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

Abstract

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.

Signaling pathways in obesity: mechanisms and therapeutic interventions

“…Latent TGF-β-binding protein 3 (LTBP3), which regulates TGFβ activity by forming intracellular complexes with the TGF-β pro-peptide, has been demonstrated to promote WAT browning by modulating UCP1 expression and mitochondrial oxygen consumption through TGF-β2 signaling. 203 However, hepatic TGF-β signaling was found to contribute to HFD-induced steatosis and obesity by reducing mitochondrial respiration and inhibiting white-to-beige fat conversion, effects that are mediated by hepatocyte-derived exosomal let-7b-5p. 204 In addition, the serum response factor (SRF)–myelin-related transcription factor (MRTF) axis transcriptionally enhances TGF-β but attenuates the BMP signaling pathway and thus suppresses brown adipogenesis.…”

The signaling pathways in obesity‐related complications

“…In animal models of obesity induced by a high‐fat diet, TGF‐β and plasminogen activator inhibitor‐1 (PAI‐1) mRNA levels were increased in adipose tissue. In murine models of obesity, TGFβ was shown to increase CD206 + M2‐like macrophages in white adipose tissue that are linked to decreased white adipose tissue browning in insulin resistance 50 . In summary, TGF‐β contributes to dysfunctional adipose tissue in obesity with impaired adipogenesis and amplified inflammation and fibrosis.…”

Molecular insights of exercise therapy in disease prevention and treatment

“… 151 In search of the molecular foundation for increased serum TGF-β2 levels observed after exercise training in humans and mice, muscle-secreted lactate was found to mediate TGF-β2 secretion from subcutaneous WAT in mice. Besides a potential autocrine stimulation of WAT, which leads to adipose tissue browning, 158 secretion of TGF-β2 from WAT induced glucose and fatty acid uptake in skeletal muscle, improved glucose tolerance and insulin sensitivity and reduced fat inflammation in mice. 151 Although the cellular mechanisms mediating these effects in the context of exercise remain uncertain, it is tempting to speculate that MAPK and SMAD proteins are involved.…”