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

• DOI: 10.2337/db14-0472
• Publication Date: 2014-05-02T04:46:15Z
• Authors: Lea Rahtu-Korpela; Sara Karsikas; Sohvi Hörkkö; Roberto Blanco Se...; Eveliina Lammenta...; Kari A. Mäkelä; Karl-Heinz Herzig; Gail Walkinshaw; Kari I. Kivirikko; Johanna Myllyharju; Raisa Serpi; Peppi Koivunen
• Keywords: Carbohydrate Metabolism

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 hypoxia-inducible factor (HIF), potent governor metabolism, with isoenzyme being main regulator. We investigated whether HIF-P4H-2 inhibition could be used treat obesity its consequences. Hif-p4h-2–deficient mice, fed normal chow or high-fat diet, had less adipose tissue, smaller adipocytes, tissue inflammation than their littermates. They also improved glucose tolerance insulin sensitivity. Furthermore, mRNA levels HIF-1 targets transporters, glycolytic enzymes, pyruvate dehydrogenase kinase-1 were increased in tissues, whereas acetyl-CoA concentration was decreased. The hepatic level HIF-2 target receptor substrate-2 higher, that two key enzymes fatty acid synthesis lower. Serum cholesterol de novo lipid decreased, mice protected against steatosis. Oral administration an HIF-P4H inhibitor, FG-4497, wild-type dysfunction phenocopied these beneficial effects. may novel therapy not only protects development consequences but reverses conditions.