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| Status |
Public on Jun 14, 2024 |
| Title |
Diacylglycerol Kinase Delta Improves Glucose Clearance and Protects Against the Development of Obesity |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
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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| Overall design |
wild-type sedentary (WT; n=5), MLC_DGKδ2 transgenic sedentary mice (TG; n=6), wild-type exercised (WT exercised; n=5) and MLC_DGKδ2 transgenic exercised mice (TG exercised; n=5)
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| Contributor(s) |
Jiang LQ, Savikj M, Pillon NJ, Zierath JR |
| Citation(s) |
38843995 |
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| Submission date |
Feb 07, 2024 |
| Last update date |
Jun 15, 2024 |
| Contact name |
Carolina Nylén |
| E-mail(s) |
[email protected]
|
| Organization name |
Karolinska Institutet
|
| Street address |
Karolinska University Hospital
|
| City |
Stockholm |
| ZIP/Postal code |
171 76 |
| Country |
Sweden |
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| Platforms (1) |
| GPL11533 |
[MoGene-1_1-st] Affymetrix Mouse Gene 1.1 ST Array [transcript (gene) version] |
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| Samples (21)
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| Relations |
| BioProject |
PRJNA1074248 |
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