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Polymethoxyselenoflavones exert anti-obesity effects through activation of lipolysis and brown adipocyte metabolism

International Journal of Obesity volume 45, pages 122–129 (2021)Cite this article

Subjects

Abstract

Background/objectives

Polymethoxyselenoflavone (PMSF) is a compound that substitutes the oxygen atom in a flavonoid with selenium. This study aimed to investigate the effects of PMSFs on lipid metabolism in adipocytes and their anti-obesity potential.

Subjects/methods

To test lipolytic and thermogenic effects of the compounds in vitro, adipocytes differentiated from immortalized pre-brown adipocyte progenitors and pre-white adipocyte cell lines were treated with 19 PMSFs. The expression levels of brown adipocyte markers and genes related to mitochondrial metabolism were analyzed by qPCR and western blot. In vivo anti-obesity effect was investigated using diet-induced obesity mouse models and adipocyte-specific ATGL knockout mice.

Results

The qPCR analysis identified 2-(3,4-dimethoxyphenyl)-4H-selenochromen-4-one (DMPSC) as the most potent brown adipogenic candidate among the 19 compounds tested in this study. DMPSC treatment significantly increased the mitochondrial content and oxidative metabolism in adipocytes in vitro. Mechanistically, DMPSC treatment increased lipolysis through activation of PKA downstream signaling. Consistently, the in vivo treatment of DMPSC increased energy consumption, reduced body weight, and improved glucose tolerance in mice fed with high-fat diets. Moreover, DMPSC treatment increased brown adipocyte marker expression and mitochondrial content in adipose tissue of mice. The anti-obesity effects were absent in adipocyte-specific ATGL knockout mice, indicating that the DMPSC effect is mediated by cytosolic lipase-dependent mechanisms.

Conclusions

Collectively, our results indicated that DMPSC exerted anti-obesity effects partially through the PKA signaling-mediated activation of lipolysis and brown adipose tissue metabolism.

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Fig. 1: In vitro effects of polymethoxyselenoflavones on brown adipogenic marker expression in brown adipocytes.
Fig. 2: 4A increases mitochondrial content in brown adipocytes.
Fig. 3: 4A increased PKA downstream signaling pathway related to lipolysis.
Fig. 4: 4A increased oxygen consumption and energy expenditure of mice.
Fig. 5: In vivo anti-obesity effects of 4A in high-fat-diet-fed obese mice.
Fig. 6: ATGL knockout attenuates effects of 4A on body weight and brown adipocyte marker expression.

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Acknowledgements

This work was supported by Research Resettlement Fund for the new faculty of Seoul National University. This research was supported by Basic Science Research Program [NRF-2018R1A5A2024425, NRF-2019R1C1C1002014] of Ministry of Science of ICT and by Korea Mouse Phenotyping Project [NRF-2013M3A9D5072550] of Ministry of Science of ICT and Future Planning through National Research Foundation of Korea (NRF).

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Author notes

  1. These authors contributed equally: Hyun-Jung Kwon, Abhirup Saha, Sang-Yeop Ahn

Authors and Affiliations

  1. College of Pharmacy, Yonsei University, Incheon, 21983, Republic of Korea

    Hyun-Jung Kwon, Sang-Yeop Ahn, Woo-Ram Yang & Jin-Hyun Jeong

  2. College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea

    Abhirup Saha, Yoon Keun Cho, Yeonho Son, Minsu Kim & Yun-Hee Lee

  3. Korea Mouse Phenotyping Center (KMPC) and College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea

    Je Kyung Seong

  4. College of Pharmacy, Pusan National University, Busan, 46241, Republic of Korea

    Young-Suk Jung

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Kwon, HJ., Saha, A., Ahn, SY. et al. Polymethoxyselenoflavones exert anti-obesity effects through activation of lipolysis and brown adipocyte metabolism. Int J Obes 45, 122–129 (2021). https://doi.org/10.1038/s41366-020-0606-7

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