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Hypoxia-inducible factor prolyl hydroxylase 1 (PHD1) deficiency promotes hepatic steatosis and liver-specific insulin resistance in mice.

Thomas A, Belaidi E, Aron-Wisnewsky J, van der Zon GC, Levy P, Clement K, Pepin JL, Godin-Ribuot D, Guigas B - Sci Rep (2016)

Bottom Line: Prolyl hydroxylases (PHDs) play an important role in regulating HIF-α isoform stability.PHD1 deficiency led to increase in glycolytic gene expression, lipogenic proteins ACC and FAS, hepatic steatosis and liver-specific insulin resistance.In conclusion, PHD1 deficiency promotes hepatic steatosis and liver-specific insulin resistance but does not worsen the deleterious effects of HFD on metabolic homeostasis.

View Article: PubMed Central - PubMed

Affiliation: Laboratoire HP2, Université Grenoble Alpes, Grenoble, F-38042 France.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus

PHD1 deficiency induces glucose intolerance and insulin resistance in standard chow-fed mice.Body weight (A) and weights of liver, epididymal white adipose tissue (eWAT) and subcutaneous white adipose tissue (scWAT) were measured at sacrifice in 12 week-old WT (open bars) and PHD1−/− (black bars) mice on standard chow diet (B). Daily food intake (C) was monitored during 5 weeks. Fasting plasma triglycerides (D), total cholesterol (E), glucose (F) and insulin (G) levels were determined in 6-hour unfed mice and HOMA-IR (H) was calculated. An intraperitoneal glucose tolerance test (ipGTT, 2 g/kg total body weight) was performed in 6-hour unfed mice. Blood glucose levels were measured at the indicated time-points (I), and the AUC of the glucose excursion curve was calculated as a surrogate for whole-body glucose tolerance (J). The plasma insulin level during ipGTT was measured at 15 minutes (K). An intraperitoneal insulin tolerance test (0.5 U/kg total body weight) was performed in 4-hour unfed mice. Blood glucose levels were measured at the indicated time-points (L), and the AUC of the glucose excursion curve was calculated as a surrogate for whole-body insulin sensitivity (M). Data are means ± SEM (n = 7 for WT; n = 13 for PHD1−/−). #p < 0.05 vs WT mice.
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f1: PHD1 deficiency induces glucose intolerance and insulin resistance in standard chow-fed mice.Body weight (A) and weights of liver, epididymal white adipose tissue (eWAT) and subcutaneous white adipose tissue (scWAT) were measured at sacrifice in 12 week-old WT (open bars) and PHD1−/− (black bars) mice on standard chow diet (B). Daily food intake (C) was monitored during 5 weeks. Fasting plasma triglycerides (D), total cholesterol (E), glucose (F) and insulin (G) levels were determined in 6-hour unfed mice and HOMA-IR (H) was calculated. An intraperitoneal glucose tolerance test (ipGTT, 2 g/kg total body weight) was performed in 6-hour unfed mice. Blood glucose levels were measured at the indicated time-points (I), and the AUC of the glucose excursion curve was calculated as a surrogate for whole-body glucose tolerance (J). The plasma insulin level during ipGTT was measured at 15 minutes (K). An intraperitoneal insulin tolerance test (0.5 U/kg total body weight) was performed in 4-hour unfed mice. Blood glucose levels were measured at the indicated time-points (L), and the AUC of the glucose excursion curve was calculated as a surrogate for whole-body insulin sensitivity (M). Data are means ± SEM (n = 7 for WT; n = 13 for PHD1−/−). #p < 0.05 vs WT mice.

Mentions: To investigate the role of PHD1 on whole-body metabolic homeostasis, 12 week-old PHD1-deficient (PHD1−/−) and WT control mice on regular chow diet were first compared. PHD1−/− mice exhibited lower body and liver weights (−8 and −18%, respectively; p < 0.05; Fig. 1A,B) and higher epididymal and subcutaneous adipose tissue weights (+83 and +58%, respectively; p < 0.05; Fig. 1A,B) compared to WT mice, suggesting that PHD1 controls adiposity. In link with decreased body weight, mean daily food intake was also lower in PHD1−/− compared to WT mice (Fig. 1C). Despite reduced body weight, PHD1 deficiency was associated with elevated fasting plasma triglycerides (TG) (Fig. 1D), glucose (Fig. 1F) and insulin (Fig. 1G) levels, whereas total cholesterol (TC) was unchanged (Fig. 1E). The calculated HOmeostasis Model Assessment of Insulin Resistance index (HOMA-IR) adjusted for rodents was increased in PHD1−/− mice compared to WT mice (Fig. 1H), suggesting systemic insulin resistance. To assess the effect of PHD1 deletion on whole-body glucose homeostasis and insulin sensitivity, mice were next subjected to intraperitoneal glucose (GTT) and insulin tolerance tests (ITT), respectively. In line with increased HOMA-IR, PHD1−/− mice displayed impaired whole-body glucose tolerance (Fig. 1I–K) and insulin sensitivity (Fig. 1L,M) compared to WT mice.


Hypoxia-inducible factor prolyl hydroxylase 1 (PHD1) deficiency promotes hepatic steatosis and liver-specific insulin resistance in mice.

Thomas A, Belaidi E, Aron-Wisnewsky J, van der Zon GC, Levy P, Clement K, Pepin JL, Godin-Ribuot D, Guigas B - Sci Rep (2016)

PHD1 deficiency induces glucose intolerance and insulin resistance in standard chow-fed mice.Body weight (A) and weights of liver, epididymal white adipose tissue (eWAT) and subcutaneous white adipose tissue (scWAT) were measured at sacrifice in 12 week-old WT (open bars) and PHD1−/− (black bars) mice on standard chow diet (B). Daily food intake (C) was monitored during 5 weeks. Fasting plasma triglycerides (D), total cholesterol (E), glucose (F) and insulin (G) levels were determined in 6-hour unfed mice and HOMA-IR (H) was calculated. An intraperitoneal glucose tolerance test (ipGTT, 2 g/kg total body weight) was performed in 6-hour unfed mice. Blood glucose levels were measured at the indicated time-points (I), and the AUC of the glucose excursion curve was calculated as a surrogate for whole-body glucose tolerance (J). The plasma insulin level during ipGTT was measured at 15 minutes (K). An intraperitoneal insulin tolerance test (0.5 U/kg total body weight) was performed in 4-hour unfed mice. Blood glucose levels were measured at the indicated time-points (L), and the AUC of the glucose excursion curve was calculated as a surrogate for whole-body insulin sensitivity (M). Data are means ± SEM (n = 7 for WT; n = 13 for PHD1−/−). #p < 0.05 vs WT mice.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4837354&req=5

f1: PHD1 deficiency induces glucose intolerance and insulin resistance in standard chow-fed mice.Body weight (A) and weights of liver, epididymal white adipose tissue (eWAT) and subcutaneous white adipose tissue (scWAT) were measured at sacrifice in 12 week-old WT (open bars) and PHD1−/− (black bars) mice on standard chow diet (B). Daily food intake (C) was monitored during 5 weeks. Fasting plasma triglycerides (D), total cholesterol (E), glucose (F) and insulin (G) levels were determined in 6-hour unfed mice and HOMA-IR (H) was calculated. An intraperitoneal glucose tolerance test (ipGTT, 2 g/kg total body weight) was performed in 6-hour unfed mice. Blood glucose levels were measured at the indicated time-points (I), and the AUC of the glucose excursion curve was calculated as a surrogate for whole-body glucose tolerance (J). The plasma insulin level during ipGTT was measured at 15 minutes (K). An intraperitoneal insulin tolerance test (0.5 U/kg total body weight) was performed in 4-hour unfed mice. Blood glucose levels were measured at the indicated time-points (L), and the AUC of the glucose excursion curve was calculated as a surrogate for whole-body insulin sensitivity (M). Data are means ± SEM (n = 7 for WT; n = 13 for PHD1−/−). #p < 0.05 vs WT mice.
Mentions: To investigate the role of PHD1 on whole-body metabolic homeostasis, 12 week-old PHD1-deficient (PHD1−/−) and WT control mice on regular chow diet were first compared. PHD1−/− mice exhibited lower body and liver weights (−8 and −18%, respectively; p < 0.05; Fig. 1A,B) and higher epididymal and subcutaneous adipose tissue weights (+83 and +58%, respectively; p < 0.05; Fig. 1A,B) compared to WT mice, suggesting that PHD1 controls adiposity. In link with decreased body weight, mean daily food intake was also lower in PHD1−/− compared to WT mice (Fig. 1C). Despite reduced body weight, PHD1 deficiency was associated with elevated fasting plasma triglycerides (TG) (Fig. 1D), glucose (Fig. 1F) and insulin (Fig. 1G) levels, whereas total cholesterol (TC) was unchanged (Fig. 1E). The calculated HOmeostasis Model Assessment of Insulin Resistance index (HOMA-IR) adjusted for rodents was increased in PHD1−/− mice compared to WT mice (Fig. 1H), suggesting systemic insulin resistance. To assess the effect of PHD1 deletion on whole-body glucose homeostasis and insulin sensitivity, mice were next subjected to intraperitoneal glucose (GTT) and insulin tolerance tests (ITT), respectively. In line with increased HOMA-IR, PHD1−/− mice displayed impaired whole-body glucose tolerance (Fig. 1I–K) and insulin sensitivity (Fig. 1L,M) compared to WT mice.

Bottom Line: Prolyl hydroxylases (PHDs) play an important role in regulating HIF-α isoform stability.PHD1 deficiency led to increase in glycolytic gene expression, lipogenic proteins ACC and FAS, hepatic steatosis and liver-specific insulin resistance.In conclusion, PHD1 deficiency promotes hepatic steatosis and liver-specific insulin resistance but does not worsen the deleterious effects of HFD on metabolic homeostasis.

View Article: PubMed Central - PubMed

Affiliation: Laboratoire HP2, Université Grenoble Alpes, Grenoble, F-38042 France.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus