Abstract
Insulin resistance is a major cause of type 2 diabetes and metabolic syndrome. Macrophage infiltration into obese adipose tissue promotes inflammatory responses that contribute to the pathogenesis of insulin resistance. Suppression of adipose tissue inflammatory responses is postulated to increase insulin sensitivity in obese patients and animals. Sarsasapogenin (ZGY) is one of the metabolites of timosaponin AIII in the gut, which has been shown to exert anti-inflammatory action. In this study, we investigated the effects of ZGY treatment on obesity-induced insulin resistance in mice. We showed that pretreatment with ZGY (80 mg·kg−1·d−1, ig, for 18 days) significantly inhibited acute adipose tissue inflammatory responses in LPS-treated mice. In high-fat diet (HFD)-fed obese mice, oral administration of ZGY (80 mg·kg−1·d−1, for 6 weeks) ameliorated insulin resistance and alleviated inflammation in adipose tissues by reducing the infiltration of macrophages. Furthermore, we demonstrated that ZGY not only directly inhibited inflammatory responses in macrophages and adipocytes, but also interrupts the crosstalk between macrophages and adipocytes in vitro, improving adipocyte insulin resistance. The insulin-sensitizing and anti-inflammatory effects of ZGY may result from inactivation of the IKK /NF-κB and JNK inflammatory signaling pathways in adipocytes. Collectively, our findings suggest that ZGY ameliorates insulin resistance and alleviates the adipose inflammatory state in HFD mice, suggesting that ZGY may be a potential agent for the treatment of insulin resistance and obesity-related metabolic diseases.
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Acknowledgements
This work was supported by grants from the Ministry of Science and Technology (2018ZX09711002-018 and 2016YFC1305505) and the National Natural Science Foundation of China (81673493).
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YYY contributed to the hypothesis, study design, data analysis, experiments, and preparation of the paper; SCC, TNZ, HJM, ZFX, HWJ, YFL, and KXZ performed the experiments, analyzed the data, provided conceptual advice and technical expertise, and edited the paper; HCG provided all the ZGY samples for the in vitro and in vivo experiments. JL and JYL conceived and supervised the study; and all authors reviewed and approved the final version of the paper.
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Yu, Yy., Cui, Sc., Zheng, Tn. et al. Sarsasapogenin improves adipose tissue inflammation and ameliorates insulin resistance in high-fat diet-fed C57BL/6J mice. Acta Pharmacol Sin 42, 272–281 (2021). https://doi.org/10.1038/s41401-020-0427-1
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DOI: https://doi.org/10.1038/s41401-020-0427-1
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