Functional validation of candidate genes as mediators of adipocyte hypertrophy

• Grant number: 23/18100-3
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: March 01, 2024
• End date: February 28, 2027
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Marcelo Alves da Silva Mori
• Grantee: Letícia Grillo Guimarães Pereira
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 21/08354-2 - The interplay between the immune system and metabolism as a key determinant of the aging process, AP.TEM

Abstract

Obesity represents a global epidemic associated with significant metabolic disorders, such as type 2 diabetes and cardiovascular diseases. Adipose tissue plays a crucial role in organismal longevity, influencing metabolic health through mechanisms that expand its storage capacity, either through adipocyte hyperplasia (increase in adipocyte number) or hypertrophy (increase in adipocyte volume). While the former type of expansion is generally linked to metabolic health, the latter is commonly associated with the pathogenesis of obesity and its inflammatory state.This project aims to investigate how the control of adipocyte size in white adipose tissue is a determinant factor for these metabolic disorders. To achieve this goal, our research seeks to characterize genes that may act as regulators of adipocyte hypertrophy. Through bioinformatics analyses and in vivo validations using human, mouse, and rat tissues, we have identified candidate genes associated with adipocyte size. These genes include those encoding matrix metalloproteinase 28 (MMP28), dehydrodolichyl diphosphate synthase (DHDDS), natriuretic peptide receptor 3 (NPR3), and inter-alpha-trypsin inhibitor heavy chain 5 (ITIH5). The selection of these genes was based on significant correlations with adipocyte size in different contexts, such as in mice exposed to a high-fat diet and obese humans. Furthermore, genome-wide association studies have provided additional evidence of the relevance of these genes in obesity and metabolic diseases. The project involves manipulating these genes using CRISPR technology to assess their direct impact on adipocyte size in vivo. This study aims to determine whether these genes play a causal role in adipocyte hypertrophy, providing possible insights into the underlying mechanisms of obesity and metabolic syndrome, and identifying potential therapeutic targets for these conditions.