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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 promotes weight gain and insulin resistance but does not worsen high fat diet-induced metabolic alterations.WT (open bars) and PHD1−/− (black bars) mice were fed a low-fat (LFD, 10% fat) or high-fat (HFD, 45% fat) diet for 12 weeks. Body weight was monitored throughout the experimental period (A). Delta (Δ) change in body weight from the start of diet (B), weight of liver, epididymal (eWAT) and subcutaneous (scWAT) white adipose tissue, and skeletal (Sk.) muscle (C) were measured after sacrifice at week 12. Mean daily food intake (D) was recorded during 12 weeks. At week 12, plasma triglycerides (E), total cholesterol (F), glucose (G) and insulin levels (H) were measured in 6-hour unfed mice and HOMA-IR (I) was calculated. An intraperitoneal GTT (2 g/kg of total body weight) was performed in 6-hour unfed mice at week 11. Blood glucose levels were measured at the indicated time-points (J), and the area under the curve (AUC) of the glucose excursion curve was calculated as a measure of glucose tolerance (K). The plasma insulin level during ipGTT was measured at 15 minutes (L). Data are means ± SEM (n = 4 for LFD-WT; n = 7 for LFD-PHD1−/−; n = 5 for HFD-WT; n = 7 for HFD-PHD1−/−). *p < 0.05 vs LFD-fed mice, #p < 0.05 vs WT mice.
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f2: PHD1 deficiency promotes weight gain and insulin resistance but does not worsen high fat diet-induced metabolic alterations.WT (open bars) and PHD1−/− (black bars) mice were fed a low-fat (LFD, 10% fat) or high-fat (HFD, 45% fat) diet for 12 weeks. Body weight was monitored throughout the experimental period (A). Delta (Δ) change in body weight from the start of diet (B), weight of liver, epididymal (eWAT) and subcutaneous (scWAT) white adipose tissue, and skeletal (Sk.) muscle (C) were measured after sacrifice at week 12. Mean daily food intake (D) was recorded during 12 weeks. At week 12, plasma triglycerides (E), total cholesterol (F), glucose (G) and insulin levels (H) were measured in 6-hour unfed mice and HOMA-IR (I) was calculated. An intraperitoneal GTT (2 g/kg of total body weight) was performed in 6-hour unfed mice at week 11. Blood glucose levels were measured at the indicated time-points (J), and the area under the curve (AUC) of the glucose excursion curve was calculated as a measure of glucose tolerance (K). The plasma insulin level during ipGTT was measured at 15 minutes (L). Data are means ± SEM (n = 4 for LFD-WT; n = 7 for LFD-PHD1−/−; n = 5 for HFD-WT; n = 7 for HFD-PHD1−/−). *p < 0.05 vs LFD-fed mice, #p < 0.05 vs WT mice.

Mentions: To further investigate the impact of PHD1 deletion on metabolic homeostasis, WT and PHD1−/− mice were next challenged with synthetic low- (LFD, 10% kcal from fat) or high-fat (HFD, 60% kcal from fat) diets for 12 weeks. PHD1−/− mice fed a LFD for 12 weeks displayed increased body weight gain and liver and fat mass compared to WT mice (Fig. 2A–C), despite similar daily food intake (Fig. 2D). In line with what was observed with regular chow diet, fasting plasma TG and insulin levels as well as HOMA-IR were significantly higher in LFD-fed PHD1−/− mice compared to WT mice (Fig. 2E,H,I), indicating impairment in whole-body metabolic homeostasis. Furthermore, intraperitoneal GTT demonstrated increased glucose intolerance and higher plasma insulin levels in LFD-fed PHD−/− mice compared to their WT counterparts (Fig. 2J–L). Of note, the differences in body weight gain, plasma parameters and whole-body metabolic homeostasis in between genotypes were already observed after 6 weeks of synthetic diet (Fig. S2). Overall, these results demonstrate that PHD1−/− mice on LFD maintain an adverse metabolic phenotype 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 promotes weight gain and insulin resistance but does not worsen high fat diet-induced metabolic alterations.WT (open bars) and PHD1−/− (black bars) mice were fed a low-fat (LFD, 10% fat) or high-fat (HFD, 45% fat) diet for 12 weeks. Body weight was monitored throughout the experimental period (A). Delta (Δ) change in body weight from the start of diet (B), weight of liver, epididymal (eWAT) and subcutaneous (scWAT) white adipose tissue, and skeletal (Sk.) muscle (C) were measured after sacrifice at week 12. Mean daily food intake (D) was recorded during 12 weeks. At week 12, plasma triglycerides (E), total cholesterol (F), glucose (G) and insulin levels (H) were measured in 6-hour unfed mice and HOMA-IR (I) was calculated. An intraperitoneal GTT (2 g/kg of total body weight) was performed in 6-hour unfed mice at week 11. Blood glucose levels were measured at the indicated time-points (J), and the area under the curve (AUC) of the glucose excursion curve was calculated as a measure of glucose tolerance (K). The plasma insulin level during ipGTT was measured at 15 minutes (L). Data are means ± SEM (n = 4 for LFD-WT; n = 7 for LFD-PHD1−/−; n = 5 for HFD-WT; n = 7 for HFD-PHD1−/−). *p < 0.05 vs LFD-fed mice, #p < 0.05 vs WT mice.
© Copyright Policy - open-access
Related In: Results  -  Collection

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f2: PHD1 deficiency promotes weight gain and insulin resistance but does not worsen high fat diet-induced metabolic alterations.WT (open bars) and PHD1−/− (black bars) mice were fed a low-fat (LFD, 10% fat) or high-fat (HFD, 45% fat) diet for 12 weeks. Body weight was monitored throughout the experimental period (A). Delta (Δ) change in body weight from the start of diet (B), weight of liver, epididymal (eWAT) and subcutaneous (scWAT) white adipose tissue, and skeletal (Sk.) muscle (C) were measured after sacrifice at week 12. Mean daily food intake (D) was recorded during 12 weeks. At week 12, plasma triglycerides (E), total cholesterol (F), glucose (G) and insulin levels (H) were measured in 6-hour unfed mice and HOMA-IR (I) was calculated. An intraperitoneal GTT (2 g/kg of total body weight) was performed in 6-hour unfed mice at week 11. Blood glucose levels were measured at the indicated time-points (J), and the area under the curve (AUC) of the glucose excursion curve was calculated as a measure of glucose tolerance (K). The plasma insulin level during ipGTT was measured at 15 minutes (L). Data are means ± SEM (n = 4 for LFD-WT; n = 7 for LFD-PHD1−/−; n = 5 for HFD-WT; n = 7 for HFD-PHD1−/−). *p < 0.05 vs LFD-fed mice, #p < 0.05 vs WT mice.
Mentions: To further investigate the impact of PHD1 deletion on metabolic homeostasis, WT and PHD1−/− mice were next challenged with synthetic low- (LFD, 10% kcal from fat) or high-fat (HFD, 60% kcal from fat) diets for 12 weeks. PHD1−/− mice fed a LFD for 12 weeks displayed increased body weight gain and liver and fat mass compared to WT mice (Fig. 2A–C), despite similar daily food intake (Fig. 2D). In line with what was observed with regular chow diet, fasting plasma TG and insulin levels as well as HOMA-IR were significantly higher in LFD-fed PHD1−/− mice compared to WT mice (Fig. 2E,H,I), indicating impairment in whole-body metabolic homeostasis. Furthermore, intraperitoneal GTT demonstrated increased glucose intolerance and higher plasma insulin levels in LFD-fed PHD−/− mice compared to their WT counterparts (Fig. 2J–L). Of note, the differences in body weight gain, plasma parameters and whole-body metabolic homeostasis in between genotypes were already observed after 6 weeks of synthetic diet (Fig. S2). Overall, these results demonstrate that PHD1−/− mice on LFD maintain an adverse metabolic phenotype 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