Endothelial c-Myc knockout disrupts metabolic homeostasis and triggers the development of obesity.

Autor:	Machi JF; Interdisciplinary Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, FL, United States.; Department of Biomedical Science, Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, United States., Altilio I; Interdisciplinary Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, FL, United States., Qi Y; Interdisciplinary Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, FL, United States., Morales AA; Interdisciplinary Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, FL, United States., Silvestre DH; Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Miller School of Medicine, University of Miami, Miami, FL, United States., Hernandez DR; DeWitt Daughtry Family Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, United States., Da Costa-Santos N; Department of Biomedical Science, Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, United States., Santana AG; Department of Biomedical Science, Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, United States., Neghabi M; Department of Electrical Engineering and Computer Science, College of Engineering and Computer Science, Florida Atlantic University, Boca Raton, FL, United States., Nategh P; Department of Electrical Engineering and Computer Science, College of Engineering and Computer Science, Florida Atlantic University, Boca Raton, FL, United States., Castro TL; School of Arts, Sciences and Humanities, University of São Paulo, São Paulo, Brazil., Werneck-de-Castro JP; Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Miller School of Medicine, University of Miami, Miami, FL, United States., Ranji M; Department of Electrical Engineering and Computer Science, College of Engineering and Computer Science, Florida Atlantic University, Boca Raton, FL, United States., Evangelista FS; School of Arts, Sciences and Humanities, University of São Paulo, São Paulo, Brazil., Vazquez-Padron RI; DeWitt Daughtry Family Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, United States., Bernal-Mizrachi E; Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Miller School of Medicine, University of Miami, Miami, FL, United States., Rodrigues CO; Interdisciplinary Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, FL, United States.; Department of Biomedical Science, Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in cell and developmental biology [Front Cell Dev Biol] 2024 Jul 19; Vol. 12, pp. 1407097. Date of Electronic Publication: 2024 Jul 19 (Print Publication: 2024).
DOI:	10.3389/fcell.2024.1407097
Abstrakt:	Introduction: Obesity is a major risk factor associated with multiple pathological conditions including diabetes and cardiovascular disease. Endothelial dysfunction is an early predictor of obesity. However, little is known regarding how early endothelial changes trigger obesity. In the present work we report a novel endothelial-mediated mechanism essential for regulation of metabolic homeostasis, driven by c-Myc. Methods: We used conditional knockout (EC-Myc KO) and overexpression (EC-Myc OE) mouse models to investigate the endothelial-specific role of c-Myc in metabolic homeostasis during aging and high-fat diet exposure. Body weight and metabolic parameters were collected over time and tissue samples collected at endpoint for biochemical, pathology and RNA-sequencing analysis. Animals exposed to high-fat diet were also evaluated for cardiac dysfunction. Results: In the present study we demonstrate that EC-Myc KO triggers endothelial dysfunction, which precedes progressive increase in body weight during aging, under normal dietary conditions. At endpoint, EC-Myc KO animals showed significant increase in white adipose tissue mass relative to control littermates, which was associated with sex-specific changes in whole body metabolism and increase in systemic leptin. Overexpression of endothelial c-Myc attenuated diet-induced obesity and visceral fat accumulation and prevented the development of glucose intolerance and cardiac dysfunction. Transcriptome analysis of skeletal muscle suggests that the protective effects promoted by endothelial c-Myc overexpression are associated with the expression of genes known to increase weight loss, energy expenditure and glucose tolerance. Conclusion: Our results show a novel important role for endothelial c-Myc in regulating metabolic homeostasis and suggests its potential targeting in preventing obesity and associated complications such as diabetes type-2 and cardiovascular dysfunction. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2024 Machi, Altilio, Qi, Morales, Silvestre, Hernandez, Da Costa-Santos, Santana, Neghabi, Nategh, Castro, Werneck-de-Castro, Ranji, Evangelista, Vazquez-Padron, Bernal-Mizrachi and Rodrigues.)
Databáze:	MEDLINE
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