Agonista duo PPAR alfa/gama: plasticidade e longevidade das ilhotas pancreáticas num modelo experimental de obesidade

Abstract

The pancreas is an essential organ for metabolic regulation but is also highly vulnerable to lipotoxicity, a condition associated with excess fat and common in obesity states. This lipotoxicity compromises the structure and function of pancreatic islets, impacting insulin secretion and worsening glycemic imbalance. Therapeutic strategies that preserve beta-cell functionality and restore metabolic homeostasis are essential to prevent or manage type 2 diabetes mellitus (T2DM). In this context, activation of peroxisome proliferator-activated receptors (PPAR)a/g, known for their role in regulating lipid metabolism and inflammation, has emerged as a promising approach. This study investigated the effects of isolated and combined activation of PPARa and PPARg receptors on pancreatic islet remodeling, beta-cell proliferation, identity, and maintenance in a diet-induced obesity experimental model. Mice were fed a high-fat diet (HF) for ten weeks, followed by four weeks of treatment with PPARa, PPARg, or dual PPARa/g receptor agonists. The HF-fed animals exhibited glucose intolerance, a pro-inflammatory adipokine profile, increased beta- and alpha-cell mass, and gene expression indicative of beta-cell dedifferentiation and impaired proliferation. The results showed that all PPAR agonist treatments alleviated glucose intolerance, reduced body weight, and promoted an anti-inflammatory profile. However, the group treated with the combined PPARa/g agonist exhibited the greatest efficacy in restoring islet cytoarchitecture and positively regulating beta-cell identity and maintenance genes, such as Pdx1, Mafa, and Nkx6.1. These findings suggest that combined PPARa/g activation can interrupt the spectrum of metabolic complications associated with obesity, preserving beta-cell functionality and offering therapeutic potential for T2DM treatment.