Loss of TLE3 Promotes Mitochondrial Program in Beige Adipocytes and Improves Glucose Metabolism

Abstract

Prolonged cold exposure stimulates the recruitment of beige adipocytes within white adipose tissue. Beige adipocytes depend on mitochondrial oxidative phosphorylation to drive thermogenesis. The transcriptional mechanisms that promote remodeling in adipose tissue are not well understood. Here we demonstrate that the transcriptional coregulator TLE3 is induced with aging and inhibits mitochondrial gene expression in beige adipocytes. Conditional deletion of TLE3 in adipocytes prevents age-and diet-induced weight gain by promoting mitochondrial oxidative metabolism and increasing energy expenditure, thereby improving glucose control.Using chromatin immunoprecipitation and deep sequencing we found that TLE3 occupies distal enhancers in proximity to nuclear-encoded mitochondrial genes and that many of these enhancers are also enriched for EBF transcription factors. TLE3 interacts with EBF2 and blocks its ability to promote the thermogenic transcriptional program. Collectively, these studies demonstrate that TLE3 mediates age-dependent beige adipose thermogenic decline through inhibition of EBF2 transcriptional activity. Inhibition of TLE3 may provide a novel therapeutic approach for obesity and diabetes. the presence of these thermogenic tissues are inversely related to metabolic disorders and obesity (7, 21), understanding the regulatory mechanisms that govern the development and activity of thermogenic adipocytes has become an area of intense therapeutic interest.All adipocyte subtypes require peroxisome proliferator-activated receptor gamma (PPARg), which is necessary and sufficient to drive adipocyte differentiation (22). A prior genomewide survey of PPARg binding profiles from primary cells isolated from three separate tissues (iWAT, eWAT, and BAT) differentiated in vitro showed an overlap in binding and similar intensities at the majority of PPARg binding sites (23). However, this study also revealed a subset of depotspecific binding sites that correlated well with depot-specific gene expression (23). These findings suggested that PPARg likely works in concert with other transcription factors and transcriptional co-regulators to regulate cell-type specific gene expression, although the identities of these auxiliary factors remain to be fully elucidated.Among the transcription factors known to work in concert with PPARg to determine adipocyte identity are those of the early B-cell factor (EBF) family. Both EBF1 and EBF2 participate in early adipogenesis (24, 25), and it has recently been demonstrated that they also play important roles in differentiated adipocytes. EBF1 positively regulates insulin-stimulated glucose uptake and lipogenesis (26), (27), while EBF2 is selectively expressed in brown adipocytes and facilitates the binding of PPARg to brown fat-specific genes to promote thermogenesis (28)-(29). The EBF DNA binding motif associates with BAT-specific PPARg binding sites (28) and enhances expression of genes important for mitochondrial function (30).The transducin-like enhancer of split (TLE) protein fam...

TET1 is a beige adipocyte-selective epigenetic suppressor of thermogenesis

“…TLE3, another whitening transcription factor, promotes adipose conversion during early differentiation by interacting with PPARγ and antagonizing Wnt signaling 59 . But a recent study identified its novel role as a suppressor of thermogenic gene expression in beige adipocytes 60 . Notably, both Zfp423 and TLE3 inhibit the activity of pro-browning transcription factor early B-cell factor 2 (EBF2) 58,60 , which cooperates with PPARγ and epigenetic modifiers, such as the chromatin remodelers BRG1 and BAF, and a long noncoding RNA, Blnc1 61 .…”

“…But a recent study identified its novel role as a suppressor of thermogenic gene expression in beige adipocytes 60 . Notably, both Zfp423 and TLE3 inhibit the activity of pro-browning transcription factor early B-cell factor 2 (EBF2) 58,60 , which cooperates with PPARγ and epigenetic modifiers, such as the chromatin remodelers BRG1 and BAF, and a long noncoding RNA, Blnc1 61 . Future studies are warranted to determine whether TET1-mediated gene repression converges with these known transcriptional regulators.…”

Regulation of adipocyte thermogenesis: mechanisms controlling obesity

“…Transducin‐like enhancer of split 3 (TLE3) is a white fat‐selective cofactor that physically disrupts the PRDM16‐PPARγ complex, while simultaneously activating PPARγ at white fat‐selective genes [70]. Fat‐specific loss of TLE3 in mice increases energy expenditure [71]. Similarly, the peroxisomal lipid synthetic enzyme, PexRAP, inhibits brown adipocyte gene expression by disrupting the PRDM16‐PPARγ complex [72].…”

The Regulatory Role of Mitochondrial MicroRNAs (MitomiRs) in Breast Cancer: Translational Implications Present and Future

“…Recently, Peng et al [ 78 ] reported the role of miR-3677 overexpression in breast cancer cells through its blocking effect on transducin-like enhancer of split3 (TLE3). Pearson et al [ 79 ] noted that TLE3 loss correlated with enhanced glucose uptake in adipose tissue and also induced a series of metabolic changes in the mitochondrion. Accordingly, tumour cells could use this mechanism for their metabolic reprogramming.…”