Defective extracellular matrix remodeling in brown adipose tissue is associated with fibro- inflammation and reduced diet-induced thermogenesis

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 thermo-genesis concomitantly with the development of fibro-inflammation in BAT. Higher markers of fibro-inflamma-tion are associated with lower cold-induced BAT activity in humans. Similarly, when mice are housed at ther-moneutrality, 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.