Loss of iRhom2 accelerates fat gain and insulin resistance in diet-induced obesity despite reduced adipose tissue inflammation

Skurski, Joseph; Penniman, Christie M.; Geesala, Ramasatyaveni; Dixit, Garima; Pulipati, Priyanjali; Bhardwaj, Gourav; Meyerholz, David K.; Issuree, Priya D.; O’Neill, Brian T.; Maretzky, Thorsten

doi:10.1016/j.metabol.2020.154194

Cited by 18 publications

(22 citation statements)

References 40 publications

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“…Adipose macrophages in obesity are associated with the production of pro-inflammatory adipokines; for instance, known ADAM17 targets, IL-6R and TNF-⍺ (Minxuan et al, 2019, Xu et al, 2020. Although two studies were contradictory in their findings, possibly as they used differently derived Rhbdf2 -/mouse models, a role for iRhom2 in modulating adipose inflammation, metabolism and obesity is proposed (Badenes et al, 2020, Skurski et al, 2020. J o u r n a l P r e -p r o o f iRhom2 may participate in the cellular response to viruses iRhom2 was recently proposed as a mediator of the antiviral response via its regulation of stimulator of interferon genes (STING) in human monocytic THP-1 cells and murine bonemarrow-derived macrophages (Luo et al, 2016).…”

Section: Irhom2: Oesophageal Cancer and Inflammatory Diseasementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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iRHOM2: A Regulator of Palmoplantar Biology, Inflammation, and Viral Susceptibility

Chao-Chu

Murtough

Zaman

et al. 2021

Journal of Investigative Dermatology

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Section: Irhom2: Oesophageal Cancer and Inflammatory Diseasementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

iRHOM2: A Regulator of Palmoplantar Biology, Inflammation, and Viral Susceptibility

Chao-Chu

Murtough

Zaman

et al. 2021

Journal of Investigative Dermatology

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“…Cultured iRhom2 KO brown adipocytes exhibited increased UCP‐1 and mitochondrial proton leak, indicating that the effect on thermogenesis was cell‐autonomous. Interestingly, other studies have reported opposing effects on weight gain and insulin resistance [88], highlighting how the roles of iRhom2 in metabolism might be dependent on yet unidentified environmental inputs, that can vary between mouse facilities (e.g., microbiota).…”

Section: Physiological Roles Of Rhomboid Pseudoproteasesmentioning

confidence: 99%

The complex life of rhomboid pseudoproteases

Adrain

Cavadas

2020

The FEBS Journal

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Rhomboid pseudoproteases are catalytically inactive members of the rhomboid superfamily. The founding members, rhomboids, were first identified in Drosophila as serine intramembrane proteases that cleave transmembrane proteins, enabling signaling. This led to the discovery of the wider rhomboid superfamily, a clan that in metazoans is dominated by pseudoproteases. These so-called rhomboid pseudoproteases inherited from their catalytically active ancestors a conserved rhomboid-like domain and a propensity to regulate signaling. Lacking catalytic activity, they developed new 'pseudoenzyme' functions that include regulating the trafficking, turnover, and activity of their client proteins. Rhomboid pseudoproteases have preeminent roles in orchestrating immune cell activation, antiviral responses, and cytokine release in response to microbial infection, or in chronic diseases, and have also been implicated in growth factor signaling, cancer, and, more recently, metabolism. Here, we discuss the mechanism(s) of action of rhomboid pseudoproteases, contrasted with rhomboid proteases. We also highlight the roles of rhomboid pseudoproteases in mammalian physiology, which, quite paradoxically among pseudoenzymes, is understood much better than active rhomboids.

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“…Loss of iRhom2 has been shown to prevent the release of TNF following lipopolysaccharide stimulation, mediated through the loss of ADAM17 activity [11]. Recent studies have shown contradicting results regarding the effect of global iRhom2 deletion on metabolic inflammation following HFD [12,13]. Badenes et al showed that deletion of iRhom2 protected against HFDinduced obesity through increased thermogenesis [13].…”

Section: Introductionmentioning

confidence: 99%

“…Badenes et al showed that deletion of iRhom2 protected against HFDinduced obesity through increased thermogenesis [13]. However, another study showed that global loss of iRhom2 resulted in increased fat gain as well as increased metabolic inflammation following HFD [12].…”

Section: Introductionmentioning

confidence: 99%

Adipocyte ADAM17 plays a limited role in metabolic inflammation

et al. 2020

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The role of ADAM17, its substrates, and its natural inhibitor has been well studied in the context of inflammation, including metabolic inflammation, with mixed results. Previous studies examining global Adam17 knockdown models and ADAM17 inhibition using overexpression of endogenous ADAM17 inhibitors have shown improved metabolic health and decreased metabolic inflammation. However, there have been no studies examining the role of adipocyte ADAM17 using in vivo models. In this study, we developed an adipocyte-specific Adam17 knockout model using Adipoq-Cre-expressing mice crossed with Adam17-floxed mice. Using this model, we show that loss of adipocyte ADAM17 plays no evident role in baseline metabolic responses. Surprisingly, in a state of metabolic stress using high-fat diet (HFD), we observed that adipocyte ADAM17 had little effect overall on the metabolic phenotype as well as inflammatory cell populations. Using whole-body metabolic phenotyping, we show that loss of ADAM17 has no effect on energy utilization both at a baseline state as well as following HFD. However, lastly, using high-parameter flow cytometry, we show that loss of adipocyte ADAM17 alters macrophage and eosinophil populations following HFD. Overall, the studies presented here give more insight into the role of ADAM17 in metabolic responses and metabolic inflammation, specifically in adipocytes.

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Loss of iRhom2 accelerates fat gain and insulin resistance in diet-induced obesity despite reduced adipose tissue inflammation

Cited by 18 publications

References 40 publications

iRHOM2: A Regulator of Palmoplantar Biology, Inflammation, and Viral Susceptibility

iRHOM2: A Regulator of Palmoplantar Biology, Inflammation, and Viral Susceptibility

The complex life of rhomboid pseudoproteases

Adipocyte ADAM17 plays a limited role in metabolic inflammation

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