HIF Prolyl 4-Hydroxylase-2 Inhibition Improves Glucose and Lipid Metabolism and Protects Against Obesity and Metabolic Dysfunction

被引:97
作者
Rahtu-Korpela, Lea [1 ]
Karsikas, Sara [1 ]
Horkko, Sohvi [2 ,3 ]
Sequeiros, Roberto Blanco [4 ,5 ]
Lammentausta, Eveliina [4 ,5 ]
Makela, Kari A. [6 ]
Herzig, Karl-Heinz [6 ]
Walkinshaw, Gail [7 ]
Kivirikko, Karl I. [1 ]
Myllyharju, Johanna [1 ]
Serpi, Raisa [1 ]
Koivunen, Peppi [1 ]
机构
[1] Univ Oulu, Bioctr Oulu, Fac Biochem & Mol Med, Oulu Ctr Cell Matrix Res, FIN-90014 Oulu, Finland
[2] Oulu Univ Hosp, Nordlab Oulu, FIN-90220 Oulu, Finland
[3] Univ Oulu, Med Res Ctr, Dept Med Microbiol & Immunol, FIN-90014 Oulu, Finland
[4] Oulu Univ Hosp, Dept Radiol, FIN-90029 Oulu, Finland
[5] Univ Oulu, FIN-90029 Oulu, Finland
[6] Univ Oulu, Dept Physiol, Bioctr Oulu, FIN-90014 Oulu, Finland
[7] FibroGen Inc, San Francisco, CA USA
基金
芬兰科学院;
关键词
HYDROXYLASE DOMAIN PROTEIN-2; OXYGEN HOMEOSTASIS; ADIPOSE-TISSUE; HYPOXIA; GENE; MICE; CHOLESTEROL; EXPRESSION; FAMILY;
D O I
10.2337/db14-0472
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Obesity is a major public health problem, predisposing subjects to metabolic syndrome, type 2 diabetes, and cardiovascular diseases. Specific prolyl 4-hydroxylases (P4Hs) regulate the stability of the hypoxia-inducible factor (HIF), a potent governor of metabolism, with isoenzyme 2 being the main regulator. We investigated whether HIF-P4H-2 inhibition could be used to treat obesity and its consequences. Hif-p4h-2-deficient mice, whether fed normal chow or a high-fat diet, had less adipose tissue, smaller adipocytes, and less adipose tissue inflammation than their littermates. They also had improved glucose tolerance and insulin sensitivity. Furthermore, the mRNA levels of the HIF-1 targets glucose transporters, glycolytic enzymes, and pyruvate dehydrogenase kinase-1 were increased in their tissues, whereas acetyl-CoA concentration was decreased. The hepatic mRNA level of the HIF-2 target insulin receptor substrate-2 was higher, whereas that of two key enzymes of fatty acid synthesis was lower. Serum cholesterol levels and de novo lipid synthesis were decreased, and the mice were protected against hepatic steatosis. Oral administration of an HIF-P4H inhibitor, FG-4497, to wild-type mice with metabolic dysfunction phenocopied these beneficial effects. HIF-P4H-2 inhibition may be a novel therapy that not only protects against the development of obesity and its consequences but also reverses these conditions.
引用
收藏
页码:3324 / 3333
页数:10
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