Gdf11 gene transfer prevents high fat diet-induced obesity and improves metabolic homeostasis in obese and STZ-induced diabetic mice

Bingxin Lu,Yuqing Yang,Jianing Zhong,Chunbo Zhang,Mingzhi Ren,Dexi Liu,Liping Jiang,Guisheng Zhang,Jianfei Pan,Xiaopeng Yuan

doi:10.1186/s12967-019-02166-1

Abstract

BackgroundThe growth differentiation factor 11 (GDF11) was shown to reverse age-related hypertrophy on cardiomyocytes and considered as anti-aging rejuvenation factor. The role of GDF11 in regulating metabolic homeostasis is unclear. In this study, we investigated the functions of GDF11 in regulating metabolic homeostasis and energy balance.MethodsUsing a hydrodynamic injection approach, plasmids carrying a mouse Gdf11 gene were delivered into mice and generated the sustained Gdf11 expression in the liver and its protein level in the blood. High fat diet (HFD)-induced obesity was employed to examine the impacts of Gdf11 gene transfer on HFD-induced adiposity, hyperglycemia, insulin resistance, and hepatic lipid accumulation. The impacts of GDF11 on metabolic homeostasis of obese and diabetic mice were examined using HFD-induced obese and STZ-induced diabetic models.ResultsGdf11 gene transfer alleviates HFD-induced obesity, hyperglycemia, insulin resistance, and fatty liver development. In obese and STZ-induced diabetic mice, Gdf11 gene transfer restores glucose metabolism and improves insulin resistance. Mechanism study reveals that Gdf11 gene transfer increases the energy expenditure of mice, upregulates the expression of genes responsible for thermoregulation in brown adipose tissue, downregulates the expression of inflammatory genes in white adipose tissue and those involved in hepatic lipid and glucose metabolism. Overexpression of GDF11 also activates TGF-β/Smad2, PI3K/AKT/FoxO1, and AMPK signaling pathways in white adipose tissue.ConclusionsThese results demonstrate that GDF11 plays an important role in regulating metabolic homeostasis and energy balance and could be a target for pharmacological intervention to treat metabolic disease.

Highlights

Growth differentiation factor 11 (GDF11), known as bone morphogenetic protein 11, is a member of the TGF-β family playing pleiotropic roles in mammalian development [1]
insulin tolerance test (ITT) assay showed that blood glucose levels in animals with Gdf11 gene transfer responds to insulin injection more readily than the High fat diet (HFD)-fed control and similar to animals fed regular Chow (Fig. 3d)
These results demonstrate the activity of growth differentiation factor 11 (GDF11) in suppressing HFDinduced glucose intolerance and insulin resistance

Summary

Introduction

Growth differentiation factor 11 (GDF11), known as bone morphogenetic protein 11, is a member of the TGF-β family playing pleiotropic roles in mammalian development [1]. Lu et al J Transl Med (2019) 17:422 has been considered as a rejuvenation factor capable of reversing aging-related dysfunctions in multiple organs including cardiac hypertrophy, skeletal muscle dysfunction, and cerebral vasculature dysfunction [1,2,3,4,5] conflict results have been reported [6,7,8,9]. The correlation of blood circulation level of GDF11 with aging was conflicting in humans showing increase, decrease, or no change with aging [6, 10,11,12,13,14]. Some reports showed that the circulation level of GDF11 increased in type 2 diabetes (T2D) or obesity in humans and mice [15, 16]. We investigated the functions of GDF11 in regulating metabolic homeostasis and energy balance

Methods

Results

Discussion

Conclusion