2. Academic Validation
  3. Perillyl alcohol ameliorates high-fat diet-induced obesity in mice by modulating gut microbiota and activating IRF4-mediated brown fat thermogenesis

Perillyl alcohol ameliorates high-fat diet-induced obesity in mice by modulating gut microbiota and activating IRF4-mediated brown fat thermogenesis

  • Phytomedicine. 2025 Oct 11:148:157400. doi: 10.1016/j.phymed.2025.157400.
Shasha Chen 1,  Songning Chen 1,  Wenwen Li 1,  Mengyao Wang 1,  Ruru Pan 2,  Yajun Duan 2,  Chenzhong Liao 3,  Shuang Zhang 4
Affiliations

Affiliations

  • 1 College of Food and Biological Engineering, Hefei University of Technology, Hefei 230601, China.
  • 2 Department of Cardiology, The First Affiliated Hospital of University of Science and Technology of China, Hefei 230001, China.
  • 3 College of Food and Biological Engineering, Hefei University of Technology, Hefei 230601, China. Electronic address: czliao@hfut.edu.cn.
  • 4 College of Food and Biological Engineering, Hefei University of Technology, Hefei 230601, China. Electronic address: zhangshuang@hfut.edu.cn.
PMID: 41138577 DOI: 10.1016/j.phymed.2025.157400
Abstract

Background: 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.

Purpose: This study aimed to evaluate the potential of POH on metabolic dysfunction in high-fat diet (HFD)-induced obese mice.

Study design and methods: 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.

Results: 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.

Conclusions: 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.

Keywords

BAT thermogenesis; Gut microbiota; IRF4; Obesity; Perillyl alcohol.

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