Elisa Einwallner1, Florian W Kiefer2, Giuseppe Di Caro3, Michael Orthofer4, Nadine Witzeneder1, Gregor Hörmann1, Bianca Itariu2, Maximilian Zeyda2, Josef M Penninger4, Thomas M Stulnig2, Harald Esterbauer1, Jelena Todoric5,6. 1. Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria. 2. Christian Doppler Laboratory for Cardio-Metabolic Immunotherapy and Clinical Division of Endocrinology and Metabolism, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria. 3. Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California, San Diego, CA, USA. 4. Institute of Molecular Biotechnology of the Austrian Academy of Science, Vienna, Austria. 5. Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria. jelena.todoric@meduniwien.ac.at. 6. Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California, San Diego, CA, USA. jelena.todoric@meduniwien.ac.at.
Abstract
BACKGROUND: Infiltration of white adipose tissue (WAT) by inflammatory cells in obesity is considered to be a key event in the development of insulin resistance. Recently, mast cells (MCs) have been identified as new players in the pathogenesis of obesity. We aimed to investigate the relationship between MCs and various inflammatory markers in serum and WAT and to determine the role of MCs in the aetiology of insulin resistance. MATERIALS AND METHODS: Gene expression was measured in WAT from 20 morbidly obese patients and 20 nonobese control subjects. Homoeostasis Model of Assessment-Insulin Resistance (HOMA-IR) was used to estimate insulin sensitivity. In addition, wild-type and mast cell-deficient mice were fed a high-fat or low-fat diet to study mast cell influence on inflammatory cell polarization in WAT and overall metabolic changes. RESULTS: WAT levels of MC-specific TPSb2 transcript were increased in obesity and significantly positively correlated with TNF, CCL2, CCL5 and CD68 gene expression levels in our study subjects after adjustment for sex, age and BMI. Accordingly, MC deficiency abrogated increase in expression of pro-inflammatory M1 macrophage marker genes in mouse WAT upon high-fat diet feeding. However, MCs accumulated in obese human WAT independent of insulin resistance and systemic changes in inflammatory mediators. CONCLUSIONS: Our results suggest that MCs contribute to the local pro-inflammatory state within WAT in obesity but do not play a primary role in causing insulin resistance.
BACKGROUND: Infiltration of white adipose tissue (WAT) by inflammatory cells in obesity is considered to be a key event in the development of insulin resistance. Recently, mast cells (MCs) have been identified as new players in the pathogenesis of obesity. We aimed to investigate the relationship between MCs and various inflammatory markers in serum and WAT and to determine the role of MCs in the aetiology of insulin resistance. MATERIALS AND METHODS: Gene expression was measured in WAT from 20 morbidly obesepatients and 20 nonobese control subjects. Homoeostasis Model of Assessment-Insulin Resistance (HOMA-IR) was used to estimate insulin sensitivity. In addition, wild-type and mast cell-deficient mice were fed a high-fat or low-fat diet to study mast cell influence on inflammatory cell polarization in WAT and overall metabolic changes. RESULTS: WAT levels of MC-specific TPSb2 transcript were increased in obesity and significantly positively correlated with TNF, CCL2, CCL5 and CD68 gene expression levels in our study subjects after adjustment for sex, age and BMI. Accordingly, MC deficiency abrogated increase in expression of pro-inflammatory M1 macrophage marker genes in mouse WAT upon high-fat diet feeding. However, MCs accumulated in obesehuman WAT independent of insulin resistance and systemic changes in inflammatory mediators. CONCLUSIONS: Our results suggest that MCs contribute to the local pro-inflammatory state within WAT in obesity but do not play a primary role in causing insulin resistance.
Authors: Daria Barwinska; Tarek M El-Achkar; Ricardo Melo Ferreira; Farooq Syed; Ying-Hua Cheng; Seth Winfree; Michael J Ferkowicz; Takashi Hato; Kimberly S Collins; Kenneth W Dunn; Katherine J Kelly; Timothy A Sutton; Brad H Rovin; Samir V Parikh; Carrie L Phillips; Pierre C Dagher; Michael T Eadon Journal: Sci Adv Date: 2021-02-10 Impact factor: 14.136