BMP4 Gene Therapy in Mature Mice Reduces BAT Activation but Protects from Obesity by Browning Subcutaneous Adipose Tissue
Jenny M. Hoffmann,
John R. Grünberg,
Christopher Church,
Ivet Elias,
Vilborg Palsdottir,
John-Olov Jansson,
Fatima Bosch,
Ann Hammarstedt,
Shahram Hedjazifar,
Ulf Smith
Affiliations
Jenny M. Hoffmann
The Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, the Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden
John R. Grünberg
Metabolic Research Laboratories, Wellcome Trust MRC Institute of Metabolic Science, Addenbrooke’s Hospital, University of Cambridge, Cambridge CB2 1TN, UK
Christopher Church
Cardiovascular and Metabolic Disease, MedImmune, Granta Park, Cambridge CB21 6GH, UK
Ivet Elias
Center of Animal Biotechnology and Gene Therapy and Department of Biochemistry and Molecular Biology, School of Veterinary Medicine, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 08029 Madrid, Spain
Vilborg Palsdottir
Department of Physiology/Endocrinology, the Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden
John-Olov Jansson
Department of Physiology/Endocrinology, the Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden
Fatima Bosch
Center of Animal Biotechnology and Gene Therapy and Department of Biochemistry and Molecular Biology, School of Veterinary Medicine, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 08029 Madrid, Spain
Ann Hammarstedt
The Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, the Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden
Shahram Hedjazifar
The Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, the Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden
Ulf Smith
The Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, the Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden; Corresponding author
Summary: We examined the effect of Bone Morphogenetic Protein 4 (BMP4) on energy expenditure in adult mature mice by targeting the liver with adeno-associated viral (AAV) BMP4 vectors to increase circulating levels. We verified the direct effect of BMP4 in inducing a brown oxidative phenotype in differentiating preadipocytes in vitro. AAV-BMP4-treated mice display marked browning of subcutaneous adipocytes, with increased mitochondria and Uncoupling Protein 1 (UCP1). These mice are protected from obesity on a high-fat diet and have increased whole-body energy expenditure, improved insulin sensitivity, reduced liver fat, and reduced adipose tissue inflammation. On a control diet, they show unchanged body weight but improved insulin sensitivity. In contrast, AAV-BMP4-treated mice showed beiging of BAT with reduced UCP1, increased lipids, and reduced hormone-sensitive lipase (HSL). Thus, BMP4 exerts different effects on WAT and BAT, but the overall effect is to enhance insulin sensitivity and whole-body energy expenditure by browning subcutaneous adipose tissue. : Hoffmann et al. show that increased circulating BMP4 in mature mice targets subcutaneous WAT, promoting its browning with increased UCP1 and mitochondria and increased energy expenditure. Increased BMP4 also targets BAT, resulting in increased lipids and reduced UCP1. Together, these findings underscore the potential of browning WAT. Keywords: BMP4, white adipose tissue, brown adipose tissue, obesity, insulin resistance, glucose tolerance, energy expenditure
