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Knockout mice for thimet oligopeptidase as a model for the study of Obesity and Obesity-associated diseases

Grant number: 19/27149-0
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): June 01, 2020
Effective date (End): November 30, 2021
Field of knowledge:Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
Principal Investigator:Emer Suavinho Ferro
Grantee:Mayara Calegaro Ferrari Gewehr
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:16/04000-3 - Pharmacology of oligopeptidases and intracellular peptides, AP.TEM


Obesity represents a major public health problem given its high prevalence and increased risk for the development of other diseases such as Heart Disease, Diabetes Mellitus, and various Cancers. The steady increase in the overweight and obese population creates opportunities for therapeutic innovation with the aim of improving their quality of life. In the present project, C57BL6 knockout mice for thimet oligopeptidase (THOP1-/-) will be investigated for resistance to Obesity and associated diseases. Wild C57BL6 (WT) and THOP1-/- will be fed a standard (SD) or hyperlipid (DH) diet for a period of 24 weeks. Both WT and THOP1-/- mice will be monitored for blood glucose, insulin resistance, cholesterolemia, fat levels in adipose and liver tissues, lipolytic activity following adrenergic stimulation in adipose tissue, and endurance in high running tests. treadmill intensity. THOP1-/- mice will be compared to WT for possible changes in the expression levels of Obesity-specific genes and microRNAs, as well as the relative levels of intracellular peptides in inguinal adipose tissue. Some of these possibly altered peptides will be synthesized and tested for activity on Obesity-associated gene and microRNA expression levels in 3T3L1 adipocytes. Taken together, the results of this application will suggest whether intracellular peptides are important modulators of Obesity related parameters. In addition, these results will indicate a possible connection between proteasome protein degradation and gene expression. Consequently, these results may propose that THOP1 and intracellular peptides may represent new therapeutic targets for the control of Obesity and associated diseases. (AU)