Central and peripheral actions of GLP-1, GIP, and glucagon in the subclinical inflammatory process: immunometabolic contribution

• Grant number: 24/22614-5
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: March 01, 2025
• End date: September 30, 2026
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Mario Jose Abdalla Saad
• Grantee: Sónia Maria Norberto Alves
• Host Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 14/50907-5 - INCT 2014 - of obesity and diabetes, AP.TEM

Abstract

Obesity is characterized by chronic low-grade inflammation that increases the release of inflammatory mediators, impairing insulin signaling and potentially triggering insulin resistance (IR). Due to the inability to produce insulin in the pancreas or the inefficiency in effective insulin use to control hyperglycemia, IR can progress to Type 2 Diabetes Mellitus (DMT2). The prevalence of obesity has been rising exponentially, making it the primary risk factor for DMT2 development as well as other comorbidities such as cardiovascular diseases, non-alcoholic fatty liver disease, dyslipidemia, cancer, and other adverse pathological conditions. Therefore, there is a growing need for optimizing and developing drugs capable of combating the obesity and DMT2 pandemic. The development of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dual agonists for glucose-dependent insulinotropic polypeptide (GIPR)/GLP-1R has shown beneficial results in treating DMT2 and obesity. In addition to the involvement of incretin receptor agonists, and with superior therapeutic potential for DMT2/obesity treatment, the addition of glucagon receptor (GcGR) agonists is being developed to create a triple receptor agonist for GLP-1R/GIPR/GcGR (still in clinical trials). GLP-1RAs exhibit anti-inflammatory effects relevant to chronic complications of DMT2/obesity. Although GLP-1RAs reduce T-cell-mediated intestinal and systemic inflammation via the GLP-1R receptor in intestinal lymphocytes, it is still unknown how they inhibit systemic inflammation without broad GLP-1R expression in the immune system. Recent studies demonstrated that GLP-1R activation attenuates the induction of plasma tumor necrosis factor-alpha (TNF¿) by multiple Toll-like receptor (TLR) agonists, requiring actions at the level of central neuronal GLP-1Rs rather than hematopoietic or endothelial GLP-1Rs [1]. Additionally, the same group demonstrated through a cecal suspension-induced polymicrobial sepsis model that the adverse responses associated with sepsis (malaise, hypothermia, systemic inflammation, and lung injury) also require central GLP-1Rs for GLP-1RAs to mitigate these responses [1]. However, the anti-inflammatory actions of GLP-1RAs have been demonstrated primarily in acute inflammation models, and it remains unclear whether these effects are replicated in chronic inflammation models. Additionally, understanding how gut dysbiosis can be modulated in the context of low-grade chronic inflammation to strengthen the connection between gut microbiota, bacterial and host metabolites, and immune interactions requires further investigation into the underlying mechanisms. Thus, our project proposal aims to investigate the effects of GLP-1, GIP, and glucagon hormones on subclinical inflammatory processes in adipose, vascular, hepatic, intestinal, muscular, and hypothalamic tissues, as well as on the regulation of gut microbiota, using animal models of diet-induced obesity (DIO) with a high-fat diet (HFD). The effects of these hormones will be studied at both central and peripheral levels, either individually (GLP-1 - Semaglutide) or in combination (GLP-1 + GIP - Tirzepatide or GLP-1 + GIP + GcG - Retatrutide), following acute (3 days) and chronic (4 weeks) administration.