FXR-ApoC2 pathway activates UCP1-mediated thermogenesis by promoting the browning of white adipose tissues

Sang Hee Kim; Woo Yong Park; Beomsu Kim; Jin-Hyung Kim; Gahee Song; Ja Yeon Park; Wenjun Jiao; Se Jin Jung; Kwang Seok Ahn; Hyun Jeong Kwak; Jae-Young Um

doi:10.1016/j.jbc.2025.108181

FXR-ApoC2 pathway activates UCP1-mediated thermogenesis by promoting the browning of white adipose tissues

J Biol Chem. 2025 Jan 9:108181. doi: 10.1016/j.jbc.2025.108181. Online ahead of print.

Authors

Affiliations

¹ Department of Science in Korean Medicine, Graduate School, Kyung Hee University, 02447, Seoul, Korea.
² Department of Science in Korean Medicine, Graduate School, Kyung Hee University, 02447, Seoul, Korea; Department of Pharmacology, College of Korean Medicine, Kyung Hee University, 02447, Seoul, Korea.
³ Department of Biomedical and Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul 02447, South Korea.
⁴ Department of Science in Korean Medicine, Graduate School, Kyung Hee University, 02447, Seoul, Korea; Department of Pharmacology, College of Korean Medicine, Kyung Hee University, 02447, Seoul, Korea; Kyung Hee Institute of Convergence Korean Medicine, Kyung Hee University, 02447, Seoul, Korea.
⁵ Department of Science in Korean Medicine, Graduate School, Kyung Hee University, 02447, Seoul, Korea; Kyung Hee Institute of Convergence Korean Medicine, Kyung Hee University, 02447, Seoul, Korea.
⁶ Department of Bio and Fermentation Convergence Technology, Kookmin University, Seoul 02707, Republic of Korea.
⁷ Department of Science in Korean Medicine, Graduate School, Kyung Hee University, 02447, Seoul, Korea; Department of Pharmacology, College of Korean Medicine, Kyung Hee University, 02447, Seoul, Korea; Kyung Hee Institute of Convergence Korean Medicine, Kyung Hee University, 02447, Seoul, Korea. Electronic address: [email protected].

PMID: 39798876
DOI: 10.1016/j.jbc.2025.108181

Abstract

FXR, encoded by Nh1r4, is a nuclear receptor crucial in regulating bile acid, lipid, and glucose metabolism. Prior research has indicated that activating FXR in the liver and small intestine may offer protection against obesity and metabolic diseases. This study demonstrates the essential role of the FXR-ApoC2 pathway in promoting the browning of white adipose tissue (WAT). Increased FXR by treatment with the FXR agonist farnesol upregulated beige adipocyte markers, including UCP1, PGC1α, and PRDM16, and increased the FXR target gene, ApoC2, in beige adipocytes and cold-exposed mice. However, these effects were not observed in mature white adipocytes. Remarkably, the knockdown of FXR results in a significantly reduced expression of UCP1, PGC1α, PRDM16, and ApoC2 in beige adipocytes. While studying the interaction between the nuclear receptor RXRα and FXR in transcription regulation, it was found that the knockdown of RXRα did not control the expression of FXR under beige adipogenesis. We further investigated whether the expression of beige-related markers could be altered under ApoC2 overexpression to ascertain the mechanism of action of FXR in relation to ApoC2 regulation. The overexpression of ApoC2 in both preadipocytes and beige adipocytes led to a significant increase in the expression of UCP1 and PGC1α. These results indicate that the FXR-mediated ApoC2 pathway is essential in the browning of WAT by inducing beige adipogenesis from preadipocytes.

Keywords: ApoC2; Beige adipocyte; FXR; PGC1α; UCP1.