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

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, 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.

• Authors: Lea Rahtu-Korpela, Sara Karsikas, Sohvi Hörkkö, Roberto Blanco Sequeiros, Eveliina Lammentausta, Kari A Mäkelä, Karl-Heinz Herzig, Gail Walkinshaw, Kari I Kivirikko, Johanna Myllyharju, Raisa Serpi, Peppi Koivunen
• Journal: Diabetes (Diabetes) Vol. 63 Issue 10 Pg. 3324-33 (Oct 2014) ISSN: 1939-327X [Electronic] United States
• PMID: 24789921 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Chemical References

• Hypoxia-Inducible Factor-Proline Dioxygenases
• Glucose

Topics

• Adipocytes (metabolism)
• Animals
• Carbohydrate Metabolism (physiology)
• Diet
• Glucose (metabolism)
• Hypoxia-Inducible Factor-Proline Dioxygenases (genetics, metabolism)
• Inflammation (genetics, metabolism)
• Lipid Metabolism (physiology)
• Liver (metabolism)
• Metabolic Syndrome (metabolism)
• Mice
• Mice, Knockout
• Obesity (genetics, metabolism)