Endoplasmic Reticulum Stress Impaired Uncoupling Protein 1 Expression via the Suppression of Peroxisome Proliferator-Activated Receptor γ Binding Activity in Mice Beige Adipocytes

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.

Intrauterine exposure to low-dose DBP in the mice induces obesity in offspring via suppression of UCP1 mediated ER stress

“…Some studies have shown that UCP1 activity in adipose tissue was regulated by ER stress. Yuliana et al found that ER stress negatively regulates UCP1 in mice iWAT 45 . Further investigation showed that the regulatory effect of ER stress on UCP1 expression is accomplished via suppression of the peroxisome proliferator-activated receptor γ (Pparγ) in mice beige adipocytes.…”

The effect of royal jelly and tocotrienol-rich fraction along with calorie restriction on hypothalamic endoplasmic reticulum stress and adipose tissue inflammation in diet-induced obese rats

“…Glucose-regulated protein-78 (GRP78) because of its role in protein folding consider as a key regulator of ER stress (9). ER stress in adipose tissue reduces thermogenesis and plays an important role in adipose tissue dysfunction, changing cytokine secretion, and causing chronic in ammation in adipocytes (3,14).…”

The Effect of Royal Jelly and Tocotrienol-rich Fraction Along With Calorie Restriction on Hypothalamic Endoplasmic Reticulum Stress and Adipose Tissue Inflammation in Diet-induced Obese Rats

“…Glucose-regulated protein-78 (GRP78) because of its role in protein folding consider as a key regulator of ER stress (9). ER stress in adipose tissue reduces thermogenesis and plays an important role in adipose tissue dysfunction, changing cytokine secretion, and causing chronic in ammation in adipocytes (3,14). Besides, improving hypothalamic ER stress triggers WAT browning, which in turn diminish in ammatory factors secretion from adipocytes, and nally ameliorate obesity-related disorders (11).…”