FGF1 and FGF19 reverse diabetes by suppression of the hypothalamic-pituitary-adrenal axis.
FGF1 and FGF19 reverse diabetes by suppression of the hypothalamic-pituitary-adrenal axis.
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DOI：
10.1038/ncomms7980
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发表时间：
2015-04-28
影响因子：
16.6
通讯作者：
Shulman, Gerald I.
中科院分区：
文献类型：
--
作者：
Perry, Rachel J.;Lee, Sangwon;Ma, Lie;Zhang, Dongyan;Schlessinger, Joseph;Shulman, Gerald I.
成纤维细胞生长因子-1 （FGF1）和FGF19已被证明可以改善糖尿病啮齿动物的葡萄糖代谢，但其发生机制尚不清楚。为了研究这些生长因子的作用机制，我们在清醒的1型糖尿病（T1D）大鼠模型中脑室内注射重组FGF1或FGF19，并测量全身脂肪分解率、肝脏乙酰辅酶a含量、丙酮酸羧化酶活性和肝脏葡萄糖生成。我们发现，ICV注射FGF19或FGF1导致肝脏葡萄糖生成、肝脏乙酰辅酶a含量和全身脂肪分解减少约60%，这是由于血浆ACTH和皮质酮浓度降低所致。动脉内输注皮质酮可消除这些作用。综上所述，这些研究确定了HPA轴的抑制和随后肝乙酰辅酶a含量的降低是在T1D控制不佳的啮齿动物中介导FGF1和FGF19的急性、胰岛素不依赖型降血糖作用的共同机制。成纤维细胞生长因子（FGF）家族蛋白具有抗糖尿病作用，但其作用机制目前尚不清楚。作者发现，在糖尿病大鼠的大脑中注射FGF1或FGF19可以通过抑制下丘脑-垂体-肾上腺信号轴的活性来改变葡萄糖和脂质稳态。
Fibroblast growth factor-1 (FGF1) and FGF19 have been shown to improve glucose metabolism in diabetic rodents, but how this occurs is unknown. Here to investigate the mechanism of action of these growth factors, we perform intracerebroventricular (ICV) injections of recombinant FGF1 or FGF19 in an awake rat model of type 1 diabetes (T1D) and measure rates of whole-body lipolysis, hepatic acetyl CoA content, pyruvate carboxylase activity and hepatic glucose production. We show that ICV injection of FGF19 or FGF1 leads to a ∼60% reduction in hepatic glucose production, hepatic acetyl CoA content and whole-body lipolysis, which results from decreases in plasma ACTH and corticosterone concentrations. These effects are abrogated by an intra-arterial infusion of corticosterone. Taken together these studies identify suppression of the HPA axis and ensuing reductions in hepatic acetyl CoA content as a common mechanism responsible for mediating the acute, insulin-independent, glucose-lowering effects of FGF1 and FGF19 in rodents with poorly controlled T1D. Fibroblast growth factor (FGF) family proteins have anti-diabetic effects, but how they work is currently unclear. Here the authors show that injections of FGF1 or FGF19 into the brain of diabetic rats alter glucose and lipid homeostasis by suppressing activity of the hypothalamic-pituitary-adrenal signalling axis.
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