Latent transforming growth factor beta binding protein 3 controls adipogenesis

Transforming growth factor-beta (TGFb) is released from cells as part of a trimeric latent complex consisting of TGF beta, the TGF beta propeptides, and either a latent TGF beta binding protein (LTBP) or glycoprotein-A repetitions predominant (GARP) protein. LTBP1 and 3 modulate latent TGF beta function with respect to secretion, matrix localization, and activation and, therefore, are vital for the proper function of the cytokine in a number of tissues. TGFb modulates stem cell differentiation into adipocytes (adipogenesis), but the potential role of LTBPs in this process has not been studied. We observed that 72 h post adipogenesis initiation Ltbp1, 2, and 4 expression levels decrease by 74-84%, whereas Ltbp3 expression levels remain constant during adipogenesis. We found that LTBP3 silencing in C3H/10T1/2 cells reduced adipogenesis, as measured by the percentage of cells with lipid vesicles and the expression of the transcription factor peroxisome proliferator-activated receptor gamma (PPAR gamma). Lentiviral mediated expression of an Ltbp3 mRNA resistant to siRNA targeting rescued the phenotype, validating siRNA specificity. Knockdown (KD) of Ltbp3 expression in 3T3-L1, M2, and primary bone marrow stromal cells (BMSC) indicated a similar requirement for Ltbp3. Epididymal and inguinal white adipose tissue fat pad weights of Ltbp3(-/-) mice were reduced by 62% and 57%, respectively, compared to wild-type mice. Inhibition of adipogenic differentiation upon LTBP3 loss is mediated by TGF beta, as TGF beta neutralizing antibody and TGF beta receptor I kinase blockade rescue the LTBP3 KD phenotype. These results indicate that LTBP3 has a TGF beta-dependent function in adipogenesis both in vitro and possibly in vivo. Significance: Understanding the control of mesenchymal stem cell fate is crucial for the potential use of these cells for regenerative medicine. (C) 2022 The Author(s). Published by Elsevier B.V.

Automated summary

LTBP3 plays a crucial role in adipogenesis, and its deficiency inhibits adipocyte differentiation, which is regulated by TGF beta. Understanding the control of mesenchymal stem cell fate is essential for the potential use of these cells for regenerative medicine.