GDF3 simultaneously antagonizes BMP signaling and activates TGFβ receptor signaling

Abstract

Growth differentiation factor 3 (GDF3) is a relatively understudied member of the TGF{beta} superfamily that is highly expressed during development. However, the function of GDF3 in adult biology is contentious. We use in vivo approaches to show that GDF3 loss-of-function in adipose tissue of obese adult mice causes reduced body weight and improved whole-body insulin sensitivity. These effects are accompanied by altered regulation of genes targeted by the TGF{beta} superfamily in vivo. Using in vitro approaches, we show that GDF3 can influence both arms of the TGF{beta} superfamily: GDF3 simultaneously inhibits BMP signaling and activates activin-like SMAD 2/3 signaling. We identify the type II receptors mediating this activity. GDF3 binds to the type II receptors BMPR2, ACTRIIA and ACTRIIB and achieves dose-dependent inhibition of multiple BMP proteins including BMP2, BMP7, BMP9, BMP10, and BMP15 in vitro. We also find that GDF3 activates TGF{beta}/activin-like SMAD2/3 signaling. Unbiased expression profiling confirms that GDF3 both attenuates BMP2-regulated gene expression and drives TGF{beta}/activin-like gene expression. Together these results provide much needed clarity to both the molecular pathways involved in GDF3 signaling and the physiological effects of GDF3 loss of function.