RIPK1 gene variants associate with obesity in humans and can be therapeutically silenced to reduce obesity in mice.

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.

Citation

Denuja Karunakaran, Adam W Turner, Anne-Claire Duchez, Sebastien Soubeyrand, Adil Rasheed, David Smyth, David P Cook, Majid Nikpay, Joshua W Kandiah, Calvin Pan, Michele Geoffrion, Richard Lee, Ludovic Boytard, Hailey Wyatt, My-Anh Nguyen, Paulina Lau, Markku Laakso, Bhama Ramkhelawon, Marcus Alvarez, Kirsi H Pietiläinen, Päivi Pajukanta, Barbara C Vanderhyden, Peter Liu, Scott B Berger, Peter J Gough, John Bertin, Mary-Ellen Harper, Aldons J Lusis, Ruth McPherson, Katey J Rayner. RIPK1 gene variants associate with obesity in humans and can be therapeutically silenced to reduce obesity in mice. Nature metabolism. 2020 Oct;2(10):1113-1125

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PMID: 32989316

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