Defective extracellular matrix remodeling in brown adipose tissue is associated with fibro-inflammation and reduced diet-induced thermogenesis
Vanessa Pellegrinelli, Elizabeth Figueroa‐Juárez, Isabella Samuelson, Mueez U-Din, Sonia Rodríguez‐Fdez, Sam Virtue, Jennifer Leggat, Cankut Çubuk, Vivian Peirce, Tarja Niemi, Mark Campbell, Sergio Rodríguez‐Cuenca, Joaquín Dopazo Blázquez, Stefania Carobbio, Kirsi A. Virtanen, Antonio Vidal‐Puig
Abstract
The relevance of extracellular matrix (ECM) remodeling is reported in white adipose tissue (AT) and obesity-related dysfunctions, but little is known about the importance of ECM remodeling in brown AT (BAT) function. Here, we show that a time course of high-fat diet (HFD) feeding progressively impairs diet-induced thermogenesis concomitantly with the development of fibro-inflammation in BAT. Higher markers of fibro-inflammation are associated with lower cold-induced BAT activity in humans. Similarly, when mice are housed at thermoneutrality, inactivated BAT features fibro-inflammation. We validate the pathophysiological relevance of BAT ECM remodeling in response to temperature challenges and HFD using a model of a primary defect in the collagen turnover mediated by partial ablation of the Pepd prolidase. Pepd-heterozygous mice display exacerbated dysfunction and BAT fibro-inflammation at thermoneutrality and in HFD. Our findings show the relevance of ECM remodeling in BAT activation and provide a mechanism for BAT dysfunction in obesity.