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

• Grant number: 19/15025-5
• Support Opportunities: Research Grants - Young Investigators Grants
• Start date: April 01, 2020
• End date: March 31, 2026
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Carlos Henrique Grossi Sponton
• Grantee: Carlos Henrique Grossi Sponton
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated researchers: Leonardo dos Reis Silveira ; Marcelo Alves da Silva Mori ; Shingo Kajimura
• Associated scholarship(s): 25/09842-1 - Evaluation of Nr6a1-Dependent Thermogenic Activity in Brown Adipocytes, BP.IC; 25/09845-0 - In silico identification of transcriptional mediators responsible for adipocyte de-differentiation in humans., BP.IC; 24/20562-8 - Unlocking the thermogenic program in mature white adipocytes through transdifferentiation, BP.DD; + associated scholarships 23/05370-2 - Unlocking the thermogenic program in mature white adipocytes through transdifferentiation., BP.MS; 22/09364-4 - Influence of NFIL3 circadian pattern on thermogenesis in brown adipose tissue, BP.MS; 21/11841-2 - Unveiling the PRDM16 transcriptional complex related to the inhibition of ceramides synthesis genes in adipocytes, BP.TT; 21/02937-6 - Unveiling the PRDM16 transcriptional complex related to the inhibition of ceramides synthesis genes in adipocytes., BP.TT; 20/14725-0 - Unveiling the PRDM16 transcriptional complex related to the inhibition of ceramides synthesis genes in adipocytes, BP.DD; 20/09308-1 - Unveiling the PRDM16 transcriptional complex related to the inhibition of ceramides synthesis genes in adipocytes, BP.JP - associated scholarships

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)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

BLADIMIR, FERNANDO; DE OLIVEIRA, VANESSA; HENRIQUE, CARLOS. Investigation of Beige Fat Biology and Metabolism Using the CRISPR SunTag-p65-HSF1 Activation System. JOVE-JOURNAL OF VISUALIZED EXPERIMENTS, v. N/A, n. 191, p. 1-pg., 2023-01-01. (19/15025-5, 20/14725-0, 21/11841-2, 20/09308-1)

SPONTON, CARLOS H.; DE LIMA-JUNIOR, JOSE CARLOS; LEIRIA, LUIZ O.. What puts the heat on thermogenic fat: metabolism of fuel substrates. TRENDS IN ENDOCRINOLOGY AND METABOLISM, v. 33, n. 8, p. 13-pg., 2022-07-12. (20/05040-4, 17/08264-8, 19/26008-4, 19/15025-5)