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Targeting FFA1 and FFA4 receptors in cancer-induced cachexia.
American Journal of Physiology-Endocrinology and Metabolism ( IF 5.1 ) Pub Date : 2020-09-07 , DOI: 10.1152/ajpendo.00509.2019
Raquel D S Freitas 1, 2 , Thaís C Muradás 1, 2 , Ana Paula A Dagnino 1, 2 , Fernanda L Rost 2 , Kesiane M Costa 1 , Gianina T Venturin 3 , Samuel Greggio 3 , Jaderson C da Costa 1, 3 , Maria M Campos 1, 2, 4
Affiliation  

Free fatty acid (FFA) receptors FFA1 and FFA4 are omega-3 molecular targets in metabolic diseases; however, their function in cancer cachexia remains unraveled. We assessed the role of FFA1 and FFA4 receptors in the mouse model of cachexia induced by Lewis lung carcinoma (LLC) cell implantation. Naturally-occurring ligands α-linolenic acid (ALA) and docosahexaenoic acid (DHA), the synthetic FFA1/FFA4 agonists GW9508 and TUG891, or the selective FFA1 GW1100 or FFA4 AH7614 antagonists were tested. FFA1 and FFA4 expression and other cachexia-related parameters were evaluated. GW9508 and TUG891 decreased tumor weight in LLC-bearing mice. Regarding cachexia-related endpoints, ALA, DHA, and the preferential FFA1 agonist GW9508 rescued body weight loss. Skeletal muscle mass was reestablished by ALA treatment, but this was not reflected in the fiber cross-sectional areas (CSA) measurement. Otherwise, TUG891, GW1100, or AH7614 reduced the muscle fiber CSA. Treatments with ALA, GW9508, GW1100, or AH7614 restored WAT depletion. As for inflammatory outcomes, ALA improved anemia, while GW9508 reduced splenomegaly. Concerning behavioral impairments, ALA and GW9508 rescued locomotor activity, while ALA improved motor coordination. Additionally, DHA improved grip strength. Notably, GW9508 restored abnormal brain glucose metabolism in different brain regions. The GW9508 treatment increased leptin levels, without altering UCP-1 downregulation in visceral fat. LLC-cachectic mice displayed FFA1 upregulation in subcutaneous fat, but not in visceral fat or gastrocnemius muscle, while FFA4 was unaltered. Overall, the present study shed new light on FFA1 and FFA4 receptors' role in metabolic disorders, indicating FFA1 receptor agonism as a promising strategy in mitigating cancer cachexia.

中文翻译:

在癌症引起的恶病质中靶向FFA1和FFA4受体。

游离脂肪酸(FFA)受体FFA1和FFA4是代谢疾病中的omega-3分子靶标;然而,它们在癌症恶病质中的功能尚未阐明。我们评估了FFA1和FFA4受体在刘易斯肺癌(LLC)细胞植入诱导的恶病质小鼠模型中的作用。测试了天然存在的配体α-亚麻酸(ALA)和二十二碳六烯酸(DHA),合成FFA1 / FFA4激动剂GW9508和TUG891或选择性FFA1 GW1100或FFA4 AH7614拮抗剂。评估了FFA1和FFA4表达以及其他恶病质相关参数。GW9508和TUG891降低了LLC小鼠的肿瘤重量。关于恶病质相关的终点,ALA,DHA和优先的FFA1激动剂GW9508挽救了体重。通过ALA治疗重建骨骼肌质量,但这并未反映在纤维横截面积(CSA)的测量中。否则,TUG891,GW1100或AH7614会减少肌纤维CSA。用ALA,GW9508,GW1100或AH7614处理可恢复WAT消耗。至于炎症结果,ALA改善了贫血,而GW9508减少了脾肿大。关于行为障碍,ALA和GW9508挽救了运动活动,而ALA改善了运动协调能力。此外,DHA改善了握力。值得注意的是,GW9508在不同的大脑区域恢复了异常的大脑葡萄糖代谢。GW9508处理可增加瘦素水平,而不会改变内脏脂肪中UCP-1的下调。LLC恶病质小鼠在皮下脂肪中显示FFA1上调,但在内脏脂肪或腓肠肌中则未显示,而FFA4不变。总体,
更新日期:2020-09-08
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