Tirzepatida demonstra benefícios no remodelamento do tecido adiposo marrom em camundongos ovariectomizados obesos e diabéticos

Abstract

This study investigated the effects of tirzepatide (TZP) on interscapular brown adipose tissue (BAT) thermogenesis in an obese/diabetic (Od) and ovariectomy-induced menopause (O) mouse model. Eighty-three-month-old female C57BL/6 mice were divided into two main groups: bilateral ovariectomy (O, n=40) and sham (n=40). Each group was subdivided and fed for 12 weeks with a control diet (C) or a high-fat, high-sucrose diet (HFHS) to induce obesity and diabetes (Od) (n=20/group). After the induction period, the animals were treated daily with TZP (T) (10 nmol/kg) for four weeks, forming eight experimental groups: C, CT, CO, COT, Od, OdT, OdO, OdOT (n=10/group). At week 16, the Od and OdO groups showed higher body mass than their controls and a significant reduction in body temperature compared to their respective controls, while TZP treatment reduced body mass and significantly increased temperature in the OdT and OdOT groups. Histological analysis of the interscapular BAT showed signs of whitening in the Od and OdO groups, including a reduction in multiloculated brown adipocytes and an increase in adipocytes with characteristics of white adipocytes. These changes were reversed in the TZP-treated groups. The immunostaining and protein expression of UCP1 and B3AR, reduced in the Od and OdO groups, showed a significant increase after TZP treatment. At the gene level, the Od groups demonstrated greater expression of ER-associated genes, while the TZP-treated groups exhibited an increase in the levels of thermogenic genes and batokines. Principal Component Analysis (PCA) highlighted the distinction of the groups, clustering Od and OdO on an axis opposite to that of the TZP-treated groups. In conclusion, TZP induces improved thermogenesis, increased body temperature, and reduced ER stress in BAT, demonstrating efficacy in the context of obesity, diabetes, and menopause.