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

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

doi:10.1038/s42255-020-00279-2

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

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. PietiläinenPäivi 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

Research output: Contribution to journal › Article › peer-review

33 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1113-1125
Number of pages	13
Journal	Nature Metabolism
Volume	2
Issue number	10
DOIs	https://doi.org/10.1038/s42255-020-00279-2
State	Published - Oct 1 2020

ASJC Scopus subject areas

Internal Medicine
Endocrinology, Diabetes and Metabolism
Physiology (medical)
Cell Biology

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10.1038/s42255-020-00279-2

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Karunakaran, D., Turner, A. W., Duchez, A. C., Soubeyrand, S., Rasheed, A., Smyth, D., Cook, D. P., Nikpay, M., Kandiah, J. W., Pan, C., Geoffrion, M., Lee, R., Boytard, L., Wyatt, H., Nguyen, M. A., Lau, P., Laakso, M., Ramkhelawon, B., Alvarez, M., ... Rayner, K. J. (2020). RIPK1 gene variants associate with obesity in humans and can be therapeutically silenced to reduce obesity in mice. Nature Metabolism, 2(10), 1113-1125. https://doi.org/10.1038/s42255-020-00279-2

Karunakaran, D, Turner, AW, Duchez, AC, Soubeyrand, S, Rasheed, A, Smyth, D, Cook, DP, Nikpay, M, Kandiah, JW, Pan, C, Geoffrion, M, Lee, R, Boytard, L, Wyatt, H, Nguyen, MA, Lau, P, Laakso, M, Ramkhelawon, B, Alvarez, M, Pietiläinen, KH, Pajukanta, P, Vanderhyden, BC, Liu, P, Berger, SB, Gough, PJ, Bertin, J, Harper, ME, Lusis, AJ, McPherson, R & Rayner, KJ 2020, 'RIPK1 gene variants associate with obesity in humans and can be therapeutically silenced to reduce obesity in mice', Nature Metabolism, vol. 2, no. 10, pp. 1113-1125. https://doi.org/10.1038/s42255-020-00279-2

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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.",

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AU - Soubeyrand, Sebastien

AU - Rasheed, Adil

AU - Smyth, David

AU - Cook, David P.

AU - Nikpay, Majid

AU - Kandiah, Joshua W.

AU - Pan, Calvin

AU - Geoffrion, Michele

AU - Lee, Richard

AU - Boytard, Ludovic

AU - Wyatt, Hailey

AU - Nguyen, My Anh

AU - Lau, Paulina

AU - Laakso, Markku

AU - Ramkhelawon, Bhama

AU - Alvarez, Marcus

AU - Pietiläinen, Kirsi H.

AU - Pajukanta, Päivi

AU - Vanderhyden, Barbara C.

AU - Liu, Peter

AU - Berger, Scott B.

AU - Gough, Peter J.

AU - Bertin, John

AU - Harper, Mary Ellen

AU - Lusis, Aldons J.

AU - McPherson, Ruth

AU - Rayner, Katey J.

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N2 - 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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RIPK1 gene variants associate with obesity in humans and can be therapeutically silenced to reduce obesity in mice

Abstract

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