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Unveiling the PRDM16 transcriptional complex related to the inhibition of ceramides synthesis genes in adipocytes

Grant number: 19/15025-5
Support type:Research Grants - Young Investigators Grants
Duration: April 01, 2020 - March 31, 2025
Field of knowledge:Biological Sciences - Physiology - Physiology of Organs and Systems
Principal Investigator:Carlos Henrique Grossi Sponton
Grantee:Carlos Henrique Grossi Sponton
Home Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Assoc. researchers:Leonardo dos Reis Silveira ; Marcelo Alves da Silva Mori ; Shingo Kajimura

Abstract

Beige adipocytes are well-recognized for its ability to dissipate energy in form of heat. Recent studies also suggest the multifaced roles of beige adipocytes in the regulation of glucose and lipid homeostasis beyond thermogenesis. The induction of beige adipocytes in dedicated subcutaneous white adipocyte depots protects mice from oxidative stress, inflammation, mitochondrial dysfunction, hypoxia, fibrosis and de novo ceramides synthesis - all major causes of dysfunction adipocytes in obesity and related disorders. In particular, adipocyte-related ceramides synthesis has proven to be a central modulator of obesity-induced insulin resistance. In contrast, recent evidence showed that the induction of beige adipocyte by cold exposure or pharmacological stimulus leads to decreased expression of ceramides biosynthesis genes and consequently the systemic ceramides concentration. Despite such findings, the transcriptional regulation of ceramides synthesis remains unknown. The transcriptional factor PRDM16 is well established as the master regulator of brown and beige adipocyte development. Our preliminary data demonstrate that adipose tissue PRDM16 transgenic mice (PRDM16 Tg) robustly decrease the expression of several ceramides synthesis genes in subcutaneous inguinal white adipose depots compared to control mice. Interestingly, the repression of ceramides genes in PRDM16 Tg mice was observed even in the absence of uncoupling protein 1 (UCP1) - (PRDM16 Tg x UCP1 KO mice) compared to respective control group. These data suggest that PRDM16 controls the expression of ceramide synthesis genes in a thermogenic independent manner. Thus, the goal of this study is to understand the transcriptional machinery that repress ceramides gene expression in beige adipocytes. The findings of this study might open new therapeutic possibilities to reverse the obesity-induced insulin resistance due to increased ceramides synthesis. (AU)