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RIPK1 gene variants associate with obesity in humans and can be therapeutically silenced to reduce obesity in mice.
- Source :
-
Nature metabolism [Nat Metab] 2020 Oct; Vol. 2 (10), pp. 1113-1125. Date of Electronic Publication: 2020 Sep 28. - Publication Year :
- 2020
-
Abstract
- Obesity is a major public health burden worldwide and is 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. Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) 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 and obesity. We show that one of these single nucleotide polymorphisms 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 that RIPK1 is genetically associated with obesity, and reducing RIPK1 expression is a potential therapeutic approach to target obesity and related diseases.
- Subjects :
- Adipocytes metabolism
Adipose Tissue
Animals
Basic-Leucine Zipper Transcription Factors genetics
Energy Metabolism
Glucose Tolerance Test
Humans
Male
Mice
Mice, Inbred C57BL
Mice, Obese
Polymorphism, Genetic
Subcutaneous Fat metabolism
Gene Silencing
Obesity genetics
Obesity therapy
Receptor-Interacting Protein Serine-Threonine Kinases genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2522-5812
- Volume :
- 2
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Nature metabolism
- Publication Type :
- Academic Journal
- Accession number :
- 32989316
- Full Text :
- https://doi.org/10.1038/s42255-020-00279-2