Active integrins regulate white adipose tissue insulin sensitivity and brown fat thermogenesis Ruiz Ojeda, Francisco Javier Wang, Jiefu Bäcker, Theresa Krueger, Martin Zamani, Samira Rosowski, Simon Gruber, Tim Onogi, Yasuhiro Feuchtinger, Annette Schulz, Tim J Fässler, Reinhard Müller, Timo D García-Cáceres, Cristina Meier, Matthias Blüher, Matthias Ussar, Siegfried Integrins Kindlin-2 Insulin resistance Adipose tissue obesity Brown fat Insulin receptor Lipodystrophy Objective: Reorganization of the extracellular matrix is a prerequisite for healthy adipose tissue expansion, whereas fibrosis is a key feature of adipose dysfunction and inflammation. However, very little is known about the direct effects of impaired cell-matrix interaction in adipocyte function and insulin sensitivity. The objective of this study was to determine whether integrin activity can regulate insulin sensitivity in adipocytes and thereby systemic metabolism. Methods: We characterized integrin activity in adipose tissue and its consequences on whole-body metabolism using adipose-selective deletion of β1 integrin (Itgb1adipo-cre) and Kindlin-2 (Kind2adipo-cre) in mice. Results: We demonstrate that integrin signaling regulates white adipocyte insulin action and systemic metabolism. Consequently, loss of adipose integrin activity, similar to loss of adipose insulin receptors, results in a lipodystrophy-like phenotype and systemic insulin resistance. However, brown adipose tissue of Kind2adipo-cre and Itgb1adipo-cre mice is chronically hyperactivated and has increased substrate delivery, reduced endothelial basement membrane thickness, and increased endothelial vesicular transport. Conclusions: Thus, we establish integrin-extracellular matrix interactions as key regulators of white and brown adipose tissue function and whole-body metabolism. 2025-01-29T07:20:47Z 2025-01-29T07:20:47Z 2021-03-21 journal article Ruiz-Ojeda FJ, Wang J, Bäcker T, Krueger M, Zamani S, Rosowski S, Gruber T, Onogi Y, Feuchtinger A, Schulz TJ, Fässler R, Müller TD, García-Cáceres C, Meier M, Blüher M, Ussar S. Active integrins regulate white adipose tissue insulin sensitivity and brown fat thermogenesis. Mol Metab. 2021 Mar;45:101147. doi: 10.1016/j.molmet.2020.101147. Epub 2021 Jan 7. PMID: 33359386; PMCID: PMC7808956. https://hdl.handle.net/10481/100851 https://doi.org/10.1016/j.molmet.2020.101147 eng http://creativecommons.org/licenses/by-nc-nd/4.0/ open access Attribution-NonCommercial-NoDerivatives 4.0 Internacional