Abstract
Endoplasmic reticulum (ER) homeostasis is critical in maintaining metabolic regulation. Once it is disrupted due to accumulated unfolded proteins, ER homeostasis is restored via activation of the unfolded protein response (UPR); hence, the UPR affects diverse physiological processes. However, how ER stress influences adipocyte functions is not well known. In this study, we investigated the effect of ER stress in thermogenic capacity of mice beige adipocytes. Here, we show that the expression of uncoupling protein 1 (Ucp1) involved in thermoregulation is severely suppressed under ER stress conditions (afflicted by tunicamycin) in inguinal white adipose tissue (IWAT) both in vitro and in vivo. Further investigation showed that extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) were both activated after ER stress stimulation and regulated the mRNA levels of Ucp1 and peroxisome proliferator-activated receptor γ (Pparγ), which is known as a Ucp1 transcriptional activator, in vitro and ex vivo. We also found that Pparγ protein was significantly degraded, reducing its recruitment to the Ucp1 enhancer, thereby downregulating Ucp1 expression. Additionally, only JNK inhibition, but not ERK, rescued the Pparγ protein. These findings provide novel insights into the regulatory effect of ER stress on Ucp1 expression via Pparγ suppression in beige adipocytes.
Highlights
Adipose tissue has been broadly characterized as white and brown adipocytes through their distinct characteristics in lipid metabolism
Endoplasmic reticulum (ER) stress stimulation was confirmed by the upregulation of ER stress markers: binding immunoglobulin protein (Bip) and CCAAT-enhancer-binding protein homologous protein (Chop) (Figure 1A)
The addition of chemical chaperone 4-phenylbutyrate (PBA) alleviated ER stress markers Bip and Chop, while rescued uncoupling protein 1 (Ucp1) expression (Figure 1A). These results indicate that ER stress suppressed Ucp1 expression in beige adipocytes
Summary
Adipose tissue has been broadly characterized as white and brown adipocytes through their distinct characteristics in lipid metabolism. Several studies have shown a significant activation of ER stress in high-fat-induced obesity [20,21,22] Both brown and beige adipocyte activation stimulated by cold exposure was impaired in obese adipose tissue [23]. The inactivation of ER stress in BAT, WAT, or macrophages resulted in an improved adaptive thermogenesis response [6,24], while treatment of chemical chaperones (ER stress inhibitor) could increase energy expenditure and activate browning of WAT [25,26,27] These reports suggest a possible unknown regulatory mechanism of ER stress in the browning of WAT. We investigated the effect of ER stress stimulation on Ucp, an adipocyte browning marker, in beige adipocytes
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