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

Karunakaran, Denuja; Turner, Adam; Duchez, Anne‐Claire; Soubeyrand, Sébastien; Rasheed, Adil; Smyth, David; Cook, David P.; Nikpay, Majid; Kandiah, Joshua W.; Pan, Calvin; Geoffrion, Michèle; Lee, Richard; Boytard, Ludovic; Wyatt, Hailey; Nguyen, My-Anh; Lau, Paulina; Laakso, Markku; Ramkhelawon, Bhama; Alvarez, Marcus; Pietiläinen, Kirsi H.; Pajukanta, Päivi; Vanderhyden, Barbara C.; Liu, Peter; Berger, Scott B.; Gough, Peter J.; Bertin, John; Harper, Mary‐Ellen; Lusis, Aldons J.; McPherson, Ruth; Rayner, Katey J.

doi:10.1038/s42255-020-00279-2

Cited by 36 publications

(38 citation statements)

References 76 publications

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“…For example, although the cause of neuronal cell loss during ischemic and neurodegenerative disease is still mysterious [155] , the inflammasome [156] , CASP8 [157] and RIPK1 [158] , [159] , core components of the PANoptosome, are implicated in neuronal death [155] . Similar involvement of key PANoptosome molecules and pyroptosis, apoptosis and necroptosis are also seen in metabolic diseases [160] , [161] , [162] , [163] . Therefore, the physiological function of PANoptosis likely extends widely across the disease spectrum [38] , [141] .…”

Section: Panoptosis In Diseasementioning

confidence: 54%

From pyroptosis, apoptosis and necroptosis to PANoptosis: A mechanistic compendium of programmed cell death pathways

Wang

Kanneganti

2021

Computational and Structural Biotechnology Journal

247

169

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Section: Panoptosis In Diseasementioning

confidence: 54%

From pyroptosis, apoptosis and necroptosis to PANoptosis: A mechanistic compendium of programmed cell death pathways

Wang

Kanneganti

2021

Computational and Structural Biotechnology Journal

247

169

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“…Whilst comparable at baseline, after 16 weeks of HFD, Mlkl −/− mice gained significantly less body weight, notably visceral adipose tissue, than their wild-type littermates [59]. Blocking upstream RIPK1, has a similar effect [84]. Yet, in another study, after 12 weeks of HFD there were no significant differences found in body weight between Mlkl −/− and wild-type [56].…”

Section: Metabolic Diseasementioning

confidence: 93%

The Role of the Key Effector of Necroptotic Cell Death, MLKL, in Mouse Models of Disease

2021

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Necroptosis is an inflammatory form of lytic programmed cell death that is thought to have evolved to defend against pathogens. Genetic deletion of the terminal effector protein—MLKL—shows no overt phenotype in the C57BL/6 mouse strain under conventional laboratory housing conditions. Small molecules that inhibit necroptosis by targeting the kinase activity of RIPK1, one of the main upstream conduits to MLKL activation, have shown promise in several murine models of non-infectious disease and in phase II human clinical trials. This has triggered in excess of one billion dollars (USD) in investment into the emerging class of necroptosis blocking drugs, and the potential utility of targeting the terminal effector is being closely scrutinised. Here we review murine models of disease, both genetic deletion and mutation, that investigate the role of MLKL. We summarize a series of examples from several broad disease categories including ischemia reperfusion injury, sterile inflammation, pathogen infection and hematological stress. Elucidating MLKL’s contribution to mouse models of disease is an important first step to identify human indications that stand to benefit most from MLKL-targeted drug therapies.

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“…A positive feedback loop may link inflammation and obesity. Genetic polymorphisms near a central regulator of inflammatory cell function that coordinates inflammation is associated with obesity in humans, and silencing it in the laboratory setting reduces obesity ( Karunakaran et al, 2020 ). This points to the complex relationship between inflammation and obesity.…”

Section: Obesitymentioning

confidence: 99%

A Proposed Hypothesis on Dementia: Inflammation, Small Vessel Disease, and Hypoperfusion Is the Sequence That Links All Harmful Lifestyles to Cognitive Impairment

Hakim

2021

Front. Aging Neurosci.

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There is growing consensus that certain lifestyles can contribute to cognitive impairment and dementia, but the physiological steps that link a harmful lifestyle to its negative impact are not always evident. It is also unclear whether all lifestyles that contribute to dementia do so through the same intermediary steps. This article will focus on three lifestyles known to be risk factors for dementia, namely obesity, sedentary behavior, and insufficient sleep, and offer a unifying hypothesis proposing that lifestyles that negatively impact cognition do so through the same sequence of events: inflammation, small vessel disease, decline in cerebral perfusion, and brain atrophy. The hypothesis will then be tested in a recently identified risk factor for dementia, namely hearing deficit. If further studies confirm this sequence of events leading to dementia, a significant change in our approach to this debilitating and costly condition may be necessary, possible, and beneficial.

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

Cited by 36 publications

References 76 publications

From pyroptosis, apoptosis and necroptosis to PANoptosis: A mechanistic compendium of programmed cell death pathways

From pyroptosis, apoptosis and necroptosis to PANoptosis: A mechanistic compendium of programmed cell death pathways

The Role of the Key Effector of Necroptotic Cell Death, MLKL, in Mouse Models of Disease

A Proposed Hypothesis on Dementia: Inflammation, Small Vessel Disease, and Hypoperfusion Is the Sequence That Links All Harmful Lifestyles to Cognitive Impairment

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