Effect of leukotrienes on lipic metabolism in type 1 diabetic mice

Abstract

Type 1 diabetes (T1D) is a metabolic disease related to persistence of low gradesystemic inflammation. Fat mass loss is one of the characteristics of T1D in patients andmice. Our group has shown that T1D mice have high systemic levels of leukotriene B4(LTB4) and this lipid mediator is involved in metabolic alterations as well in systemic andcellular inflammation in T1D animals. We reported that macrophage's reprogramming toclassically activated profile (M1) was significantly reduced in DT1 mice in which the enzymethat produces leukotrienes, 5-lipoxigenese, was depleted, even as in T1D mice whose highaffinity LBT4 receptor, BLT1, was antagonized. Our group also showed that the activation ofBLT1 in macrophages from T1D mice increases lipids uptake and increased mitochondrialrespiration, dependent on Uncoupling protein 1 (UCP1). This suggests that the metabolicalterations caused by LTB4 could contribute to fat loss observed in this model. The presentwork aims to investigate if the leukotrienes modify the lipid metabolism in system and inmonocytes and macrophages from T1D mice, and if these events contribute to fat loss,comorbidity frequently observed in DT1. For this, we will induce T1D by injectingstreptozotocin in WT and 5-LO -/- mice. Then body composition, energy expenditure andmeasurement of lipids and glycerol will be measured. We will also investigate the expressionof markers related to lipid uptake, lipolysis, thermogenesis and lipogenesis in peripheralmonocytes and resident peritoneal macrophages. In these cells, we will also analyze themitochondrial respiration activity profile. A better comprehension of the mechanismsinvolved in systemic and cellular metabolism in T1D can help not only in prevention ofcomorbidities as help to clarify common aspects of metabolic disorders in other inflammatorychronic diseases.