HIF prolyl 4-hydroxylase-2 inhibition improves glucose and lipid metabolism and protects against obesity and metabolic dysfunction

  1. Peppi Koivunen1
  1. 1Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, FIN-90014 Oulu, Finland;
  2. 2Nordlab Oulu, Oulu University Hospital, FIN-90220, Oulu, Finland, Department of Medical Microbiology and Immunology, Medical Research Center, University of Oulu, FIN-90014 Oulu, Finland;
  3. 3Department of Radiology, Oulu University Hospital and University of Oulu, FIN-90029 Oulu, Finland;
  4. 4Biocenter Oulu, Department of Physiology, University of Oulu, FIN-90014 Oulu, Finland;
  5. 5FibroGen Inc., San Francisco, CA 94158, USA
  1. Corresponding author: Peppi Koivunen, Email: peppi.koivunen{at}oulu.fi

Abstract

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, isoenzyme 2 being the main regulator. We investigated here 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. The mRNA levels of the HIF-1 targets glucose transporters, glycolytic enzymes and pyruvate dehydrogenase kinase-1 were increased in their tissues, while acetyl-CoA concentration was decreased. The hepatic mRNA level of the HIF-2 target insulin receptor substrate-2 was higher, while those of two key enzymes of fatty acid synthesis were lowered. Serum cholesterol levels and de novo lipid synthesis were decreased and the mice were protected against hepatic steatosis. Oral administration of a HIF-P4H inhibitor, FG-4497, to wild-type mice with a 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.

  • Received March 21, 2014.
  • Accepted April 23, 2014.

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