Journal article
Loss of iRhom2 accelerates fat gain and insulin resistance in diet-induced obesity despite reduced adipose tissue inflammation
Metabolism, clinical and experimental, Vol.106, pp.154194-154194
05/2020
DOI: 10.1016/j.metabol.2020.154194
PMID: 32135161
Abstract
Low-grade inflammation and metabolic dysregulation are common comorbidities of obesity, both of which are associated with alterations in iRhom2-regulated pro-inflammatory cytokine and epidermal growth factor receptor (EGFR) ligand signaling.
Our objective was to determine the role of iRhom2 in the regulation of low-grade inflammation and metabolic dysregulation in a murine model of diet-induced obesity.
Wild type (WT) and iRhom2-deficient mice were fed normal chow (NC) or a high-fat diet (HFD) starting at 5 weeks of age for up to 33 weeks. Body composition, glucose and insulin tolerance, feeding behavior, and indirect calorimetry were measured at defined time points. Adipose tissue cytokine expression and inflammatory lesions known as crown-like structures (CLS) were analyzed at the end-point of the study.
iRhom2-deficient mice show accelerated fat gain on a HFD, accompanied by insulin resistance. Indirect calorimetry did not demonstrate changes in energy expenditure or food intake, but locomotor activity was significantly reduced in HFD iRhom2-deficient mice. Interestingly, CLS, macrophage infiltration, and tumor necrosis factor (TNF) production were decreased in adipose tissue from HFD iRhom2-deficient mice, but circulating cytokines were unchanged. In inguinal and perigonadal fat, the EGFR ligand amphiregulin was markedly induced in HFD controls but completely prevented in iRhom2-deficient mice, suggesting a potentially dominant role of EGFR-dependent mechanisms over TNF in the modulation of insulin sensitivity.
This study elucidates a novel role for iRhom2 as an immuno-metabolic regulator that affects adipose tissue inflammation independent of insulin resistance.
•iRhom2 is an immuno-metabolic regulator that can dissociate adipose tissue inflammation from insulin resistance•iRhom2-deficient mice show accelerated fat gain on a high-fat diet accompanied by insulin resistance•Crown-like structures are reduced in adipose tissue from obese iRhom2-/- mice, but other inflammatory markers are unchanged•In white adipose tissue, amphiregulin is markedly induced in obese controls but completely prevented in iRhom2−/−mice•Metabolic dysbiosis in diet-induced obesity can occur independent of myeloid cell-derived low-grade inflammation
Details
- Title: Subtitle
- Loss of iRhom2 accelerates fat gain and insulin resistance in diet-induced obesity despite reduced adipose tissue inflammation
- Creators
- Joseph Skurski - University of IowaChristie M Penniman - University of IowaRamasatyaveni Geesala - University of IowaGarima Dixit - University of IowaPriyanjali Pulipati - University of IowaGourav Bhardwaj - University of IowaDavid K Meyerholz - Roy J. and Lucille A. Carver College of MedicinePriya D Issuree - University of IowaBrian T O'Neill - University of IowaThorsten Maretzky - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Metabolism, clinical and experimental, Vol.106, pp.154194-154194
- Publisher
- Elsevier Inc
- DOI
- 10.1016/j.metabol.2020.154194
- PMID
- 32135161
- ISSN
- 0026-0495
- eISSN
- 1532-8600
- Grant note
- name: Carver Trust Collaborative Pilot Grant; DOI: 10.13039/100000048, name: American Cancer Society, award: ACS-IRG-18-165-43; name: Carver College of Medicine University of Iowa Research Start-Up funds; DOI: 10.13039/100000002, name: National Institutes of Health, award: T32 AI007485
- Language
- English
- Date published
- 05/2020
- Academic Unit
- Infectious Diseases; Pathology; Biology; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984186541102771
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