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Endothelial Overexpression protects Metabolic Homeostasis and the Development of Obesity and cardiovascular disease

ABSTRACT: 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 overexpression (EC-Myc OE) mouse models to investigate the role of endothelial-specific c-Myc in metabolic homeostasis during high-fat diet exposure. Body weight, metabolic parameters and cardiovascular function were collected over time and tissue samples collected at endpoint for biochemical, pathology and RNA-sequencing analysis. Results: In the present study we demonstrate that Overexpression of endothelial c-Myc attenuated diet-induced obesity and visceral fat accumulation and prevented the development of glucose tolerance 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. Discussion: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE267493 | GEO | 2024/05/31

REPOSITORIES: GEO

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Project description:Background and aim: Diacylglycerol kinase (DGK) isoforms catalyze an enzymatic reaction that removes diacylglycerol (DAG) and thereby terminates protein kinase C (PKC) signaling by converting DAG to phosphatidic acid (PA). We have reported that downregulation of DGKδ (type II isozyme) causes peripheral insulin resistance, metabolic inflexibility, and obesity. Our aim was to determine whether overexpression of DGKδ protects against the development of metabolic impairments and obesity. Methods: We generated a transgenic mouse model overexpressing the human DGKδ2 isoform under the myosin light change promoter (DGKδ TG). We performed deep metabolic phenotyping of DGKδ TG and wild-type mice fed chow or high-fat diet. Mice were also given free access to running wheels to examine the effects of DGKδ overexpression on exercise-induced metabolic outcomes. Results: DGKδ TG mice were leaner than wild-type littermates, with improved glucose tolerance, increased glycogen storage in skeletal muscle, and enhanced glucose uptake in white adipose tissue. Moreover, DGKδ TG mice were protected against high fat diet (HFD)-induced glucose intolerance and obesity. DGKδ TG mice had reduced epididymal fat pad weight, and enhanced lipolysis. Strikingly, DGKδ overexpression recapitulates the beneficial effects exercise on metabolic outcomes. DGKδ overexpression and exercise have a synergistic effect on body weight reduction. Microarray analysis of skeletal muscle confirmed an overlap between genes associated with exercise and DGKδ overexpression. Gene ontology signatures of exercise and DGKδ overexpression were related to lipid storage, extracellular matrix, and glycogen biosynthesis pathways. Conclusion: We identify a role for DGKδ in glucose and energy homeostasis. Overexpression of DGKδ induces adaptive changes in both skeletal muscle and adipose tissue, resulting in protection against high fat diet-induced obesity. DGKδ overexpression recapitulates exercise-induced adaptations on energy homeostasis and skeletal muscle gene expression profiles.

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Endothelial Overexpression protects Metabolic Homeostasis and the Development of Obesity and cardiovascular disease

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