BMP4 Gene Therapy in Mature Mice Reduces BAT Activation but Protects from Obesity by Browning Subcutaneous Adipose Tissue

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. [Display omitted] •Increased circulating BMP4 in adult mice prevents obesity and insulin resistance•Subcutaneous fat undergoes browning, and whole-body energy expenditure is increased•BMP4 reduces BAT activation•The results highlight the importance of browning subcutaneous fat 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.