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. 2025 Mar 19:16:1565030.
doi: 10.3389/fphar.2025.1565030. eCollection 2025.

Transdermal administration of herbal essential oil alleviates high-fat diet-induced obesity by regulating metabolism and gut microbiota

Zu-Wen Ye  1 , Qi-Yue Yang  2 , Dong-Hua Yang  3 , Qiao-Hong Lin  1 , Xiao-Xia Liu  1 , Feng-Qin Li  1 , Fang-Fang Yan  2 , Ping Luo  1 , Si Qin  4 , Fang Wang  1
Affiliations

Transdermal administration of herbal essential oil alleviates high-fat diet-induced obesity by regulating metabolism and gut microbiota

Zu-Wen Ye et al. Front Pharmacol. .

Abstract

Introduction: Obesity, a global health challenge, is characterized by excessive fat accumulation and associated metabolic disorders. The ZhiZhu decoction, a traditional Chinese herbal formula consisting of Citrus aurantium L. (ZS, ZhiShi in Chinese) and Atractylodes macrocephala Koidz (BZ, Baizhu in Chinese), is widely recognized in clinics for its gastrointestinal regulatory effects.

Methods: The chemical composition of ZS-BZ essential oil (ZBEO) was characterized using gas chromatography-mass spectrometry (GC-MS). Concurrently, we conducted in vitro investigations using HepG2 hepatoma cells to evaluate its anti-lipid deposition potential. To further elucidate the anti-obesity mechanisms, an in vivo model was established through high-fat diet (HFD)-induced obese rats, followed by transdermal ZBEO administration. Systemic analyses were performed integrating serum metabolomic profiling via UPLC-QTOF-MS and gut microbiota dynamics assessment through 16S rRNA gene sequencing.

Results: ZBEO, rich in atractylon, D-limonene, and γ-elemene and shown to reduce lipid accumulation. Transdermal ZBEO administration in obese rats led to significant weight loss and improved serum metabolic indexes related to the POMC/CART signaling pathway. Additionally, ZBEO altered gut microbiota, enhancing beneficial bacteria and affecting metabolic pathways linked to obesity.

Discussion: We discovered that ZBEO exerts a significant influence on obesity by modulating key biological processes, including glucose metabolism, lipid metabolism, and the composition of gut microbiota.

Keywords: essential oil; gut microbiota; inflammation; lipid mechanism; obesity.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Figures

FIGURE 1
FIGURE 1
The composition and biological activity assessment of ZBEO. (A) GC-MS profile of ZBEO; (B) Structures of D-limonene, atractylon, and γ-elemene. (C) Lipid deposition in HepG2 cells analyzed by Oil Red O staining (scale bar = 40 μm). (D) The content of total lipid. (E) The content of TC. (F) The content of TG. Statistical analysis was performed using ANOVA and Student’s t test. ***P < 0.001 represented statistical significance. Data were expressed as the mean ± SD, n = 6. C: normal control group; M: model group, ZBEO: Citrus aurantium L.-Atractylodes macrocephala Koidz essential oil.
FIGURE 2
FIGURE 2
Effects of ZBEO on body weight and glucose and lipid metabolism in HFD-fed rats. (A) Body weights change (n = 8). (B) Food intake change (n = 8). (C) Histopathological analysis of metabolic tissues in HFD-induced obese rats. Top panel: Representative H&E-stained sections of white adipose tissue and brown adipose tissue (Scale bar = 100μm). Bottom panel: Oil Red O-stained liver sections (Scale bar = 100 μm). (D) Percentage of white adipose tissue adipocytes >80 microns in diameter (n = 3). (E) Percentage of brown adipose tissue adipocytes >20 microns in diameter (n = 3). (F) Percentage of area of liver tissue fat (n = 3). Statistical analysis was performed using ANOVA and Student’s t test. *P < 0.05, **P < 0.01, and ***P < 0.001 represented different statistical significances. Data were expressed as the mean ± SD. ZBEO: Citrus aurantium L.-Atractylodes macrocephala Koidz essential oil; C: normal control group; M: model group; P: orlistat group; L-ZBEO: 2.50% ZBEO dosage group; M-ZBEO: 5.00% ZBEO dosage group; H-ZBEO: 10.00% ZBEO dosage group.
FIGURE 3
FIGURE 3
Effects of ZBEO on the levels of serum inflammatory factors and adipocytokines in HFD-induced rats. (A) IL-17. (B) IL-6. (C) TNF-ɑ. (D) Adiponectin. (E) AQP7. (F) Visfatin. Statistical analysis was performed using ANOVA and Student’s t test. *P < 0.05, **P < 0.01, and ***P < 0.001 represented different statistical significances. Data were expressed as the mean ± SD, n = 8. ZBEO: Citrus aurantium L.-Atractylodes macrocephala Koidz essential oil; C: normal control group; M: model group; P: orlistat group; L-ZBEO: 2.50% ZBEO dosage group; M-ZBEO: 5.00% ZBEO dosage group; H-ZBEO: 10.00% ZBEO dosage group.
FIGURE 4
FIGURE 4
Effects of ZBEO on appetite-related gastrointestinal hormones in HFD-fed rats. (A) The content of GLP-1 in serum (n = 6). (B) The content of CCK in serum (n = 6). (C) The content of leptin in serum (n = 6). (D) The content of ghrelin in serum (n = 6). (E) The content of orexin A in serum (n = 6). (F) The mRNA level of AMPK-α, POMC and NPY in the hypothalamus (n = 5). (G) The level of AMPK-α, POMC, NPY, CART proteins, and β-actin content was used as the loading control in the hypothalamus (n = 3). (H) Quantification of AMPK-α, POMC, NPY and CART protein expression levels in the hypothalamus (G) (n = 3). Statistical analysis was performed using ANOVA and Student’s t test. *P < 0.05, **P < 0.01, and ***P < 0.001 represented different statistical significance. Data were expressed as the mean ± SD. ZBEO: Citrus aurantium L.-Atractylodes macrocephala Koidz essential oil; C: normal control group; M: model group; P: orlistat group; L-ZBEO: 2.50% ZBEO dosage group; M-ZBEO: 5.00% ZBEO dosage group; H-ZBEO: 10.00% ZBEO dosage group.
FIGURE 5
FIGURE 5
Effects of ZBEO on serum metabolite profiles. (A) Volcanic map of differential metabolites (M vs. H-ZBEO) (OPLS-DA). (B) Bubble map of KEGG pathway analysis. ZBEO: Citrus aurantium L.-Atractylodes macrocephala Koidz essential oil; C: normal control group; M: model group; H-ZBEO: 10.00% ZBEO dosage group.
FIGURE 6
FIGURE 6
Effects of ZBEO on the gut flora in obese rats. (A) α-diversity analyses of intestinal flora measured by chao1 index. (B) α-diversity analyses of intestinal flora measured by Shannon index. (C) β-diversity analyses of the composition of bacterial communities. (D, E) Abundance of intestinal flora at the phylum and genus levels; (F) Evolutionary branch diagram. (G) LDA value distribution histogram, with taxa meeting LDA score threshold >4 being listed. ZBEO: Citrus aurantium L.-Atractylodes macrocephala Koidz essential oil; C: normal control group; M: model group; P: orlistat group; H: 10.00% ZBEO dosage group.
FIGURE 7
FIGURE 7
Correlation analysis between gut microbiota and serum biomarkers. (A) RDA correlation analysis between environmental factors and gut microbial genus level. (B) Heatmap of RDA correlation analysis between serum metabolites and gut microbiota at the genus level.
FIGURE 8
FIGURE 8
Schema showing the mechanism by which ZBEO exerts its anti-obesity effects. ZBEO: Citrus aurantium L.-Atractylodes macrocephala Koidz essential oil.
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