选择性PPARγ调节剂alpinetin可恢复2型糖尿病患者的胰岛素敏感性并防止骨质流失

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-06-18 DOI:10.1016/j.phymed.2025.157003

Yaoyu Zhao , Hantao Yao , Yilin Liao , Bulin Jiang , Ting Li , Jingqiu Chen , Yue Sheng , Mengjie Yin , Wengwanyue Ye , Qi Yan , Yaoting Ji

{"title":"选择性PPARγ调节剂alpinetin可恢复2型糖尿病患者的胰岛素敏感性并防止骨质流失","authors":"Yaoyu Zhao , Hantao Yao , Yilin Liao , Bulin Jiang , Ting Li , Jingqiu Chen , Yue Sheng , Mengjie Yin , Wengwanyue Ye , Qi Yan , Yaoting Ji","doi":"10.1016/j.phymed.2025.157003","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><div>Type 2 diabetes mellitus (T2DM) poses a significant global health burden, with its escalating prevalence and related complications. Although peroxisome proliferator–activated receptor gamma (PPARγ) agonists such as thiazolidinediones effectively enhance insulin sensitivity, their use is limited by adverse effects, including bone loss. Recent research has focused on developing selective PPARγ modulators with improved safety profiles. Alpinetin (Apt), a naturally occurring flavonoid, has demonstrated anti-inflammation potential; however, its impact on insulin signaling and bone metabolism under diabetic conditions has yet to be investigated.</div></div><div><h3>Purpose</h3><div>This study aims to investigate whether Apt acts as a selective PPARγ modulator that can restore insulin sensitivity while preventing diabetes-associated bone deterioration.</div></div><div><h3>Methods</h3><div>Molecular docking and dynamics simulations assessed the interaction between Apt and PPARγ. The cellular thermal shift assay (CETSA) evaluated Apt’s binding affinity, and dual-luciferase reporter assays measured its activation of PPARγ. Single-cell RNA sequencing analysis, network pharmacology and RNA sequencing were used to explore Apt’s mechanisms in T2DM treatment. The insulin-sensitizing and bone-protecting effects of Apt were tested both <em>in vitro</em> and in a streptozotocin (STZ)-induced T2DM mouse model.</div></div><div><h3>Results</h3><div>Apt was found to enhance glucose uptake in insulin-resistant adipocytes through the PI3K/AKT signaling pathway and facilitate GLUT4 translocation. Furthermore, Apt was identified as a selective PPARγ agonist, binding directly to Ser342 of PPARγ and inhibiting phosphorylation at Ser273. Besides, Apt inhibited osteoclast differentiation <em>in vitro. In vivo</em>, Apt exhibited comparable glycemic control to rosiglitazone (Rosi) while protecting against bone loss in STZ-induced T2DM mice.</div></div><div><h3>Conclusions</h3><div>These findings suggest that Apt is a promising therapeutic candidate for T2DM treatment, selectively activating PPARγ to improve insulin sensitivity and prevent skeletal complications.</div></div>","PeriodicalId":20212,"journal":{"name":"Phytomedicine","volume":"145 ","pages":"Article 157003"},"PeriodicalIF":6.7000,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Selective PPARγ modulator alpinetin restores insulin sensitivity and protects from bone loss in type 2 diabetes\",\"authors\":\"Yaoyu Zhao , Hantao Yao , Yilin Liao , Bulin Jiang , Ting Li , Jingqiu Chen , Yue Sheng , Mengjie Yin , Wengwanyue Ye , Qi Yan , Yaoting Ji\",\"doi\":\"10.1016/j.phymed.2025.157003\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Background</h3><div>Type 2 diabetes mellitus (T2DM) poses a significant global health burden, with its escalating prevalence and related complications. Although peroxisome proliferator–activated receptor gamma (PPARγ) agonists such as thiazolidinediones effectively enhance insulin sensitivity, their use is limited by adverse effects, including bone loss. Recent research has focused on developing selective PPARγ modulators with improved safety profiles. Alpinetin (Apt), a naturally occurring flavonoid, has demonstrated anti-inflammation potential; however, its impact on insulin signaling and bone metabolism under diabetic conditions has yet to be investigated.</div></div><div><h3>Purpose</h3><div>This study aims to investigate whether Apt acts as a selective PPARγ modulator that can restore insulin sensitivity while preventing diabetes-associated bone deterioration.</div></div><div><h3>Methods</h3><div>Molecular docking and dynamics simulations assessed the interaction between Apt and PPARγ. The cellular thermal shift assay (CETSA) evaluated Apt’s binding affinity, and dual-luciferase reporter assays measured its activation of PPARγ. Single-cell RNA sequencing analysis, network pharmacology and RNA sequencing were used to explore Apt’s mechanisms in T2DM treatment. The insulin-sensitizing and bone-protecting effects of Apt were tested both <em>in vitro</em> and in a streptozotocin (STZ)-induced T2DM mouse model.</div></div><div><h3>Results</h3><div>Apt was found to enhance glucose uptake in insulin-resistant adipocytes through the PI3K/AKT signaling pathway and facilitate GLUT4 translocation. Furthermore, Apt was identified as a selective PPARγ agonist, binding directly to Ser342 of PPARγ and inhibiting phosphorylation at Ser273. Besides, Apt inhibited osteoclast differentiation <em>in vitro. In vivo</em>, Apt exhibited comparable glycemic control to rosiglitazone (Rosi) while protecting against bone loss in STZ-induced T2DM mice.</div></div><div><h3>Conclusions</h3><div>These findings suggest that Apt is a promising therapeutic candidate for T2DM treatment, selectively activating PPARγ to improve insulin sensitivity and prevent skeletal complications.</div></div>\",\"PeriodicalId\":20212,\"journal\":{\"name\":\"Phytomedicine\",\"volume\":\"145 \",\"pages\":\"Article 157003\"},\"PeriodicalIF\":6.7000,\"publicationDate\":\"2025-06-18\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Phytomedicine\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0944711325006427\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Phytomedicine","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0944711325006427","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}

引用次数: 0

摘要

背景2型糖尿病（T2DM）随着其不断上升的患病率和相关并发症，构成了重大的全球健康负担。虽然过氧化物酶体增殖物激活受体γ (PPARγ)激动剂如噻唑烷二酮类能有效提高胰岛素敏感性，但其使用受到包括骨质流失在内的副作用的限制。最近的研究重点是开发具有改进安全性的选择性PPARγ调节剂。Alpinetin （Apt）是一种天然存在的类黄酮，具有抗炎症的潜力；然而，其对糖尿病患者胰岛素信号传导和骨代谢的影响尚未被研究。本研究旨在探讨Apt是否作为一种选择性的PPARγ调节剂，在恢复胰岛素敏感性的同时预防糖尿病相关的骨退化。方法通过分子对接和动力学模拟评估Apt与PPARγ的相互作用。细胞热移测定（CETSA）评估了Apt的结合亲和力，双荧光素酶报告基因测定了其对PPARγ的激活。采用单细胞RNA测序、网络药理学、RNA测序等方法探讨Apt治疗2型糖尿病的作用机制。在体外及链脲佐菌素（STZ）诱导的T2DM小鼠模型中测试了Apt的胰岛素增敏和骨保护作用。结果发现apt通过PI3K/AKT信号通路增强胰岛素抵抗脂肪细胞的葡萄糖摄取，促进GLUT4易位。此外，Apt被鉴定为选择性PPARγ激动剂，直接结合PPARγ的Ser342并抑制Ser273的磷酸化。此外，Apt还能抑制体外破骨细胞的分化。在体内，Apt表现出与罗格列酮（Rosi）相当的血糖控制能力，同时防止stz诱导的T2DM小鼠骨质流失。结论Apt可选择性激活PPARγ，改善胰岛素敏感性，预防骨骼并发症。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Selective PPARγ modulator alpinetin restores insulin sensitivity and protects from bone loss in type 2 diabetes

查看原文本刊更多论文

Selective PPARγ modulator alpinetin restores insulin sensitivity and protects from bone loss in type 2 diabetes

Background

Type 2 diabetes mellitus (T2DM) poses a significant global health burden, with its escalating prevalence and related complications. Although peroxisome proliferator–activated receptor gamma (PPARγ) agonists such as thiazolidinediones effectively enhance insulin sensitivity, their use is limited by adverse effects, including bone loss. Recent research has focused on developing selective PPARγ modulators with improved safety profiles. Alpinetin (Apt), a naturally occurring flavonoid, has demonstrated anti-inflammation potential; however, its impact on insulin signaling and bone metabolism under diabetic conditions has yet to be investigated.

Purpose

This study aims to investigate whether Apt acts as a selective PPARγ modulator that can restore insulin sensitivity while preventing diabetes-associated bone deterioration.

Methods

Molecular docking and dynamics simulations assessed the interaction between Apt and PPARγ. The cellular thermal shift assay (CETSA) evaluated Apt’s binding affinity, and dual-luciferase reporter assays measured its activation of PPARγ. Single-cell RNA sequencing analysis, network pharmacology and RNA sequencing were used to explore Apt’s mechanisms in T2DM treatment. The insulin-sensitizing and bone-protecting effects of Apt were tested both in vitro and in a streptozotocin (STZ)-induced T2DM mouse model.

Results

Apt was found to enhance glucose uptake in insulin-resistant adipocytes through the PI3K/AKT signaling pathway and facilitate GLUT4 translocation. Furthermore, Apt was identified as a selective PPARγ agonist, binding directly to Ser342 of PPARγ and inhibiting phosphorylation at Ser273. Besides, Apt inhibited osteoclast differentiation in vitro. In vivo, Apt exhibited comparable glycemic control to rosiglitazone (Rosi) while protecting against bone loss in STZ-induced T2DM mice.

Conclusions

These findings suggest that Apt is a promising therapeutic candidate for T2DM treatment, selectively activating PPARγ to improve insulin sensitivity and prevent skeletal complications.

求助全文

通过发布文献求助，成功后即可免费获取论文全文。去求助

来源期刊

Phytomedicine 医学-药学

CiteScore

10.30

自引率

5.10%

发文量

670

审稿时长

91 days

期刊介绍： Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.