蛋白质组学

FIH蛋白可控小鼠体重 研发减肥药物新思路

美国研究人员日前报告说,他们发现小鼠体重与一种名为FIH的蛋白质有关,这一发现为研制减肥药物提供了新思路。

美国加州大学圣迭戈分校的研究人员在新一期美国《细胞—代谢》(Cell Metabolism)杂志上报告说,FIH是一种负责调节缺氧反应的蛋白质,缺乏这种蛋白质的小鼠会保持苗条和健康,哪怕它们进食的是高脂肪食物。

在实验过程中,研究人员通过基因技术培育出缺乏FIH蛋白质的实验鼠,然后让它们和普通实验鼠同时进食脂肪含量高达60%的食物。结果发现,缺乏FIH蛋白质的实验鼠平均身材明显比普通实验鼠“娇小”,并且具有更强的新陈代谢能力。而普通实验鼠不仅体重增加,还出现了脂肪肝等。

研究人员表示,将进一步研究FIH蛋白质的功能,以促进减肥新药的研发。

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           The Asparaginyl Hydroxylase Factor Inhibiting HIF-1α Is an Essential 
                                        Regulator of Metabolism

Na Zhang1, Zhenxing Fu2, Sarah Linke4, Johana Chicher5, Jeffrey J. Gorman5, DeeAnn Visk3,
Gabriel G. Haddad3,Lorenz Poellinger6, Daniel J. Peet4, Frank Powell, Randall S. Johnson1

1 Molecular Biology Section, Division of Biological Sciences, University of California, San Diego,
La Jolla, CA 92093,USA
2 Department of Medicine, School of Medicine, University of California, San Diego, La Jolla,
CA 92093, USA
3 Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla,
CA 92093, USA
4 School of Molecular and Biomedical Science, University of Adelaide, Adelaide,
SA 5005, Australia
5 Protein Discovery Centre, Queensland Institute of Medical Research, PO Royal Brisbane
Hospital, QLD 4029, Australia
6 Karolinska Institute, Stockholm S-17177, Sweden

Factor inhibiting HIF-1α (FIH) is an asparaginyl hydroxylase. Hydroxylation of HIF-α proteins by FIH blocks association of HIFs with the transcriptional coactivators CBP/p300, thus inhibiting transcriptional activation. We have created mice with a null mutation in the FIH gene and found that it has little or no discernable role in mice in altering classical aspects of HIF function, e.g., angiogenesis, erythropoiesis, or development. Rather, it is an essential regulator of metabolism: mice lacking FIH exhibit reduced body weight, elevated metabolic rate, hyperventilation, and improved glucose and lipid homeostasis and are resistant to high-fat-diet-induced weight gain and hepatic steatosis. Neuron-specific loss of FIH phenocopied some of the major metabolic phenotypes of the global null animals: those mice have reduced body weight, increased metabolic rate, and enhanced insulin sensitivity and are also protected against high-fat-diet-induced weight gain. These results demonstrate that FIH acts to a significant degree through the nervous system to regulate metabolism.

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