HIF prolyl 4-hydroxylase-2 inhibition improves glucose and lipid metabolism and protects against obesity and metabolic dysfunction.
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.
Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, FIN-90014 Oulu, Finland.
Lea
L
Rahtu-Korpela
Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, FIN-90014 Oulu, Finland.
Sara
S
Karsikas
Nordlab Oulu, Oulu University Hospital, FIN-90220 Oulu, Finland Department of Medical Microbiology and Immunology, Medical Research Center, University of Oulu, FIN-90014 Oulu, Finland.
Sohvi
S
Hörkkö
Department of Radiology, Oulu University Hospital and University of Oulu, FIN-90029 Oulu, Finland.
Roberto
R
Blanco Sequeiros
Department of Radiology, Oulu University Hospital and University of Oulu, FIN-90029 Oulu, Finland.
Eveliina
E
Lammentausta
Biocenter Oulu, Department of Physiology, University of Oulu, FIN-90014 Oulu, Finland.
Kari A
KA
Mäkelä
Biocenter Oulu, Department of Physiology, University of Oulu, FIN-90014 Oulu, Finland.
Karl-Heinz
KH
Herzig
FibroGen, Inc., San Francisco, CA.
Gail
G
Walkinshaw
Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, FIN-90014 Oulu, Finland.
Kari I
KI
Kivirikko
Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, FIN-90014 Oulu, Finland.
Johanna
J
Myllyharju
Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, FIN-90014 Oulu, Finland.
Raisa
R
Serpi
Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, FIN-90014 Oulu, Finland peppi.koivunen@oulu.fi.
Peppi
P
Koivunen
D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D050260:Carbohydrate Metabolism / Q000502:physiology*; D004032:Diet; D005947:Glucose / Q000378:metabolism*; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D050356:Lipid Metabolism / Q000502:physiology*; D008099:Liver / Q000378:metabolism; D024821:Metabolic Syndrome / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000235:genetics / Q000378:metabolism*
D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D005947:Glucose