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Evaluation of the effect of leukotrienes and the renin angiotensin system in metabolically active tissues from mice with type 1 diabetes and obesity

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João Pedro Tôrres Guimarães
Total Authors: 1
Document type: Doctoral Thesis
Press: São Paulo.
Institution: Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI)
Defense date:
Examining board members:
Joilson de Oliveira Martins; Jose Alexandre Marzagao Barbuto; Ana Cristina Breithaupt Faloppa; Rosália Santos Amorim Jesuino
Advisor: Joilson de Oliveira Martins; Sonia Jancar Negro

Diabetes and obesity are chronic metabolic diseases that are associated with several physiological disorders. Some studies have shown common pathways linking these diseases to insulin resistance and the renin-angiotensin system (RAS), one of the main regulators of blood pressure. Angiotensinogen (Agt) is the main precursor of RAS, and its activation has pro-inflammatory effects, often linked to dysfunctions in cellular processes, such as autophagy. Deregulated autophagy is believed to be linked to diabetogenesis through the development of inflammation and insulin resistance. Leukotrienes (LTs), specifically leukotriene B4 (LTB4), play a central role in establishing insulin resistance. Thus, we intend to investigate: (1) the involvement of LTs in the insulin signaling pathway and in the inflammatory process in muscles of mice with type 1 diabetes (T1D); (2) the involvement of RAS and LTs in the muscle and liver of mice with T1D, in the autophagy and insulin pathways; and (3) the involvement of SARS in the muscle and liver of mice with T1D and obesity, in the autophagy and insulin pathways. T1D was chemically induced with streptozotocin (STZ), while obesity with a high-fat diet. To inhibit RAS, we treated the mice with captopril. We observed, in muscles of T1D mice knockouts for LTs (5LO-/-), that there was an increase in the expression of Arg1 and Ym1, in addition to the increased phosphorylation of AKT and increased expression of Insr. We also observed that in muscle of T1D mice, treatment with captopril increased the expression of Agt, At1, Insr, Irs1, Ampk, Beclin1, Atg5, Atg7, Atg12, Atg14 and LC3 in a similar pattern in the two mice strain. In liver of T1D Wt and 5LO-/- mice, the treatment with captopril increased the expression of Agt, At1, Insr, Irs1 and Ampk. Similarities were also observed in the liver and muscle of these mice, with similarities in the expression of autophagy markers independent of LTs. In obese mice, captopril did not increase At1 expression. However, in liver of obese mice, we found decreased gene expression of Insr, Irs1 and Ampk , regardless of treatment with captopril or overexpression of Agt. Analyzing the set of results, we conclude that LTs have a fundamental role in the development of insulin resistance in the muscle of mice with T1D. In addition, treatment with captopril recovered the gene expression of the main markers of the insulin signaling pathway, as well as those related to the functioning of the autophagy pathway in these tissues, both in T1D and in obesity, indicating a possible role of captopril in insulin sensitivity and activation of autophagy in these diseases. (AU)

FAPESP's process: 18/23266-0 - Mechanisms linking angiotensin to Obesity and Diabetes: role of inflammation and autophagy
Grantee:João Pedro Tôrres Guimarães
Support Opportunities: Scholarships in Brazil - Doctorate