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Lack of significant metabolic abnormalities in mice with liver-specific disruption of 11β-hydroxysteroid dehydrogenase type 1.

Lavery GG, Zielinska AE, Gathercole LL, Hughes B, Semjonous N, Guest P, Saqib K, Sherlock M, Reynolds G, Morgan SA, Tomlinson JW, Walker EA, Rabbitt EH, Stewart PM - Endocrinology (2012)

Bottom Line: Liver-specific deletion of 11β-HSD1 reduces corticosterone regeneration and may be important for setting aspects of HPA axis tone, without impacting upon urinary steroid metabolite profile.These discordant data have significant implications for the use of these biomarkers of 11β-HSD1 activity in clinical studies.The paucity of metabolic abnormalities in LKO points to important compensatory effects by HPA activation and to a crucial role of extrahepatic 11β-HSD1 expression, highlighting the contribution of cross talk between GC target tissues in determining metabolic phenotype.

View Article: PubMed Central - PubMed

Affiliation: Centre for Endocrinology, Diabetes and Metabolism, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, United Kingdom. g.g.lavery@bham.ac.uk

ABSTRACT
Glucocorticoids (GC) are implicated in the development of metabolic syndrome, and patients with GC excess share many clinical features, such as central obesity and glucose intolerance. In patients with obesity or type 2 diabetes, systemic GC concentrations seem to be invariably normal. Tissue GC concentrations determined by the hypothalamic-pituitary-adrenal (HPA) axis and local cortisol (corticosterone in mice) regeneration from cortisone (11-dehydrocorticosterone in mice) by the 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme, principally expressed in the liver. Transgenic mice have demonstrated the importance of 11β-HSD1 in mediating aspects of the metabolic syndrome, as well as HPA axis control. In order to address the primacy of hepatic 11β-HSD1 in regulating metabolism and the HPA axis, we have generated liver-specific 11β-HSD1 knockout (LKO) mice, assessed biomarkers of GC metabolism, and examined responses to high-fat feeding. LKO mice were able to regenerate cortisol from cortisone to 40% of control and had no discernible difference in a urinary metabolite marker of 11β-HSD1 activity. Although circulating corticosterone was unaltered, adrenal size was increased, indicative of chronic HPA stimulation. There was a mild improvement in glucose tolerance but with insulin sensitivity largely unaffected. Adiposity and body weight were unaffected as were aspects of hepatic lipid homeostasis, triglyceride accumulation, and serum lipids. Additionally, no changes in the expression of genes involved in glucose or lipid homeostasis were observed. Liver-specific deletion of 11β-HSD1 reduces corticosterone regeneration and may be important for setting aspects of HPA axis tone, without impacting upon urinary steroid metabolite profile. These discordant data have significant implications for the use of these biomarkers of 11β-HSD1 activity in clinical studies. The paucity of metabolic abnormalities in LKO points to important compensatory effects by HPA activation and to a crucial role of extrahepatic 11β-HSD1 expression, highlighting the contribution of cross talk between GC target tissues in determining metabolic phenotype.

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Hepatic gene expression: glucose homeostasis. A, Relative glucose homeostasis gene mRNA levels in control and LKO mice on high-fat (HF) diet. B, Fold induction from fed to fasting state of G6Pase and PEPCK (*, P < 0.05; **, P < 0.01 vs. fed state). Con, Control; PGC1a, peroxisome proliferator-activated receptor gamma coactivator 1-α; GK, glucokinase.
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Figure 4: Hepatic gene expression: glucose homeostasis. A, Relative glucose homeostasis gene mRNA levels in control and LKO mice on high-fat (HF) diet. B, Fold induction from fed to fasting state of G6Pase and PEPCK (*, P < 0.05; **, P < 0.01 vs. fed state). Con, Control; PGC1a, peroxisome proliferator-activated receptor gamma coactivator 1-α; GK, glucokinase.

Mentions: We examined the expression of hepatic phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase catalytic subunit (G6Pase), glucokinase, and peroxisome proliferator-activated receptor gamma coactivator 1α mRNA levels and determined them to be unaltered in LKO compared with control mice on a high-fat diet, suggesting that there is no major change to the gluconeogenic pathway or a major regulator of hepatic glucose homeostasis (Fig. 4A). Fasting is a stress status that invokes GC stimulation of hepatic glucose output. We assessed the expression of PEPCK and G6Pase in fed and overnight-fasted LKO and control mice on a regular chow diet. In either nutritional state, there was no difference in expression levels between LKO and controls, with mRNA induction to fasting being similar in both (Fig. 4B), corroborating the notion that loss of hepatic 11β-HSD1 activity has minimal impact upon liver-mediated glucose homeostasis.


Lack of significant metabolic abnormalities in mice with liver-specific disruption of 11β-hydroxysteroid dehydrogenase type 1.

Lavery GG, Zielinska AE, Gathercole LL, Hughes B, Semjonous N, Guest P, Saqib K, Sherlock M, Reynolds G, Morgan SA, Tomlinson JW, Walker EA, Rabbitt EH, Stewart PM - Endocrinology (2012)

Hepatic gene expression: glucose homeostasis. A, Relative glucose homeostasis gene mRNA levels in control and LKO mice on high-fat (HF) diet. B, Fold induction from fed to fasting state of G6Pase and PEPCK (*, P < 0.05; **, P < 0.01 vs. fed state). Con, Control; PGC1a, peroxisome proliferator-activated receptor gamma coactivator 1-α; GK, glucokinase.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3475725&req=5

Figure 4: Hepatic gene expression: glucose homeostasis. A, Relative glucose homeostasis gene mRNA levels in control and LKO mice on high-fat (HF) diet. B, Fold induction from fed to fasting state of G6Pase and PEPCK (*, P < 0.05; **, P < 0.01 vs. fed state). Con, Control; PGC1a, peroxisome proliferator-activated receptor gamma coactivator 1-α; GK, glucokinase.
Mentions: We examined the expression of hepatic phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase catalytic subunit (G6Pase), glucokinase, and peroxisome proliferator-activated receptor gamma coactivator 1α mRNA levels and determined them to be unaltered in LKO compared with control mice on a high-fat diet, suggesting that there is no major change to the gluconeogenic pathway or a major regulator of hepatic glucose homeostasis (Fig. 4A). Fasting is a stress status that invokes GC stimulation of hepatic glucose output. We assessed the expression of PEPCK and G6Pase in fed and overnight-fasted LKO and control mice on a regular chow diet. In either nutritional state, there was no difference in expression levels between LKO and controls, with mRNA induction to fasting being similar in both (Fig. 4B), corroborating the notion that loss of hepatic 11β-HSD1 activity has minimal impact upon liver-mediated glucose homeostasis.

Bottom Line: Liver-specific deletion of 11β-HSD1 reduces corticosterone regeneration and may be important for setting aspects of HPA axis tone, without impacting upon urinary steroid metabolite profile.These discordant data have significant implications for the use of these biomarkers of 11β-HSD1 activity in clinical studies.The paucity of metabolic abnormalities in LKO points to important compensatory effects by HPA activation and to a crucial role of extrahepatic 11β-HSD1 expression, highlighting the contribution of cross talk between GC target tissues in determining metabolic phenotype.

View Article: PubMed Central - PubMed

Affiliation: Centre for Endocrinology, Diabetes and Metabolism, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham B15 2TT, United Kingdom. g.g.lavery@bham.ac.uk

ABSTRACT
Glucocorticoids (GC) are implicated in the development of metabolic syndrome, and patients with GC excess share many clinical features, such as central obesity and glucose intolerance. In patients with obesity or type 2 diabetes, systemic GC concentrations seem to be invariably normal. Tissue GC concentrations determined by the hypothalamic-pituitary-adrenal (HPA) axis and local cortisol (corticosterone in mice) regeneration from cortisone (11-dehydrocorticosterone in mice) by the 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme, principally expressed in the liver. Transgenic mice have demonstrated the importance of 11β-HSD1 in mediating aspects of the metabolic syndrome, as well as HPA axis control. In order to address the primacy of hepatic 11β-HSD1 in regulating metabolism and the HPA axis, we have generated liver-specific 11β-HSD1 knockout (LKO) mice, assessed biomarkers of GC metabolism, and examined responses to high-fat feeding. LKO mice were able to regenerate cortisol from cortisone to 40% of control and had no discernible difference in a urinary metabolite marker of 11β-HSD1 activity. Although circulating corticosterone was unaltered, adrenal size was increased, indicative of chronic HPA stimulation. There was a mild improvement in glucose tolerance but with insulin sensitivity largely unaffected. Adiposity and body weight were unaffected as were aspects of hepatic lipid homeostasis, triglyceride accumulation, and serum lipids. Additionally, no changes in the expression of genes involved in glucose or lipid homeostasis were observed. Liver-specific deletion of 11β-HSD1 reduces corticosterone regeneration and may be important for setting aspects of HPA axis tone, without impacting upon urinary steroid metabolite profile. These discordant data have significant implications for the use of these biomarkers of 11β-HSD1 activity in clinical studies. The paucity of metabolic abnormalities in LKO points to important compensatory effects by HPA activation and to a crucial role of extrahepatic 11β-HSD1 expression, highlighting the contribution of cross talk between GC target tissues in determining metabolic phenotype.

Show MeSH
Related in: MedlinePlus