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
{"title":"Supplementation with GPR120 (Ffar4) ligand omega-3 does not improve survival in murine sepsis models.","authors":"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","doi":"10.1152/ajpendo.00147.2025","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":7594,"journal":{"name":"American journal of physiology. Endocrinology and metabolism","volume":" ","pages":""},"PeriodicalIF":3.1000,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"American journal of physiology. Endocrinology and metabolism","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1152/ajpendo.00147.2025","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}
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.
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.