Chen Shasha, Chen Songning, Li Wenwen, Wang Mengyao, Pan Ruru, Duan Yajun, Liao Chenzhong, Zhang Shuang
College of Food and Biological Engineering, Hefei University of Technology, Hefei 230601, China.
Department of Cardiology, The First Affiliated Hospital of University of Science and Technology of China, Hefei 230001, China.
Phytomedicine. 2025 Nov 25;148:157400. doi: 10.1016/j.phymed.2025.157400. Epub 2025 Oct 11.
An imbalance between energy intake and output underlies obesity, which is commonly associated with dysregulated lipid metabolism, insulin resistance, and chronic inflammation. Perillyl alcohol (POH) is a plant-derived monoterpene present in species such as cherry, cranberry, and mint. Although it is known for its anti-inflammatory, antioxidant, and potential anti-cancer properties, its impact on obesity and metabolic diseases remains poorly understood.
This study aimed to evaluate the potential of POH on metabolic dysfunction in high-fat diet (HFD)-induced obese mice.
Male C57BL/6 J mice were fed an HFD and treated with POH. Metabolic phenotypes were assessed by measuring body weight, serum lipid levels, insulin sensitivity, liver histology, and gut barrier integrity. The composition of gut microbiota was analyzed using 16S rRNA sequencing. Targeted metabolomics based on UPLC-MS/MS was employed to quantify fecal short-chain fatty acids (SCFAs). Thermogenic capacity of brown adipose tissue (BAT) was assessed through cold exposure, immunohistochemistry, and mitochondrial functional assays. RNA sequencing and loss-of-function experiments were performed to identify molecular targets involved in POH's action.
POH treatment significantly reduced weight gain, improved lipid profiles, enhanced insulin sensitivity, and alleviated hepatic steatosis and gut barrier disruption in HFD-fed mice. These metabolic improvements were accompanied by notable alterations in gut microbiota composition, including enrichment of Ligilactobacillus murinus, a species linked to gut barrier protection and energy regulation. POH significantly increased levels of key SCFAs, especially acetate and lactic acid, which are known to influence lipid metabolism and thermogenesis. Consistently, POH enhanced thermogenic capacity and mitochondrial content in BAT upon cold exposure. Mechanistically, transcriptomic analysis and functional experiments identified IRF4 as a central regulator mediating POH-induced activation of the PGC1α-UCP1 pathway and mitochondrial biogenesis in BAT, linking gut microbiota-derived metabolites to adipose tissue thermogenic function.
POH ameliorates obesity and associated metabolic dysfunction by modulating the gut-adipose axis, in part through activation of an IRF4-dependent thermogenic program in BAT. The integration of metabolomics highlights a potential link between SCFA-mediated microbial-host interactions and BAT thermogenic activation. Our study is the first to demonstrate that POH promotes BAT thermogenesis by modulating the IRF4-PGC1α-UCP1 signaling axis, and links this mechanism with gut microbiota alterations-proposing a novel "gut-adipose axis" regulatory pathway.
能量摄入与输出失衡是肥胖的根本原因，肥胖通常与脂质代谢失调、胰岛素抵抗和慢性炎症相关。紫苏醇（POH）是一种植物来源的单萜，存在于樱桃、蔓越莓和薄荷等植物中。尽管它以其抗炎、抗氧化和潜在的抗癌特性而闻名，但其对肥胖和代谢性疾病的影响仍知之甚少。
本研究旨在评估POH对高脂饮食（HFD）诱导的肥胖小鼠代谢功能障碍的潜在作用。
雄性C57BL/6 J小鼠喂食高脂饮食并接受POH治疗。通过测量体重、血清脂质水平、胰岛素敏感性、肝脏组织学和肠道屏障完整性来评估代谢表型。使用16S rRNA测序分析肠道微生物群的组成。基于超高效液相色谱-串联质谱（UPLC-MS/MS）的靶向代谢组学用于定量粪便短链脂肪酸（SCFA）。通过冷暴露、免疫组织化学和线粒体功能测定来评估棕色脂肪组织（BAT）的产热能力。进行RNA测序和功能丧失实验以鉴定参与POH作用的分子靶点。
POH治疗显著减轻了高脂饮食喂养小鼠的体重增加，改善了脂质谱，增强了胰岛素敏感性，并减轻了肝脂肪变性和肠道屏障破坏。这些代谢改善伴随着肠道微生物群组成的显著变化，包括鼠李糖乳杆菌的富集，该菌与肠道屏障保护和能量调节有关。POH显著提高了关键SCFA的水平，尤其是乙酸盐和乳酸，已知它们会影响脂质代谢和产热。一致地，冷暴露后POH增强了BAT的产热能力和线粒体含量。从机制上讲，转录组分析和功能实验确定IRF4是介导POH诱导的BAT中PGC1α-UCP1途径激活和线粒体生物发生的核心调节因子，将肠道微生物群衍生的代谢物与脂肪组织产热功能联系起来。
POH通过调节肠道-脂肪轴改善肥胖和相关的代谢功能障碍，部分是通过激活BAT中依赖IRF4的产热程序。代谢组学的整合突出了SCFA介导的微生物-宿主相互作用与BAT产热激活之间的潜在联系。我们的研究首次证明POH通过调节IRF4-PGC1α-UCP1信号轴促进BAT产热，并将这一机制与肠道微生物群改变联系起来——提出了一种新的“肠道-脂肪轴”调节途径。
