Abstract
Background
Suppression of adipogenesis has been considered as a potential target for the prevention and treatment of obesity and associated metabolic disorders, and the nuclear receptor 4A1 (NR4A1/Nur77) and AMPKα are known to play important roles during early and intermediate stages of adipogenesis. Therefore, we hypothesized that dual targeting Nur77 and AMPKα would show strong inhibitory effect on adipogenesis.
Methods
We screened a herbal medicine-based small molecule library to identify novel natural compounds dual targeting Nur77 and AMPKα, and the antiadipogenic effects and mechanisms of action of a “hit” compound were studied in 3T3-L1 cells. In vivo antiobesity effects of the compound were also investigated in high-fat diet (HFD)-induced obese mice.
Results
We identified isoalantolactone (ISO) as a new NR4A1 inactivator that also activates AMPKα in 3T3-L1 cells. ISO, as expected, inhibited adipogenic differentiation of 3T3-L1 preadipocytes, accompanied by reduced mitotic clonal expansion (MCE) which occurs in the early stage of adipogenesis and decreased expression of genes required for MCE and cell cycle markers including cyclin A, cyclin D1. Furthermore, ISO reduced body weight gain and fat mass (epididymal, subcutaneous, perirenal, and inguinal white adipose tissues) in the high-fat diet-fed C57BL/6 N mice. Serum levels of triglycerides, aspartate transaminase, and alanine transaminase and hepatic steatosis were also significantly improved in the ISO-treated group compared to the high-fat diet control group.
Conclusions
These results suggest that ISO dual targeting Nur77 and AMPKα during adipogenesis represents a novel class of mechanism-based antiadipogenic agents for treatment of obesity and associated metabolic disorders, including hyperlipidemia and fatty liver.
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Acknowledgements
This work was supported by the Cooperative Research Program for Agriculture Science and Technology Development [Project No. PJ012284012018], Rural Development Administration, Republic of Korea.
Funding
This work was supported by the Cooperative Research Program for Agriculture Science and Technology Development [Project No. PJ012284012018], Rural Development Administration, Republic of Korea.
Author contributions
Conception and design: SOL. Acquisition of data: YSJ, HSL, HRC, KJK, JHK. Analysis and interpretation of data: YSJ, HSL, KJK, JHK. Writing, review, and/or revision of the manuscript: SOL, YSJ, SS. Study supervision: SOL.
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Jung, YS., Lee, HS., Cho, HR. et al. Dual targeting of Nur77 and AMPKα by isoalantolactone inhibits adipogenesis in vitro and decreases body fat mass in vivo. Int J Obes 43, 952–962 (2019). https://doi.org/10.1038/s41366-018-0276-x
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DOI: https://doi.org/10.1038/s41366-018-0276-x
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