Zhao Yaoyu, Yao Hantao, Liao Yilin, Jiang Bulin, Li Ting, Chen Jingqiu, Sheng Yue, Yin Mengjie, Ye Wengwanyue, Yan Qi, Ji Yaoting
State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, PR China.
State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, PR China; Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou 310000, PR China.
Phytomedicine. 2025 Sep;145:157003. doi: 10.1016/j.phymed.2025.157003. Epub 2025 Jun 18.
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.
This study aims to investigate whether Apt acts as a selective PPARγ modulator that can restore insulin sensitivity while preventing diabetes-associated bone deterioration.
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.
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.
These findings suggest that Apt is a promising therapeutic candidate for T2DM treatment, selectively activating PPARγ to improve insulin sensitivity and prevent skeletal complications.
2型糖尿病（T2DM）给全球健康带来了重大负担，其患病率不断上升且伴有相关并发症。尽管噻唑烷二酮类等过氧化物酶体增殖物激活受体γ（PPARγ）激动剂能有效增强胰岛素敏感性，但其使用受到包括骨质流失在内的不良反应的限制。最近的研究集中在开发具有更好安全性的选择性PPARγ调节剂。高山黄芩素（Apt）是一种天然存在的黄酮类化合物，已显示出抗炎潜力；然而，其在糖尿病条件下对胰岛素信号传导和骨代谢的影响尚未得到研究。
本研究旨在探讨Apt是否作为一种选择性PPARγ调节剂，能够恢复胰岛素敏感性，同时预防糖尿病相关的骨质恶化。
通过分子对接和动力学模拟评估Apt与PPARγ之间的相互作用。细胞热位移分析（CETSA）评估Apt的结合亲和力，双荧光素酶报告基因分析测量其对PPARγ的激活作用。采用单细胞RNA测序分析、网络药理学和RNA测序来探索Apt在T2DM治疗中的作用机制。在体外和链脲佐菌素（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。
发现Apt通过PI3K/AKT信号通路增强胰岛素抵抗脂肪细胞对葡萄糖的摄取，并促进GLUT4易位。此外，Apt被鉴定为一种选择性PPARγ激动剂，直接与PPARγ的Ser342结合并抑制Ser273处的磷酸化。此外，Apt在体外抑制破骨细胞分化。在体内，Apt在STZ诱导的T2DM小鼠中表现出与罗格列酮（Rosi）相当的血糖控制效果，同时预防骨质流失。
这些发现表明，Apt是一种有前途的T2DM治疗候选药物，可选择性激活PPARγ以改善胰岛素敏感性并预防骨骼并发症。
