Kotikalapudi Nagasuryaprasad, Ramachandran Deepti, Vieira Daniel, Rubio William B, Gipson Gregory R, Troncone Luca, Vestal Kylie, Maridas David E, Rosen Vicki, Yu Paul B, Thompson Thomas B, Banks Alexander S
Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
Department of Molecular & Cellular Biosciences, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Nat Commun. 2025 May 13;16(1):4432. doi: 10.1038/s41467-025-59673-7.
TGFβ superfamily proteins can affect cellular differentiation, thermogenesis, and fibrosis in mammalian adipose tissue. Here we describe a role for Growth Differentiation Factor 3 (GDF3) on mature adipocyte biology. We find inducible GDF3 loss of function in obese adult mice leads to reduced lipolysis, improved glucose tolerance, and reduced glycemic variability. The effects on lipolysis are driven by lower levels of β3-adrenergic receptor, decreased cAMP and PKA signaling. GDF3 is an ALK5, ALK7, ACVR2A and ACVR2B agonist and also a BMPR2 antagonist. Unlike ALK7 or activin E knockouts, acute GDF3 loss of function does not affect body weight or energy balance but significantly improves metabolic health. These results suggest that blocking GDF3 can improve metabolic health independent of body weight and food intake, an intriguing new model for developing anti-diabetic therapies. Together these results provide much-needed clarity to both the molecular pathways involved in GDF3 signaling and its physiological effects.
转化生长因子β（TGFβ）超家族蛋白可影响哺乳动物脂肪组织中的细胞分化、产热和纤维化。在此，我们描述了生长分化因子3（GDF3）在成熟脂肪细胞生物学中的作用。我们发现，肥胖成年小鼠中可诱导的GDF3功能丧失会导致脂肪分解减少、葡萄糖耐量改善和血糖变异性降低。对脂肪分解的影响是由较低水平的β3-肾上腺素能受体、降低的cAMP和PKA信号传导驱动的。GDF3是ALK5、ALK7、ACVR2A和ACVR2B的激动剂，也是BMPR2的拮抗剂。与ALK7或激活素E基因敲除不同，急性GDF3功能丧失不影响体重或能量平衡，但能显著改善代谢健康。这些结果表明，阻断GDF3可以独立于体重和食物摄入量改善代谢健康，这是一种开发抗糖尿病疗法的有趣新模型。这些结果共同为GDF3信号传导所涉及的分子途径及其生理效应提供了急需的清晰认识。
