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| Status |
Public on Jun 06, 2020 |
| Title |
RIPK1 gene variants associate with increased obesity in humans and can be therapeutically silenced to improve metabolic dysfunction in obese mice |
| Organisms |
Homo sapiens; Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Obesity is a major public health burden worldwide, greatly increasing the risk of diabetes, cardiovascular diseases and cancer. Obesity and associated insulin resistance are characterized by chronic low-grade inflammation driven by the cooperation of the innate immune system and dysregulated metabolism in adipose tissue and other metabolic organs. RIPK1 (Receptor-Interacting serine/threonine Protein Kinase 1) is a central regulator of inflammatory cell function that coordinates inflammation, apoptosis and necroptosis in response to inflammatory stimuli. Here, we show that genetic polymorphisms near the human RIPK1 locus associate with increased RIPK1 gene expression in adipose tissue and are strongly linked with the risk of obesity in a human population. We show that one of these SNPs is within a binding site for E4BP4 and increases RIPK1 promoter activity and RIPK1 gene expression in adipose tissue. Therapeutic silencing of RIPK1 in vivo in a mouse model of diet-induced obesity dramatically reduces fat mass, total body weight and improves insulin sensitivity, while simultaneously reducing macrophage and promoting invariant natural killer T-cell accumulation in adipose tissue. These findings demonstrate RIPK1 is a genetic driver of obesity in humans, and that reducing RIPK1 expression is a potential novel therapeutic approach to target obesity and related diseases.
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| Overall design |
Single-cell RNA sequencing (scRNA-seq) profiles of adipose tissues from mice treated with Control or RIPK1-targeting antisense oligonucleotides, and scRNA-seq profiles of human omentum.
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| Contributor(s) |
Cook DP, Rayner K |
| Citation(s) |
32989316 |
| |
| Submission date |
Jun 05, 2020 |
| Last update date |
Aug 17, 2021 |
| Contact name |
David Cook |
| E-mail(s) |
David.cook@uottawa.ca
|
| Organization name |
Ottawa Hospital Research Institute
|
| Department |
Cancer Therapeutics Program
|
| Street address |
501 Smyth Rd
|
| City |
Ottawa |
| State/province |
ON |
| ZIP/Postal code |
K1H8L6 |
| Country |
Canada |
| |
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| Platforms (2) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
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| Samples (5)
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| Relations |
| BioProject |
PRJNA637592 |
| SRA |
SRP266138 |
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