Supplementation with GPR120 (Ffar4) ligand omega-3 does not improve survival in murine sepsis models.

IF 3.1 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM
Susana Castelo Branco Ramos Nakandakari, Eric Isaac Elliott, Renan Fudoli Lins Vieira, Thaiane da Silva Rios, Andin Fosam, Isadora Carolina Betim Pavan, Maíra Maftoum Costa, Luiz Guilherme Salvino da Silva, Camila de Oliveira Ramos, Giovana Rios Gonçalves, Ngozi D Akingbesote, Davi Sidarta-Oliveira, Ana Paula Moreli, Renata Rosseto Braga, Ana Paula Pinto, Anna Eisenstein, Licio Augusto Velloso, Fernando Moreira Simabuco, José Rodrigo Pauli, Eduardo Rochete Ropelle, Adelino Sanchez Ramos da Silva, Andrew Wang, Rachel J Perry, Dennys Esper Cintra
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引用次数: 0

Abstract

Sepsis is a condition marked by physiologic dysregulation secondary to infection and is influenced by the nutritional state. Despite several preclinical studies and clinical trials examining nutrition and supplements in sepsis, there are no clear guidelines. Omega-3 fatty acids are poly-unsaturated fatty acids with anti-inflammatory properties, represented mainly by alpha-linolenic (ALA - C18:3), eicosapentaenoic (EPA - C20:5), and docosahexaenoic (DHA - C22:6). Since sepsis is characterized with high levels of inflammation and subsequent organ dysfunction, we hypothesised that omega-3 ingestion would improve sepsis survival by attenuating inflammation via activation of GPR120 in immune cells. Here, we aimed to experimentally explore the role of omega-3 and the receptor that mediates their anti-inflammatory functions, GPR120, during sepsis. To evaluate GPR120 functionality, acute inflammation was induced via lipopolysaccharide (LPS) treatment in Raw 264.7 cells, 3T3-L1 cells, bone marrow derived macrophages and primary adipocytes. To evaluate the impact of omega-3 in sepsis, C57BL/6J mice were supplemented with omega-3 before LPS administration or cecal ligation and puncture (CLP) surgery. GPR120 mRNA expression decreased during inflammation. Unexpectedly, omega-3 supplementation preceding CLP worsened sepsis survival in mice. In addition, omega-3 did not affect inflammatory markers such as TNFα, IL1}, IL10, and IL6. Overall, our findings that omega-3 do not influence inflammation or improve survival in sepsis are surprising given that omega-3 supplementation is recommended for the prevention of cardiovascular diseases due to its anti-inflammatory properties. The negative impact of omega-3 supplementation on survival in the CLP model raises caution for future clinical studies involving sepsis.

补充GPR120 (Ffar4)配体omega-3并不能提高小鼠脓毒症模型的存活率。
脓毒症是一种以继发于感染的生理失调为特征的疾病,受营养状况的影响。尽管有一些临床前研究和临床试验检查了败血症的营养和补充剂,但没有明确的指导方针。Omega-3脂肪酸是具有抗炎作用的多不饱和脂肪酸,主要有α -亚麻酸(ALA - C18:3)、二十碳五烯酸(EPA - C20:5)和二十二碳六烯酸(DHA - C22:6)。由于脓毒症的特点是高水平的炎症和随后的器官功能障碍,我们假设摄入omega-3可以通过激活免疫细胞中的GPR120来减轻炎症,从而提高脓毒症的生存率。在这里,我们旨在通过实验探索ω -3和介导其抗炎功能的受体GPR120在败血症中的作用。为了评估GPR120的功能,在Raw 264.7细胞、3T3-L1细胞、骨髓源性巨噬细胞和原代脂肪细胞中,通过脂多糖(LPS)处理诱导急性炎症。为了评估omega-3对脓毒症的影响,C57BL/6J小鼠在LPS给药或盲肠结扎穿刺(CLP)手术前补充omega-3。炎症过程中GPR120 mRNA表达降低。出乎意料的是,在CLP之前补充omega-3会恶化小鼠的败血症存活率。此外,omega-3不影响炎症标志物,如TNFα、IL1、IL10和IL6。总的来说,考虑到omega-3补充剂因其抗炎特性而被推荐用于预防心血管疾病,我们发现omega-3不会影响炎症或提高败血症患者的生存率,这令人惊讶。在CLP模型中,补充omega-3对生存的负面影响引起了对未来涉及败血症的临床研究的谨慎。
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来源期刊
CiteScore
9.80
自引率
0.00%
发文量
98
审稿时长
1 months
期刊介绍: The American Journal of Physiology-Endocrinology and Metabolism publishes original, mechanistic studies on the physiology of endocrine and metabolic systems. Physiological, cellular, and molecular studies in whole animals or humans will be considered. Specific themes include, but are not limited to, mechanisms of hormone and growth factor action; hormonal and nutritional regulation of metabolism, inflammation, microbiome and energy balance; integrative organ cross talk; paracrine and autocrine control of endocrine cells; function and activation of hormone receptors; endocrine or metabolic control of channels, transporters, and membrane function; temporal analysis of hormone secretion and metabolism; and mathematical/kinetic modeling of metabolism. Novel molecular, immunological, or biophysical studies of hormone action are also welcome.
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