Ellagic Acid Alleviates Abnormal Fat Reduction by Activating the RXRβ-PPARγ Path...

연구 요약

Ellagic Acid Alleviates Abnormal Fat Reduction by Activating the RXRβ-PPARγ Pathways in a CT26 Tumour-Induced Cachexia Mouse Model.

Journal of cachexia, sarcopenia and muscle 학술지에 발표된 이 연구는 Park WY, Kim B, Song G 외 연구팀이 수행하였습니다.

이 연구는 'Ellagic Acid Alleviates Abnormal Fat Reduction by Activating the RXRβ-PPARγ Pathways in a CT26 Tumour-Induced Cachexia Mouse Model.'에 대한 과학적 분석을 제공합니다.

핵심 내용

BACKGROUND: Cancer cachexia is a syndrome characterized by significant weight loss, particularly of adipose tissue, which negatively impacts patient survival. Pharmacological approaches to prevent this abnormal fat reduction remain poorly defined. This study investigated the potential of ellagic acid (EA) to mitigate cancer-induced fat loss. METHODS: In vitro, 3T3-L1 adipocytes were exposed to 50% conditioned medium (CM) from CT26 colon cancer cells to mimic cachectic conditions. The effects of EA on lipid accumulation and adipogenesis-related markers (PPARγ and RXRβ) were analysed. The mechanism was validated using molecular docking and siRNA-mediated gene silencing. In vivo, a cachexia mouse model was established by subcutaneous injection of CT26 cells into BALB/c mice. Mice were orally administered EA at dose of 10, 20 and 40 mg/kg, respectively (n = 7 per group) for 14 days to evaluate its protective effects. RESULTS: In 3T3-L1 cells, the 50% CM-treatment reduced lipid accumulation by 14% (p < 0.05) and downregulated PPARγ (p < 0.05) and RXRβ (p < 0.01) expression. The EA treatment restored diminished lipid levels and rescued downregulated the expression of PPARγ (p < 0.05) and RXRβ (p < 0.01). This pro-adipogenic effect was abolished by siRNA-mediated inhibition of RXRβ. In the cachexia mouse model, EA treatment significantly improved physical performance and body composition. Specifically, EA enhanced grip strength by 1.32-fold (10 mg/kg, p < 0.0001) and 1.24-fold (20 mg/kg, p < 0.001), increased the inguinal white adipose tissue (iWAT) mass by 59.8% (10 mg/kg, p < 0.01), and 56.1% (20 mg/kg, p < 0.05), and was accompanied by a significant increase in the tumour-free body weight of 6.4% (10 mg/kg, p < 0.05), and 5.6% (20 mg/kg, p < 0.01) compared to cachectic mice. EA treatment did not affect tumour growth. It increased the adipogenesis-related protein expression of C/EBPα (2.1-fold, p < 0.05), PPARγ (1.5-fold, p < 0.05) and SREBP1 (1.5-fold, p < 0.05) in the iWAT. The EA treatment enhanced the nuclear localization index of RXRβ in the iWAT by 0.51 (10 mg/kg, 1.9-fold, p < 0.05) and 0.46 (20 mg/kg, 1.7-fold, p < 0.05) compared to cachectic mice. CONCLUSIONS: EA mitigates cancer cachexia-induced fat loss by the activation of the RXRβ-PPARγ pathway. These findings present EA as a potential pharmacological agent to improve the abnormal fat reduction and muscle dysfunction associated with cachexia.

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