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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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Metabolic parameters on low- and high-fat diet. In all cases n = 7–9 with data collected after 18 wk on diet. A, Growth curve on low-fat (LF) and high-fat (HF) diet in control and LKO mice. B, Average daily food intake (n = 5 from 6 wk). Glucose tolerance in control and LKO mice on LF (C) and HF (D) diet (**, P < 0.01 vs. control). E, Insulin tolerance in control and LKO mice on HF diet. Fed (F) and fasted (G) insulin on LF and HF diets (**, P < 0.01 vs. HF control; #, P < 0.05 vs. fed; ††, P < 0.01 vs. LF). Control, Con.
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Figure 3: Metabolic parameters on low- and high-fat diet. In all cases n = 7–9 with data collected after 18 wk on diet. A, Growth curve on low-fat (LF) and high-fat (HF) diet in control and LKO mice. B, Average daily food intake (n = 5 from 6 wk). Glucose tolerance in control and LKO mice on LF (C) and HF (D) diet (**, P < 0.01 vs. control). E, Insulin tolerance in control and LKO mice on HF diet. Fed (F) and fasted (G) insulin on LF and HF diets (**, P < 0.01 vs. HF control; #, P < 0.05 vs. fed; ††, P < 0.01 vs. LF). Control, Con.

Mentions: LKO exhibited no difference in the rate of weight gain compared with control on either low-fat or high-fat feeding (Fig. 3A). Similarly, liver, kidney, epididymal, and renal fat pad weights between LKO and control were unchanged (Table 2). We also assessed the expression of peroxisome proliferator-activated receptor gamma, uncoupling protein 2, fatty acid synthase (FAS), Acetyl-CoA carboxylase 1, hormone sensitive lipase, adiponectin, leptin, and resistin, lipid homeostasis genes fat known to be either GC regulated or altered in expression in the epididymal fat of 11β-HSD1KO mice (10). On high-fat diet, we detected no difference in the expression levels of these genes between LKO and control mice. Food intake on normal chow diet over a 4-wk period was marginally reduced in LKO compared with control mice with an average daily consumption of 3.6 vs. 4.1 g/d per mouse (Fig. 3B). LKO had normal fed blood glucose levels on both low-fat and high-fat diets (Table 2). They also had normal fasting glucose, and on a high-fat diet, fasting glucose was similarly elevated in both LKO and control mice compared with low fat-fed groups, indicating a degree of insulin resistance in both (Table 1). LKO mice also displayed normal glucose tolerance on a low-fat diet (Fig. 3C). However, on a high-fat diet, LKO resisted glucose intolerance having enhanced glucose clearance 30 min after glucose injection (Fig. 3D). An additional group of LKO and control mice fed a high-fat diet was subjected to an ITT. However, the LKO were not more tolerant of insulin as anticipated, showing no difference in response compared with control (Fig. 3E). In the fed state, LKO mice had normal insulin levels on a low-fat diet. However, on high-fat diet, insulin levels in control mice increased 5-fold, whereas in LKO mice, they only increased 3-fold. This constitutes a significant 40% reduction in circulating insulin in LKO mice and may be a result of the mildly decreased food intake (Fig. 3F). Fasting insulin levels were normal in LKO mice on a low-fat diet and significantly increased in both LKO and control mice on a high-fat diet, indicative of similar levels of insulin resistance (Fig. 3G).


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)

Metabolic parameters on low- and high-fat diet. In all cases n = 7–9 with data collected after 18 wk on diet. A, Growth curve on low-fat (LF) and high-fat (HF) diet in control and LKO mice. B, Average daily food intake (n = 5 from 6 wk). Glucose tolerance in control and LKO mice on LF (C) and HF (D) diet (**, P < 0.01 vs. control). E, Insulin tolerance in control and LKO mice on HF diet. Fed (F) and fasted (G) insulin on LF and HF diets (**, P < 0.01 vs. HF control; #, P < 0.05 vs. fed; ††, P < 0.01 vs. LF). Control, Con.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Metabolic parameters on low- and high-fat diet. In all cases n = 7–9 with data collected after 18 wk on diet. A, Growth curve on low-fat (LF) and high-fat (HF) diet in control and LKO mice. B, Average daily food intake (n = 5 from 6 wk). Glucose tolerance in control and LKO mice on LF (C) and HF (D) diet (**, P < 0.01 vs. control). E, Insulin tolerance in control and LKO mice on HF diet. Fed (F) and fasted (G) insulin on LF and HF diets (**, P < 0.01 vs. HF control; #, P < 0.05 vs. fed; ††, P < 0.01 vs. LF). Control, Con.
Mentions: LKO exhibited no difference in the rate of weight gain compared with control on either low-fat or high-fat feeding (Fig. 3A). Similarly, liver, kidney, epididymal, and renal fat pad weights between LKO and control were unchanged (Table 2). We also assessed the expression of peroxisome proliferator-activated receptor gamma, uncoupling protein 2, fatty acid synthase (FAS), Acetyl-CoA carboxylase 1, hormone sensitive lipase, adiponectin, leptin, and resistin, lipid homeostasis genes fat known to be either GC regulated or altered in expression in the epididymal fat of 11β-HSD1KO mice (10). On high-fat diet, we detected no difference in the expression levels of these genes between LKO and control mice. Food intake on normal chow diet over a 4-wk period was marginally reduced in LKO compared with control mice with an average daily consumption of 3.6 vs. 4.1 g/d per mouse (Fig. 3B). LKO had normal fed blood glucose levels on both low-fat and high-fat diets (Table 2). They also had normal fasting glucose, and on a high-fat diet, fasting glucose was similarly elevated in both LKO and control mice compared with low fat-fed groups, indicating a degree of insulin resistance in both (Table 1). LKO mice also displayed normal glucose tolerance on a low-fat diet (Fig. 3C). However, on a high-fat diet, LKO resisted glucose intolerance having enhanced glucose clearance 30 min after glucose injection (Fig. 3D). An additional group of LKO and control mice fed a high-fat diet was subjected to an ITT. However, the LKO were not more tolerant of insulin as anticipated, showing no difference in response compared with control (Fig. 3E). In the fed state, LKO mice had normal insulin levels on a low-fat diet. However, on high-fat diet, insulin levels in control mice increased 5-fold, whereas in LKO mice, they only increased 3-fold. This constitutes a significant 40% reduction in circulating insulin in LKO mice and may be a result of the mildly decreased food intake (Fig. 3F). Fasting insulin levels were normal in LKO mice on a low-fat diet and significantly increased in both LKO and control mice on a high-fat diet, indicative of similar levels of insulin resistance (Fig. 3G).

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