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Aurantio-obtusin ameliorates obesity by activating PPARα-dependent mitochondrial thermogenesis in brown adipose tissues

Acta Pharmacologica Sinica volume 44, pages 1826–1840 (2023)Cite this article

Abstract

Obesity contributes to the progression of various chronic diseases, and shortens life expectancy. With abundant mitochondria, brown adipose tissue (BAT) dissipates energy through heat to limit weight gain and metabolic dysfunction in obesity. Our previous studies have shown that aurantio-obtusin (AO), a bioactive ingredient in Chinese traditional medicine Cassiae semen significantly improves hepatic lipid metabolism in a steatotic mouse model. In the current study we investigated the effects of AO on lipid metabolism in the BAT of diet-induced obesity mice and in oleic acid and palmitic acid (OAPA)-stimulated primary mature BAT adipocytes. Obese mice were established by feeding a HFHS diet for 4 weeks, and then administered AO (10 mg/kg, i.g.) for another 4 weeks. We showed that AO administration significantly increased the weight of BAT and accelerated energy expenditure to protect the weight increase in the obese mice. Using RNA sequencing and molecular biology analysis we found that AO significantly enhanced mitochondrial metabolism and UCP1 expression by activating PPARα both in vivo and in vitro in the primary BAT adipocytes. Interestingly, AO administration did not improve metabolic dysfunction in the liver and white adipose tissue of obese mice after interscapular BAT excision. We demonstrated that low temperature, a trigger of BAT thermogenesis, was not a decisive factor for AO to stimulate the growth and activation of BATs. This study uncovers a regulatory network of AO in activating BAT-dependent lipid consumption and brings up a new avenue for the pharmaceutical intervention in obesity and related comorbidities.

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Fig. 1: AO improves BAT in the HFHS-induced obese mice.
Fig. 2: AO distinctly changes the DEGs involved in mitochondrial function and energy consumption.
Fig. 3: AO increases the activity of mitochondrial complexes.
Fig. 4: Effects of AO on lipid metabolism in the cold environment.
Fig. 5: Low temperature has less effect on the AO-induced therapeutic function.
Fig. 6: The function of AO is markedly diminished after BAT resection.
Fig. 7: AO improves lipid accumulation in the primary BAT adiposes.
Fig. 8: The inhibition of PPARα worsens lipid metabolism caused by AO in vivo.

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Acknowledgements

This work was supported by grants from National Natural Science Foundation of China (Grant No. 82274186 to XJYL, 82274201 and 82004029 to RPL); the National High-Level Talents Special Support Program to XJYL; Beijing Nova Program of Science & Technology (Z201100006820025 and Z211100002121167 to RPL); Young Talents Promotion Project of China Association of Traditional Chinese Medicine (Grant No. 2020-QNRC2-01 to XJYL and CACM-2020-QNRC2-04 to RPL); Beijing Municipal Science & Technology Commission (Grant No. 7212174 to XJYL); Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine (Grant No. ZYYCXTD-C-202006 to XJYL).

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Author notes

  1. These authors contributed equally: Yi-jie Li, Rui-yu Wu.

Authors and Affiliations

  1. School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 100029, China

    Yi-jie Li, Ming-ning Ding, Fei Zhou, Jian-zhi Wu, Yin-hao Zhang & Xiaojiaoyang Li

  2. School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029, China

    Rui-yu Wu, Run-ping Liu, Yi-qing Gu, Qi Zheng, Shu-ni Duan & Fang-hong Li

  3. The Second Hospital of Shandong University, Shandong University, Ji-nan, 250033, China

    Kai-yi Wu, Rong Sun & Rong-rong Li

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Contributions

XJYL, RPL: designed the study, performed data analysis, and revised the paper. YJL, RYW: performed the experiments, analyzed the data, and wrote the paper. RS: contributed new reagents. KYW, MND, YQG, FZ, JZW, QZ, SND, RRL: assisted with the experiments. YHZ, FHL: contributed analytic tools.

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Correspondence to Run-ping Liu or Xiaojiaoyang Li.

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Li, Yj., Wu, Ry., Liu, Rp. et al. Aurantio-obtusin ameliorates obesity by activating PPARα-dependent mitochondrial thermogenesis in brown adipose tissues. Acta Pharmacol Sin 44, 1826–1840 (2023). https://doi.org/10.1038/s41401-023-01089-4

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