Hypoxia-inducible factor prolyl hydroxylase 1 (PHD1) deficiency promotes hepatic steatosis and liver-specific insulin resistance in mice.
Obesity is associated with local tissue hypoxia and elevated hypoxia-inducible factor 1 alpha (HIF-1α) in metabolic tissues. Prolyl hydroxylases (PHDs) play an important role in regulating HIF-α isoform stability. In the present study, we investigated the consequence of whole-body PHD1 gene (Egln2) inactivation on metabolic homeostasis in mice. At baseline, PHD1-/- mice exhibited higher white adipose tissue (WAT) mass, despite lower body weight, and impaired insulin sensitivity and glucose tolerance when compared to age-matched wild-type (WT) mice. When fed a synthetic low-fat diet, PHD1-/- mice also exhibit a higher body weight gain and WAT mass along with glucose intolerance and systemic insulin resistance compared to WT mice. PHD1 deficiency led to increase in glycolytic gene expression, lipogenic proteins ACC and FAS, hepatic steatosis and liver-specific insulin resistance. Furthermore, gene markers of inflammation were also increased in the liver, but not in WAT or skeletal muscle, of PHD1-/- mice. As expected, high-fat diet (HFD) promoted obesity, hepatic steatosis, tissue-specific inflammation and systemic insulin resistance in WT mice but these diet-induced metabolic alterations were not exacerbated in PHD1-/- mice. In conclusion, PHD1 deficiency promotes hepatic steatosis and liver-specific insulin resistance but does not worsen the deleterious effects of HFD on metabolic homeostasis.
Laboratoire HP2, Université Grenoble Alpes, Grenoble, F-38042 France.|INSERM U1042, Grenoble, F-38042 France.
Amandine
A
Thomas
Laboratoire HP2, Université Grenoble Alpes, Grenoble, F-38042 France.|INSERM U1042, Grenoble, F-38042 France.
Elise
E
Belaidi
Institute of Cardiometabolism and Nutrition (ICAN), Assistance Publique Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Paris, France.|INSERM, U1166, Nutriomics Team 6, Paris, France.|Sorbonne Universités, UPMC University Paris 06, UMR_S 1166, Nutriomics Team, Paris, France.
Judith
J
Aron-Wisnewsky
Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.
Gerard C
GC
van der Zon
Laboratoire HP2, Université Grenoble Alpes, Grenoble, F-38042 France.|INSERM U1042, Grenoble, F-38042 France.
Patrick
P
Levy
Institute of Cardiometabolism and Nutrition (ICAN), Assistance Publique Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Paris, France.|INSERM, U1166, Nutriomics Team 6, Paris, France.|Sorbonne Universités, UPMC University Paris 06, UMR_S 1166, Nutriomics Team, Paris, France.
Karine
K
Clement
Laboratoire HP2, Université Grenoble Alpes, Grenoble, F-38042 France.|INSERM U1042, Grenoble, F-38042 France.
Jean-Louis
JL
Pepin
Laboratoire HP2, Université Grenoble Alpes, Grenoble, F-38042 France.|INSERM U1042, Grenoble, F-38042 France.
Diane
D
Godin-Ribuot
Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.|Department of Parasitology, Leiden University Medical Center, Leiden, The Netherlands.
Bruno
B
Guigas
D050154:Adiposity; D000818:Animals; D001835:Body Weight; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D050171:Dyslipidemias / Q000378:metabolism; D004734:Energy Metabolism; D005234:Fatty Liver / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D018149:Glucose Intolerance / Q000378:metabolism; D006706:Homeostasis; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009928:Organ Specificity / Q000235:genetics; D011393:Procollagen-Proline Dioxygenase / Q000172:deficiency*
C522721:PHD1 protein, mouse; D011393:Procollagen-Proline Dioxygenase