The involvement of non-canonical NF-kB pathway in the inflammatory response of macrophages and its effect on insulin signaling in hepatocytes

Author(s)

Fernanda Oliveira Borges

• Document type: Master's Dissertation
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Aplicadas
• Defense date: 2016-07-15

Examining board members

Adriana Souza Torsoni; Hosana Gomes Rodrigues; Patricia da Silva Melo

• Advisor: Adriana Souza Torsoni; Fernando Moreira Simabuco

Abstract

The obesity has acquired epidemic characteristics and the same numbers that indicate the increase in obesity also showed a significant increase in individuals with diabetes mellitus type 2. It is now known that both diseases exhibit a metabolic response characteristic, which leads to changes in intracellular signaling pathways and glucose homeostasis. High fat diet (HFD) consumption is responsible for the increased fat mass leading to an increased production of pro-inflammatory cytokines. Several studies indicate the involvement of macrophages in this process. The non-canonical NF-?B pathway contributes to the pro-inflammatory signaling activation, and may represent a key metabolic pathway in response to obesity, especially in insulin resistance. Our aim was to evaluate if the nutritional overload trigger macrophage polarization in metabolic tissues, resulting in an increase in the gene expression of proinflammatory cytokines, inducing not only the inflammatory condition, but the resistance to the insulin signal in hepatocytes. Mouse macrophage cell line (RAW 264.7) were treated with NIK siRNA, and challenged with palmitate. Macrophage-conditioned medium was used to treat hepatocytes (Hepa1c1c7). Our results showed that palmitate was able to induce an inflammatory response in macrophages leading to insulin resistance in hepatocytes, through NIK activation by TRAF-3 degradation in immune cells. NIK knockdown in macrophages reduced the pro-inflammatory profile induced by palmitate treatment, and ameliorated insulin resistance in hepatocytes treated with macrophage-conditioned medium. Therefore, the present study suggests the communication between hepatocytes and macrophages in the liver on development of insulin resistance through non-canonical NF-kB pathway (AU)

• FAPESP's process: 13/23072-7 - The involvement of non-canonical NFºB pathway in the inflammatory response of monocytes and their effect on insulin signaling in hepatocytes
• Grantee: Fernanda Oliveira Borges
• Support Opportunities: Scholarships in Brazil - Master