4-hydroxybenzoic acid induces browning of white adipose tissue through the AMPK-DRP1 pathway in HFD-induced obese mice

Sang Hee Kim; Woo Yong Park; Gahee Song; Ja Yeon Park; Se Jin Jung; Kwang Seok Ahn; Jae-Young Um

doi:10.1016/j.phymed.2024.156353

4-hydroxybenzoic acid induces browning of white adipose tissue through the AMPK-DRP1 pathway in HFD-induced obese mice

Phytomedicine. 2024 Dec 27:137:156353. doi: 10.1016/j.phymed.2024.156353. Online ahead of print.

Authors

Sang Hee Kim¹, Woo Yong Park², Gahee Song³, Ja Yeon Park¹, Se Jin Jung¹, Kwang Seok Ahn⁴, Jae-Young Um⁵

Affiliations

¹ Department of Science in Korean Medicine, Graduate School, Kyung Hee University, 02447, Seoul, South Korea.
² Department of Pharmacology, College of Korean Medicine, Kyung Hee University, 02447, Seoul, South Korea.
³ Department of Pharmacology, College of Korean Medicine, Kyung Hee University, 02447, Seoul, South Korea; Kyung Hee Institute of Convergence Korean Medicine, Kyung Hee University, 02447, Seoul, South Korea.
⁴ Department of Science in Korean Medicine, Graduate School, Kyung Hee University, 02447, Seoul, South Korea; Kyung Hee Institute of Convergence Korean Medicine, Kyung Hee University, 02447, Seoul, South Korea.
⁵ Department of Science in Korean Medicine, Graduate School, Kyung Hee University, 02447, Seoul, South Korea; Department of Pharmacology, College of Korean Medicine, Kyung Hee University, 02447, Seoul, South Korea; Kyung Hee Institute of Convergence Korean Medicine, Kyung Hee University, 02447, Seoul, South Korea. Electronic address: jyum@khu.ac.kr.

PMID: 39799892
DOI: 10.1016/j.phymed.2024.156353

Abstract

Background: Beige adipocytes have physiological functions similar to brown adipocytes, which are available to increase energy expenditure through uncoupling protein 1 (UCP1) within mitochondria. Recently, many studies showed white adipocytes can undergo remodeling into beige adipocytes, called "browning", by increasing fusion and fission events referred to as mitochondrial dynamics.

Purpose: In this study, we aimed to investigate the browning effects of 4-hydroxybenzoic acid (4-HA), one of the major compounds of black raspberries.

Methods: We examined the mechanism underlying the browning properties of 4-HA focusing on UCP1-dependent non-shivering thermogenesis in 3T3-L1 white adipocytes, high-fat diet (HFD)-induced obese male C57BL/6J mice, and cold-exposed male C57BL/6J mice.

Results: 4-HA treatment elevates browning markers such as UCP1, T-Box transcription factor 1, and PR domain containing 16, mitochondrial function factors like oxidative phosphorylation complex as well as mitochondrial dynamic-related factors like phosphorylated dynamin-related protein 1 (p-DRP1), DRP1, and mitofusin 1 in 3T3-L1 white adipocytes, which were also confirmed in inguinal white adipose tissue (iWAT) of HFD-induced obese mice. Mdivi-1 blocked the increased DRP1-mediated mitochondrial fission by 4-HA, and even the browning effect of 4-HA was abolished. Furthermore, 4-HA increased AMP-activated protein kinase (AMPK) in both the 3T3-L1 white adipocytes and iWAT of HFD-induced obese mice. Inhibition of AMPK with Compound C also blocked the 4-HA-induced mitochondrial fission and browning effect.

Conclusions: 4-HA induces the browning of white adipocytes into beige adipocytes by regulating the DRP1-mediated mitochondrial dynamics through AMPK. These findings suggest that 4-HA could serve as a therapeutic candidate for obesity and related metabolic disorders.

Keywords: 4-hydroxybenzoic acid; AMPK; DRP1; Mitochondrial dynamics; Obesity.