Efeitos de bloqueadores do receptor AT1 no adipócito e na ilhota pancreática: benefícios morfofuncionais em modelo murino de obesidade induzida por dieta

Abstract

The present study aimed to evaluate AT1 receptor blockers on the formation of beige adipocytes, adipocyte remodeling in subcutaneous white adipose tissue with a focus on the expression of thermogenic genes; and the effects of lonsartan (a pure BRA) and telmisartan (dual BRA, PPAR-gamma partial agonist), focusing on islet remodeling, glucose detection via the Akt-FOXO1 and PDX1 pathway in a diet-induced obesity model. C57BL/6 mice were fed a standard chow (C; 10 % lipids) or a high-fat diet (HF; 50 % lipids) for 10 weeks. Then, treatment started with Telmisartan (T) or Losartan (L), forming the following groups: C, C-L, C-T, HF, HF-L, and HF-T. Treatment lasted 5 weeks. Pair feeding (PF) groups were carried out with telmisartan treated groups (C-T/PF and HF-T/PF) to isolate the effects of the treatment. Biochemical, morphometrical, stereological and molecular approaches were used to evaluate the outcomes. Differences between groups were tested with one-way ANOVA and Holm-Sidak post-test. The HF diet elicited overweight, insulin resistance, hypertension, adipocyte hypertrophy, great alpha and beta-cell masses. Despite tackling the majority of the alterations, losartan did not reduce fasting glycaemia as telmisartan did. In the adipose tissue, HF-L group presented greatest energy expenditure among the groups along with the presence UCP1 positive multilocular adipocytes with enhanced PGC1-alpha and PRDM16 mRNA levels, indicating a significant potential for mitochondrial biogenesis and adaptive thermogenesis, besides the induction of beige adipocytes within the subcutaneous fat. Suitable insulin levels and preserved endocrine pâncreas structure are correlated to adequate AKT-FOXO1 pathway functioning in HF-L animals. Conversely, telmisartan yielded enhanced PDX1 and GLP-1 islet expression along with greater GLP-1 levels, with the consequent better islet glucose sensing and uptake. Greater islet vascularisation coupled with reduced apoptosis and macrophage infiltration seems to underlie the beneficial findings in both treatments. Our results show compelling evidence that losartan countered diet-induced obesity in mice by enhancing energy expenditure through beige adipocytes induction. Reduced body mass, increased insulin sensitivity, decreased adipocyte size and marked expression of UCP1 by ectopic multilocular adipocytes support these findings. The use of losartan as a coadjutant medicine to tackle obesity and its related disorders merits further investigation. Additional telmisartan effects include restoration of body mass, with no influence of energy intake, coupled with normal glycaemia. However, both ARBs yielded reduced apoptosis and islet preservation.