenic gene expression required at least 48 h treatment. TGF-? expression increased within 24 h of estradiol treatment, and TGF-? inhibition reversed estradiol influences on adipogenesis and adipocyte gene expression. Connective tissue growth factor (CTGF) mediates TGF-? suppression of adipogenesis in mouse 3T3-L1 cells. CTGF expression was induced within 24 h of TGF-? treatment, whereas estradiol-mediated induction required 48 h treatment. Moreover, estradiol-mediated induction of CTGF was abrogated by TGF-? inhibition. These data support that estradiol effects on adipogenesis involves TGF-? induction, which then induces CTGF to suppress adipogenesis.

SUBMITTER: Kumar A

PROVIDER: S-EPMC3249674 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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TGF-β mediates suppression of adipogenesis by estradiol through connective tissue growth factor induction.

Kumar Ashok A Ruan Ming M Clifton Kari K Syed Farhan F Khosla Sundeep S Oursler Merry Jo MJ

Endocrinology 20111108 1

In the bone marrow cavity, adipocyte numbers increase, whereas osteoblast progenitor numbers decrease with aging. Because adipocytes and osteoblasts share a common progenitor, it is possible that this shift is due to an increase in adipocyte-lineage cells at the expense of osteoblast-lineage commitment. Estrogens inhibit adipocyte differentiation, and in both men and women, circulating estrogens correlate with bone loss with aging. In bone cells, estrogens stimulate expression of TGF-β and suppr ...[more]

PMID: 22067314

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Project description:BACKGROUND:Adenomyosis is a medical condition defined by the abnormal presence of endometrial tissue within the myometrium, in which fibrosis occurs with new collagen deposition and myofibroblast differentiation. In this study, the effect of several mediators and growth factors on collagen expression was investigated on human endometrial stromal cells (fibroblasts) derived from adenomyotic endometrium. EXPERIMENTAL APPROACH:RT-PCR, Western blot analysis, pharmacological interventions and siRNA interference were applied to primary cultured human endometrial stromal cells (fibroblasts). Immunohistochemistry was used to analyze protein expression in adenomyotic endometrium tissue specimens. RESULTS:Of the tested mediators, transforming growth factor β1 (TGFβ1) and its isoforms were effective to induce collagen and connective tissue growth factor (CTGF) expression. Collagen and CTGF induction by TGFβ1 could be reduced by the inhibitors targeting DNA transcription, protein translation, and Smad2/3 signaling. Interestingly, TGFβ1 induced Smad2/3 phosphorylation and CTGF mRNA expression, but not collagen mRNA expression, suggesting that TGFβ1 mediates collagen expression through CTGF induction and Smad2/3 activation. In parallel, TGFβ1 and CTGF also induced expression of heat shock protein (HSP) 47, a protein required for the synthesis of several types of collagens. However, only CTGF siRNA knockdown, could compromise TGFβ1-induced collagen expression. Finally, the immunohistochemistry revealed vimentin- and α-SMA-positive staining for (myo)fibroblasts, TGFβ1, collagen, and CTGF in the subepithelial stroma region of human adenomyotic endometria. CONCLUSION AND IMPLICATIONS:We reveal here that TGFβ1, collagen, and CTGF are expressed in the stroma of adenomyotic endometria and demonstrate that TGFβ1 can induce collagen production in endometrium-derived fibroblasts through cellular Smad2/3-dependent signaling pathway and CTGF expression, suggesting that endometrial TGFβ may take part in the pathogenesis of adenomyosis and ectopic endometrium may participate in uterine adenomyosis.

Project description:Primordial follicle assembly is a process that occurs in the embryonic or early post natal ovary in which oocyte nests break down to form individual primordial follicles. The size of this initial pool of primordial follicles in part determines the reproductive lifespan of the female. Connective tissue growth factor (CTGF) was identified as a potential regulatory candidate for this process in a previous microarray analysis of follicle development. The current study examines the effects of CTGF and associated transforming growth factor beta 1 (TGFbeta-1) on follicle assembly. Ovaries were removed from newborn rat pups and placed in an organ culture system for two days to measure the effect of these factors on follicle assembly. In addition, ovaries were cultured and treated for ten days to determine the potential of CTGF and TGFbeta-1 to manipulate the primordial follicle pool size over a longer developmental time period. The ovaries treated with CTGF for two days were found to have an increased proportion of assembled follicles. TGFbeta-1 had no effect on primordial follicle assembly and in combination with CTGF decreased oocyte number in the ovary after two days of culture. Over ten days of treatment only the combined treatment of CTGF and TGFbeta-1 was found to cause an increase in the proportion of assembled follicles. Interestingly, treatment with TGFbeta-1 alone resulted in fewer total oocytes in the ovary and decreased the primordial follicle pool size after ten days of culture. Observations indicate that CTGF alone or in combination with TGFbeta-1 stimulates primordial follicle assembly and TGFbeta-1 can decrease the primordial follicle pool size. CTGF was found to regulate the ovarian transcriptome during primordial follicle assembly and an integrative network of genes was identified. CTGF is one of the first growth factors shown to promote primordial follicle assembly, while TGFbeta-1 is one of the first factors shown to decrease the primordial follicle pool size. These observations suggest the possibility of manipulating primordial follicle pool size and influencing female reproductive lifespan. We used microarrays to determine genes expressed differentially between control and CTGF (connective tissue growth factor) treated P0 ovary

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TGF-? mediates suppression of adipogenesis by estradiol through connective tissue growth factor induction.

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TGF-β mediates suppression of adipogenesis by estradiol through connective tissue growth factor induction.

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