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Int J Mol Sci. 2019 Jan 11;20(2). pii: E274. doi: 10.3390/ijms20020274.

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

Author information

1
Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho, Uji, Kyoto 611-0011, Japan. anayulia@kais.kyoto-u.ac.jp.
2
Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho, Uji, Kyoto 611-0011, Japan. asumi.7.9.2.8@gmail.com.
3
Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho, Uji, Kyoto 611-0011, Japan. ydnas@kais.kyoto-u.ac.jp.
4
Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho, Uji, Kyoto 611-0011, Japan. kwon.jungin.34r@st.kyoto-u.ac.jp.
5
Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho, Uji, Kyoto 611-0011, Japan. nom2@kais.kyoto-u.ac.jp.
6
Research Unit for Physiological Chemistry, the Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, Kyoto 606-8501, Japan. nom2@kais.kyoto-u.ac.jp.
7
Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho, Uji, Kyoto 611-0011, Japan. haruya@kais.kyoto-u.ac.jp.
8
Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho, Uji, Kyoto 611-0011, Japan. ara@kais.kyoto-u.ac.jp.
9
Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho, Uji, Kyoto 611-0011, Japan. fat@kais.kyoto-u.ac.jp.
10
Research Unit for Physiological Chemistry, the Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, Kyoto 606-8501, Japan. fat@kais.kyoto-u.ac.jp.
11
Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho, Uji, Kyoto 611-0011, Japan. tgoto@kais.kyoto-u.ac.jp.
12
Research Unit for Physiological Chemistry, the Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, Kyoto 606-8501, Japan. tgoto@kais.kyoto-u.ac.jp.

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.

KEYWORDS:

beige adipocytes; endoplasmic reticulum stress; peroxisome proliferator-activated receptor γ; uncoupling protein 1

PMID:
30641938
PMCID:
PMC6359291
DOI:
10.3390/ijms20020274
[Indexed for MEDLINE]
Free PMC Article

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