Effect of oleoil-12-hydroxystearic acid (12-OAHSA) in the activation of macrophages

Author(s)

Ana Campos Codo

• Document type: Master's Dissertation
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia
• Defense date: 2021-03-18

Examining board members

Pedro Manoel Mendes de Moraes Vieira; Alexandre Salgado Basso; Fabio Papes

• Advisor: Pedro Manoel Mendes de Moraes Vieira

Abstract

In obesity, with the expansion of white adipose tissue, occurs increased migration and infiltration of leukocytes. In this environment, macrophages acquire a classic pro-inflammatory phenotype and produce inflammatory cytokines (such as TNF-? and IL-1?), which lead adipose tissue inflammation and the subsequent systemic insulin resistance. In contrast, mice that overexpress the Glut4 glucose transporter in adipocytes have increased lipogenesis, are obese and have elevated circulating levels of fatty acids and high glucose tolerance. Glut4 overexpressing mice have increased levels of fatty acyl hydroxyl fatty acids (FAHFAs), a class of lipids recently described in mammals. Treatment with several types of FAHFAs reduces the inflammatory activation of macrophages and dendritic cells. However, the described FAHFAs have low potency, requiring high doses to promote their beneficial effects. In this context, we conducted a screening with several FAHFAs and found one never studied before, which has high capacity in inhibit LPS-induced TNF-? secretion at low doses: oleoyl-12-hydroxystearic acid (12-OAHSA). Our objective was to determine the in vivo effects of 12-OAHSA on obesity-induced adipose tissue inflammation and to characterize the immunoregulatory mechanism of action of this newly discovered FAHFA in macrophages. In vivo, 12-OAHSA improved glucose tolerance, insulin sensitivity and reduced adipose inflammation in obese mice. In vitro, 12-OAHSA induced the production of IL-10 and decreased the LPS-induced secretion of TNF-? and IL-1?. 12-OAHSA inhibited LPS-induced ERK 1/2 phosphorylation with apparently no changes in NF-kB activation. Using specific metabolic inhibitors, we determined that the effects of 12-OAHSA involve the oxidation of lipids, glutamine and pyruvate coupled to mitochondrial ATP synthesis, in addition to the inhibition glycolysis and release of lactate into extracellular medium. We found that the observed effects were shown to mTORC1-dependent, since 12-OAHSA treatment requires mCTORC1 activation for IL-10 expression and the subsequent anti-inflammatory effects of 12-OAHSA. In addition, we observed that 12-OAHSA enters the cell and localizes close to the plasma membrane, where it appears to induce the production of arachidonic acid. In conclusion, we have demonstrated 12-OAHSA has an IL-10 dependent anti-inflammatory activity both in vivo and in vitro (AU)

• FAPESP's process: 18/22505-0 - Effect of 12-oleic acid ester of hydroxy fatty acid (12-OAHSA) on inflammatory and metabolic pathways of macrophage activation
• Grantee: Ana Campos Codo
• Support Opportunities: Scholarships in Brazil - Master