Latent TGFβ-binding proteins regulate UCP1 expression and function via TGFβ2

Objective: Activation of brown adipose tissue (BAT) in humans has been proposed as a new treatment approach for combating obesity and its associated diseases, as BAT participates in the regulation of energy homeostasis as well as glucose and lipid metabolism. Genetic contributors driving brown adipogenesis in humans have not been fully understood. Methods: Profiling the gene expression of progenitor cells from subcutaneous and deep neck adipose tissue, we discovered new secreted factors with potential regulatory roles in white and brown adipogenesis. Among these, members of the latent transforming growth factor beta-binding protein (LTBP) family were highly expressed in brown compared to white adipocyte progenitor cells, suggesting that these proteins are capable of promoting brown adipogenesis. To investigate this potential, we used CRISPR/Cas9 to generate LTBP-deficient human preadipocytes. Results: We demonstrate that LTBP2 and LTBP3 deficiency does not affect adipogenic differentiation, but diminishes UCP1 expression and function in the obtained mature adipocytes. We further show that these effects are dependent on TGFβ2 but not TGFβ1 signaling: TGFβ2 deficiency decreases adipocyte UCP1 expression, whereas TGFβ2 treatment increases it. The activity of the LTBP3–TGFβ2 axis that we delineate herein also significantly correlates with UCP1 expression in human white adipose tissue (WAT), suggesting an important role in regulating WAT browning as well. Conclusions: These results provide evidence that LTBP3, via TGFβ2, plays an important role in promoting brown adipogenesis by modulating UCP1 expression and mitochondrial oxygen consumption