Role of SET7 methyltransferase in obesity-induced metabolic and cardiovascular alterations in females.

Author(s)

Juliane Braga Miranda

• Document type: Master's Dissertation
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI)
• Defense date: 2022-02-16

Examining board members

Gabriela Placoná Diniz; José Cesar Rosa Neto; Ivson Bezerra da Silva; Silvana Auxiliadora Bordin da Silva

• Advisor: Gabriela Placoná Diniz; José Donato Júnior

Abstract

Obesity has growing in an alarming way in the world and along with it the incidence of several comorbidities, such as metabolic and cardiovascular diseases. The epigenetic mechanisms, which are able to regulate gene expression, have been studied in the context of various diseases, including in obesity. SET7 is a methyltransferase that can alter several histone and non-histone proteins, including proteins already described in obesity-related complications. Despite this, the role of this enzyme in metabolic and cardiovascular changes triggered by obesity remains unclear. In this sense, the aim of this study was to evaluate the role of SET7 in metabolic and cardiovascular changes induced by obesity in females. To address this question, we used wild-type or knockout female mice with total SET7 deletion, which were induced to obesity through a hypercaloric diet for 13 or 20 weeks. We also used 3T3-L1 cells treated with a specific SET7 inhibitor [(R)-PFI] to assess the role of SET7 in adipocyte differentiation in vitro. In addition to the in vivo and in vitro models, we evaluated in an ex vivo model the role of SET7 in cardiac function before and after ischemia and reperfusion using the Langendorff system. The results showed that SET7 protein expression is increased in the heart and adipose tissue of obese females, but not in obese males. We also showed that the global deletion of SET7 does not alter the weight gain and adiposity induced by hypercaloric diet in females, but it is able to prevent glucose intolerance. In vitro experiments showed that the inhibition of SET7 in 3T3-L1 cells induced to differentiate into adipocytes did not alter the lipid content or the expression of adipogenesis markers evaluated by Western Blot. In the cardiovascular context, the SET7 deletion did not alter the cardiac hypertrophy induced by hypercaloric diet, nor the basal cardiac function in females. However, the loss of SET7 prevented the impairment of cardiac function in females fed a hypercaloric diet after ischemia and reperfusion. Taken together, our results suggest that SET7 influences glucose intolerance induced by hypercaloric diet, as well as cardiac function after ischemia and reperfusion. (AU)

• FAPESP's process: 18/25814-4 - Analysis of the role of lysine methyltransferase SETD7 in metabolic and cardiovascular changes induced by obesity in females
• Grantee: Juliane Braga Miranda
• Support Opportunities: Scholarships in Brazil - Master