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

Abstract

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.

Bone morphogenetic protein 4 gene therapy in mice inhibits myeloma tumor growth, but has a negative impact on bone

“…In adult mice, the same AAV8-BMP4 vector as used here was shown to increase insulin sensitivity and protected mice on a high-fat diet from obesity (22). In line with this study, (22) we found that while control mice had a weight gain of about 5 % in the 8 weeks from viral injections until culling, the weight of BMP4 treated mice remained unchanged during the course of the study. However, it is unlikely that such a small difference in body weight will lead to a dramatic effect on trabecular bone.…”

“…AAV mediated gene delivery methods are considered safe and have high gene delivery efficacy and are therefore promising tools for gene therapy (37). In adult mice, the same AAV8-BMP4 vector as used here was shown to increase insulin sensitivity and protected mice on a high-fat diet from obesity (22). In line with this study, (22) we found that while control mice had a weight gain of about 5 % in the 8 weeks from viral injections until culling, the weight of BMP4 treated mice remained unchanged during the course of the study.…”

Obesity-linked PPARγ S273 phosphorylation promotes insulin resistance through Growth Differentiation Factor 3

“…Similar salutary effects of glucose homeostasis have been observed in mice treated with BMP6, BMP7, and BMP9 [28,30,31]. BMPs can drive cellular differentiation including potentiation of brown and beige fat activation [47,48,51]. In this context, tight control of BMP signaling is maintained by inhibitory proteins including Gdf3, Noggin and Gremlin [33,52].…”

“…Our work is consistent with studies demonstrating improvements in glucose homeostasis by increasing levels of BMP4. Conversely, BMP4 KO mice exhibit impaired glucose tolerance [47,48]. Heterozygous deletion of the type 1 BMP receptor, Bmpr1a causes impaired glucose tolerance [49], while adipocyte-specific receptor deletion does not [50].…”

Circulating molecules that control brown/beige adipocyte differentiation and thermogenic capacity

“…Proteins released by adipocytes and other mesenchymal cells, such as bone morphogenetic proteins (BMP4, BMP7, and BMP8b), have also been associated with adipocyte lineage determination (Tseng et al, 2008;Qian et al, 2013;Hoffmann et al, 2017;Whittle et al, 2012). BMP4, for example, leads to brown fat-like changes in WAT by inducing peroxisome proliferator-activated receptor gamma coactivator 1-a (PGC1a) (Qian et al, 2013;Hoffmann et al, 2017;Modica et al, 2018). This effect of BMP4 may also be extended to humans, as the level of expression of BMP4 in human WAT correlates inversely with body mass index (Modica et al, 2018).…”