Journal
NATURE METABOLISM
Volume 2, Issue 10, Pages 1113-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s42255-020-00279-2
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Funding
- Canadian Institutes of Health Research
- NIH [R01 HL119047, DK117850, HL147883, HL095056, HL28481, U01 DK105561]
- Foundation Leduc
- National Psoriasis Foundation
- Academy of Finland [272376, 266286, 314383, 315035]
- European Union
- Sigrid Juselius Foundation
- Finnish Medical Foundation
- Finnish Diabetes Research Foundation
- Novo Nordisk Foundation
- Helsinki University Hospital Research Funds
- University of Helsinki
- University of Ottawa Heart Institute Cardiac Endowment Fellowship
- HHMI Gilliam Fellowship
- Gyllenberg Foundation
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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.
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