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 Rodriguez-Fdez,
Samuel Virtue,
Jennifer Leggat,
Cankut Çubuk,
Vivian J. Peirce,
Tarja Niemi,
Mark Campbell,
Sergio Rodriguez-Cuenca,
Joaquin Dopazo Blázquez,
Stefania Carobbio,
Kirsi A. Virtanen,
Antonio Vidal-Puig
Affiliations
Vanessa Pellegrinelli
Wellcome-MRC Institute of Metabolic Science and Medical Research Council Metabolic Diseases Unit, University of Cambridge, Cambridge, UK; Corresponding author
Elizabeth Figueroa-Juárez
Wellcome-MRC Institute of Metabolic Science and Medical Research Council Metabolic Diseases Unit, University of Cambridge, Cambridge, UK
Isabella Samuelson
Wellcome-MRC Institute of Metabolic Science and Medical Research Council Metabolic Diseases Unit, University of Cambridge, Cambridge, UK
Mueez U-Din
Turku PET Centre, University of Turku, Turku, Finland; Turku PET Centre, Turku University Hospital, Turku, Finland
Sonia Rodriguez-Fdez
Wellcome-MRC Institute of Metabolic Science and Medical Research Council Metabolic Diseases Unit, University of Cambridge, Cambridge, UK
Samuel Virtue
Wellcome-MRC Institute of Metabolic Science and Medical Research Council Metabolic Diseases Unit, University of Cambridge, Cambridge, UK
Jennifer Leggat
Wellcome-MRC Institute of Metabolic Science and Medical Research Council Metabolic Diseases Unit, University of Cambridge, Cambridge, UK
Cankut Çubuk
Platform of Computational Medicine, Fundación Progreso y Salud (FPS), Hospital Virgen Del Rocío, 41013 Sevilla, Spain
Vivian J. Peirce
Wellcome-MRC Institute of Metabolic Science and Medical Research Council Metabolic Diseases Unit, University of Cambridge, Cambridge, UK
Tarja Niemi
Department of Plastic and General Surgery, Turku University Hospital, Turku, Finland
Mark Campbell
Wellcome-MRC Institute of Metabolic Science and Medical Research Council Metabolic Diseases Unit, University of Cambridge, Cambridge, UK; Cambridge University Nanjing Centre of Technology and Innovation, Nanjing, P.R. China
Sergio Rodriguez-Cuenca
Wellcome-MRC Institute of Metabolic Science and Medical Research Council Metabolic Diseases Unit, University of Cambridge, Cambridge, UK; Cambridge University Nanjing Centre of Technology and Innovation, Nanjing, P.R. China
Joaquin Dopazo Blázquez
Platform of Computational Medicine, Fundación Progreso y Salud (FPS), Hospital Virgen Del Rocío, 41013 Sevilla, Spain; Bioinformatics in RareDiseases (BiER), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 41013 Sevilla, Spain; Computational Systems Medicine, Institute of Biomedicine of Seville (IBiS), Sevilla 41013, Spain; Functional Genomics Node (INB-ELIXIR-es), Sevilla, Spain
Stefania Carobbio
Wellcome-MRC Institute of Metabolic Science and Medical Research Council Metabolic Diseases Unit, University of Cambridge, Cambridge, UK; Centro de Investigacion Principe Felipe (CIPF), Valencia, Spain
Kirsi A. Virtanen
Turku PET Centre, University of Turku, Turku, Finland; Institute of Public Health and Clinical Nutrition, University of Eastern Finland (UEF), Kuopio, Finland; Department of Endocrinology and Clinical Nutrition, Kuopio University Hospital, Kuopio, Finland
Antonio Vidal-Puig
Wellcome-MRC Institute of Metabolic Science and Medical Research Council Metabolic Diseases Unit, University of Cambridge, Cambridge, UK; Cambridge University Nanjing Centre of Technology and Innovation, Nanjing, P.R. China; Centro de Investigacion Principe Felipe (CIPF), Valencia, Spain; Cambridge Heart and Lung Research Institute, Cambridge, UK; Corresponding author
Summary: 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.
