生物谷报道:来自西南医学中心的研究者称,一个关键的激素可以改变饥饿小鼠的代谢途径,并且以类似冬眠的方式让小鼠保存能量。这个起着抗饥饿效果的激素,就是成纤维生长因子21(fibroblast growth factor 21;FGF21)。此项研究发表在近日的Cell Metabolism杂志上,为治疗人类肥胖症、代谢紊乱提供了一个潜在的药物靶点
在饥饿小鼠中,FGF21是受一个调控脂肪作为能量的细胞受体激活的。激活后,FGF21可以将细胞的代谢途径由原先的以碳水化合物为能量来源,转变成以脂肪为能量来源。不仅如此,FGF21还诱导小鼠体温及生理活性下降,以一种近乎“冬眠”的方式帮助小鼠度过饥饿时光,存活下来。
“这个激素可以在小鼠缺乏足够营养的时候,及时改变代谢、行为途径,”西南医学中心的分子生物学和药理学教授Steven Kliewer博士介绍说,他是此项研究的主持者,“我们希望能针对这条激素-受体信号通路,设计出攻克人类肥胖症和其他病症的新一代药物。”
原始出处:
Cell Metabolism, Vol 5, 415-425, 06 June 2007
Endocrine Regulation of the Fasting Response by PPARα-Mediated Induction of Fibroblast Growth Factor 21
Takeshi Inagaki,1 Paul Dutchak,1 Guixiang Zhao,1 Xunshan Ding,2,3 Laurent Gautron,2,4,5 Vinay Parameswara,4 Yong Li,8 Regina Goetz,9 Moosa Mohammadi,9 Victoria Esser,4 Joel K. Elmquist,2,4,5 Robert D. Gerard,1,4 Shawn C. Burgess,6 Robert E. Hammer,7 David J. Mangelsdorf,2,3 and Steven A. Kliewer1,2,
1 Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
2 Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
3 Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
4 Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
5 Division of Hypothalamic Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
6 Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
7 Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
8 Van Andel Research Institute, Grand Rapids, MI 49503, USA
9 Department of Pharmacology, New York University School of Medicine, New York, NY 10016, USA
Corresponding author
Steven A. Kliewer
steven.kliewer@utsouthwestern.edu
Summary
Peroxisome proliferator-activated receptor α (PPARα) regulates the utilization of fat as an energy source during starvation and is the molecular target for the fibrate dyslipidemia drugs. Here, we identify the endocrine hormone fibroblast growth factor 21 (FGF21) as a mediator of the pleiotropic actions of PPARα. FGF21 is induced directly by PPARα in liver in response to fasting and PPARα agonists. FGF21 in turn stimulates lipolysis in white adipose tissue and ketogenesis in liver. FGF21 also reduces physical activity and promotes torpor, a short-term hibernation-like state of regulated hypothermia that conserves energy. These findings demonstrate an unexpected role for the PPARα-FGF21 endocrine signaling pathway in regulating diverse metabolic and behavioral aspects of the adaptive response to starvation.