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Regulation of adipogenesis through retinoid X receptor and/or peroxisome proliferator-activated receptor by designed lignans based on natural products in 3T3–L1 cells

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Abstract

We previously synthesized two retinoid X receptor (RXR) agonists, 4′-hydroxy-3′-propyl-[1,1′-biphenyl]-3-propanoic acid ethyl ester (4′OHE) and 6-hydroxy-3′-propyl-[1,1′-biphenyl]-3-propanoic acid ethyl ester (6OHE), based on the structure of magnaldehyde B, a natural product obtained from Magnolia obovata. 4′OHE and 6OHE exhibited different selectivities for peroxisome proliferator-activated receptor (PPAR)/RXR heterodimers. To examine the regulatory effects of these compounds in adipogenesis, 3T3–L1 mouse preadipocytes were treated with a differentiation cocktail with or without test compounds to induce differentiation, and subsequently treated with test compounds in insulin-containing medium every alternate day. Lipid droplets were stained with Oil Red O to examine lipid accumulation. In addition, adipogenesis-related gene expression was measured using RT–qPCR and immunoblotting. The results showed that a PPARγ agonist, 4′OHE, which exerts agonistic effects on PPARγ and RXRα, enhanced adipogenesis similar to rosiglitazone. However, unlike GW501516, a PPARδ agonist, 6OHE and its hydrolysis product (6OHA), which exert agonistic effects on PPARδ and RXRα, suppressed adipogenesis. In a manner similar to 6OHE and 6OHA, bexarotene, an RXR agonist, suppressed adipocyte differentiation, and its anti-adipogenic effect was reversed by an RXR antagonist. Furthermore, 6OHA and bexarotene inhibited the increase in Pparγ2 and Cebpa mRNA levels 2 days after the induction of differentiation. We demonstrated the adipogenic effect of 4′OHE and anti-adipogenic effects of 6OHE and 6OHA in 3T3–L1 cells. Previously, RXR agonists have been reported to positively regulate the differentiation of mesenchymal stem cells into adipocytes, but our current data showed that they inhibited the differentiation of preadipocytes, at least 3T3–L1 cells, into adipocytes.

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Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We would like to thank Editage (www.editage.com) for English language editing.

Funding

This study was supported by a research grant from the Institute of Pharmaceutical Life Sciences at Aichi Gakuin University.

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Authors and Affiliations

  1. Laboratory of Medicinal Resources, School of Pharmacy, Aichi Gakuin University, 1-100 Kusumoto-cho, Chikusa-ku, Nagoya, Aichi, 464-8650, Japan

    Ken-ichi Nakashima, Marina Okamura, Imari Matsumoto, Nanae Kameda, Tomoe Tsuboi & Makoto Inoue

  2. Laboratory of Pharmaceutical Synthetic Chemistry, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, 501-1196, Japan

    Eiji Yamaguchi & Akichika Itoh

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  1. Ken-ichi Nakashima
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Correspondence to Ken-ichi Nakashima.

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Nakashima, Ki., Okamura, M., Matsumoto, I. et al. Regulation of adipogenesis through retinoid X receptor and/or peroxisome proliferator-activated receptor by designed lignans based on natural products in 3T3–L1 cells. J Nat Med 77, 315–326 (2023). https://doi.org/10.1007/s11418-022-01674-7

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