Loss of iRhom2 accelerates fat gain and insulin resistance in diet-induced obesity despite reduced adipose tissue inflammation
| Autor: | David K. Meyerholz, Priya D. Issuree, Gourav Bhardwaj, Joseph Skurski, Garima Dixit, Brian T. O’Neill, Ramasatyaveni Geesala, Priyanjali Pulipati, Thorsten Maretzky, Christie M. Penniman |
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| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine medicine.medical_specialty Panniculitis Endocrinology Diabetes and Metabolism medicine.medical_treatment Down-Regulation Adipose tissue 030209 endocrinology & metabolism Inflammation Diet High-Fat Weight Gain Mice 03 medical and health sciences 0302 clinical medicine Endocrinology Insulin resistance Amphiregulin Internal medicine Glucose Intolerance medicine Animals Obesity Cells Cultured Mice Knockout business.industry Wild type medicine.disease Mice Inbred C57BL 030104 developmental biology Cytokine Adipose Tissue Disease Progression Tumor necrosis factor alpha Insulin Resistance medicine.symptom Carrier Proteins business |
| Zdroj: | Metabolism. 106:154194 |
| ISSN: | 0026-0495 |
| Popis: | Background 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. Objective 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. Methods 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. Results 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. Conclusions This study elucidates a novel role for iRhom2 as an immuno-metabolic regulator that affects adipose tissue inflammation independent of insulin resistance. |
| Databáze: | OpenAIRE |
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