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A novel 11β-hydroxysteroid dehydrogenase type1 inhibitor CNX-010-49 improves hyperglycemia, lipid profile and reduces body weight in diet induced obese C57B6/J mice with a potential to provide cardio protective benefits.

Anil TM, Dandu A, Harsha K, Singh J, Shree N, Kumar VS, Lakshmi MN, Sunil V, Harish C, Balamurali GV, Naveen Kumar BS, Gopala AS, Pratibha S, Sadasivuni M, Anup MO, Moolemath Y, Venkataranganna MV, Jagannath MR, Somesh BP - BMC Pharmacol Toxicol (2014)

Bottom Line: The treatment with CNX-010-49 resulted in a significant decrease in fasting glucose, improved insulin sensitivity and glucose tolerance.A significant reduction in the serum biomarkers like Plasminogen activator inhibitor-1 (PAI-1), interleukin 6 (IL-6) and Fetuin-A with CNX-010-49 treatment was observed indicating a potential to modulate processes implicated in cardiovascular benefits.These results indicate that inhibition of 11β-HSD1 with CNX-010-49 can give a potential benefit in the management of metabolic dysregulations that are seen in type 2 diabetes.

View Article: PubMed Central - HTML - PubMed

Affiliation: Connexios Life Sciences Pvt Ltd, Bangalore, India. m.r.jagannath@connexios.com.

ABSTRACT

Background: 11ß-hydroxysteroid dehydrogenase type1 (11β-HSD1) converts inactive glucocorticoids to active glucocorticoids which, in excess, leads to development of the various risk factors of the metabolic syndrome. Recent studies clearly suggest that both increased expression and activity of 11β-HSD1 in metabolically active tissues such as liver, muscle and adipose are implicated in tissue specific dysregulation which collectively contribute to the whole body pathology seen in metabolic syndrome. In the present study we have evaluated CNX-010-49, a highly potent, selective and 'pan tissue' acting 11β-HSD1 inhibitor, for its potential to modulate multiple risk factors of the metabolic syndrome.

Methods: Male C57B6/J mice on high fat diet (DIO mice) were orally dosed with CNX-010-49 (30 mg/kg twice daily; n = 8) or vehicle for 10 weeks. Fasting glucose, triglycerides, glycerol, free fatty acids, body weight and feed intake were measured at selected time points. At the end of the treatment an OGTT and subsequently organ histology was performed. In vitro, CNX-010-49 was evaluated in 3T3-L1 preadipocytes to assess impact on adipocytes differentiation, hypertrophy and lipolysis whereas in fully differentiated C2C12 cells and in primary mouse hepatocytes to assess the impact on glucose metabolism and hepatic glucose output respectively.

Results: CNX-010-49 a highly potent and selective pan tissue acting 11β-HSD1 inhibitor (EC50 = 6 nM) significantly inhibits glucocorticoids and isoproterenol mediated lipolysis in mature 3T3-L1 adipocytes, improves muscle glucose oxidation, reduces proteolysis and enhances mitochondrial biogenesis. Also a significant inhibition of gluconeogenesis in primary mouse hepatocytes was observed. The treatment with CNX-010-49 resulted in a significant decrease in fasting glucose, improved insulin sensitivity and glucose tolerance. Treatment also resulted in a significant decrease in serum triglycerides levels and a complete inhibition of body weight gain without affecting feed consumption. A significant reduction in the serum biomarkers like Plasminogen activator inhibitor-1 (PAI-1), interleukin 6 (IL-6) and Fetuin-A with CNX-010-49 treatment was observed indicating a potential to modulate processes implicated in cardiovascular benefits.

Conclusions: These results indicate that inhibition of 11β-HSD1 with CNX-010-49 can give a potential benefit in the management of metabolic dysregulations that are seen in type 2 diabetes.

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Effect of CNX-010-49 on lipid profile in DIO mice. Fasting serum TG levels (A) were monitored weekly. After the study termination, liver TG (B) was analyzed. Data in all panels are mean ± SEM (n = 8 mice/group). mRNA expression levels of liver CD36 and PPARα (C & D) were measured as mentioned in Methods. Statistical comparison was conducted by One-way ANOVA followed by Dunnett’s test or repeated measures ANOVA followed by Bonferroni correction (A) (n = 8 mice/group). Two-way repeated measures ANOVA indicated that CNX-010-49 significantly reduced the Fasting serum TG (p = 0.001; F = 1.865; Df = 20). (# - significance of HFD control against lean control, *- significance of CNX-010-49 treatment against HFD control) (*P < 0.05, **P < 0.01 and ***P < 0.001).
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Figure 7: Effect of CNX-010-49 on lipid profile in DIO mice. Fasting serum TG levels (A) were monitored weekly. After the study termination, liver TG (B) was analyzed. Data in all panels are mean ± SEM (n = 8 mice/group). mRNA expression levels of liver CD36 and PPARα (C & D) were measured as mentioned in Methods. Statistical comparison was conducted by One-way ANOVA followed by Dunnett’s test or repeated measures ANOVA followed by Bonferroni correction (A) (n = 8 mice/group). Two-way repeated measures ANOVA indicated that CNX-010-49 significantly reduced the Fasting serum TG (p = 0.001; F = 1.865; Df = 20). (# - significance of HFD control against lean control, *- significance of CNX-010-49 treatment against HFD control) (*P < 0.05, **P < 0.01 and ***P < 0.001).

Mentions: The effect of treatment on circulating TG levels is represented in Figure 7A.In HFD control animals, the TG was increased by ~1.7 fold (210 ± 8 mg/dl; P < 0.001) when compared to lean control (128 ± 8 mg/dl) during the study period. On the other hand, the HFD fed animals treated with CNX-010-49 showed ~20% reduction in TG levels (165 ± 9 mg/dl; P < 0.001) when compared to HFD control. The decrease in plasma TG upon CNX-010-49 treatment was observed from week 1 and was maintained throughout the study period. Also CNX-010-49 treatment has shown a non-significant reduction in the liver TG levels as compared to HFD control (Figure 7B).We analyzed expression of fatty acid transporter CD36 and PPARα which is involved in fat oxidation in liver tissue. As expected expression of CD36 increased by ~1.5 fold and a significant decrease in PPARα in HFD animals as compared to lean control indicating increased fat uptake and decreased fatty acid oxidation. Treatment with CNX-010-49 showed a decrease in CD36 and increased PPARα expression indicating a decreased fat uptake and improved fat oxidation in liver as evident from decreased liver and serum TG levels (Figure 7C & D).


A novel 11β-hydroxysteroid dehydrogenase type1 inhibitor CNX-010-49 improves hyperglycemia, lipid profile and reduces body weight in diet induced obese C57B6/J mice with a potential to provide cardio protective benefits.

Anil TM, Dandu A, Harsha K, Singh J, Shree N, Kumar VS, Lakshmi MN, Sunil V, Harish C, Balamurali GV, Naveen Kumar BS, Gopala AS, Pratibha S, Sadasivuni M, Anup MO, Moolemath Y, Venkataranganna MV, Jagannath MR, Somesh BP - BMC Pharmacol Toxicol (2014)

Effect of CNX-010-49 on lipid profile in DIO mice. Fasting serum TG levels (A) were monitored weekly. After the study termination, liver TG (B) was analyzed. Data in all panels are mean ± SEM (n = 8 mice/group). mRNA expression levels of liver CD36 and PPARα (C & D) were measured as mentioned in Methods. Statistical comparison was conducted by One-way ANOVA followed by Dunnett’s test or repeated measures ANOVA followed by Bonferroni correction (A) (n = 8 mice/group). Two-way repeated measures ANOVA indicated that CNX-010-49 significantly reduced the Fasting serum TG (p = 0.001; F = 1.865; Df = 20). (# - significance of HFD control against lean control, *- significance of CNX-010-49 treatment against HFD control) (*P < 0.05, **P < 0.01 and ***P < 0.001).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
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Figure 7: Effect of CNX-010-49 on lipid profile in DIO mice. Fasting serum TG levels (A) were monitored weekly. After the study termination, liver TG (B) was analyzed. Data in all panels are mean ± SEM (n = 8 mice/group). mRNA expression levels of liver CD36 and PPARα (C & D) were measured as mentioned in Methods. Statistical comparison was conducted by One-way ANOVA followed by Dunnett’s test or repeated measures ANOVA followed by Bonferroni correction (A) (n = 8 mice/group). Two-way repeated measures ANOVA indicated that CNX-010-49 significantly reduced the Fasting serum TG (p = 0.001; F = 1.865; Df = 20). (# - significance of HFD control against lean control, *- significance of CNX-010-49 treatment against HFD control) (*P < 0.05, **P < 0.01 and ***P < 0.001).
Mentions: The effect of treatment on circulating TG levels is represented in Figure 7A.In HFD control animals, the TG was increased by ~1.7 fold (210 ± 8 mg/dl; P < 0.001) when compared to lean control (128 ± 8 mg/dl) during the study period. On the other hand, the HFD fed animals treated with CNX-010-49 showed ~20% reduction in TG levels (165 ± 9 mg/dl; P < 0.001) when compared to HFD control. The decrease in plasma TG upon CNX-010-49 treatment was observed from week 1 and was maintained throughout the study period. Also CNX-010-49 treatment has shown a non-significant reduction in the liver TG levels as compared to HFD control (Figure 7B).We analyzed expression of fatty acid transporter CD36 and PPARα which is involved in fat oxidation in liver tissue. As expected expression of CD36 increased by ~1.5 fold and a significant decrease in PPARα in HFD animals as compared to lean control indicating increased fat uptake and decreased fatty acid oxidation. Treatment with CNX-010-49 showed a decrease in CD36 and increased PPARα expression indicating a decreased fat uptake and improved fat oxidation in liver as evident from decreased liver and serum TG levels (Figure 7C & D).

Bottom Line: The treatment with CNX-010-49 resulted in a significant decrease in fasting glucose, improved insulin sensitivity and glucose tolerance.A significant reduction in the serum biomarkers like Plasminogen activator inhibitor-1 (PAI-1), interleukin 6 (IL-6) and Fetuin-A with CNX-010-49 treatment was observed indicating a potential to modulate processes implicated in cardiovascular benefits.These results indicate that inhibition of 11β-HSD1 with CNX-010-49 can give a potential benefit in the management of metabolic dysregulations that are seen in type 2 diabetes.

View Article: PubMed Central - HTML - PubMed

Affiliation: Connexios Life Sciences Pvt Ltd, Bangalore, India. m.r.jagannath@connexios.com.

ABSTRACT

Background: 11ß-hydroxysteroid dehydrogenase type1 (11β-HSD1) converts inactive glucocorticoids to active glucocorticoids which, in excess, leads to development of the various risk factors of the metabolic syndrome. Recent studies clearly suggest that both increased expression and activity of 11β-HSD1 in metabolically active tissues such as liver, muscle and adipose are implicated in tissue specific dysregulation which collectively contribute to the whole body pathology seen in metabolic syndrome. In the present study we have evaluated CNX-010-49, a highly potent, selective and 'pan tissue' acting 11β-HSD1 inhibitor, for its potential to modulate multiple risk factors of the metabolic syndrome.

Methods: Male C57B6/J mice on high fat diet (DIO mice) were orally dosed with CNX-010-49 (30 mg/kg twice daily; n = 8) or vehicle for 10 weeks. Fasting glucose, triglycerides, glycerol, free fatty acids, body weight and feed intake were measured at selected time points. At the end of the treatment an OGTT and subsequently organ histology was performed. In vitro, CNX-010-49 was evaluated in 3T3-L1 preadipocytes to assess impact on adipocytes differentiation, hypertrophy and lipolysis whereas in fully differentiated C2C12 cells and in primary mouse hepatocytes to assess the impact on glucose metabolism and hepatic glucose output respectively.

Results: CNX-010-49 a highly potent and selective pan tissue acting 11β-HSD1 inhibitor (EC50 = 6 nM) significantly inhibits glucocorticoids and isoproterenol mediated lipolysis in mature 3T3-L1 adipocytes, improves muscle glucose oxidation, reduces proteolysis and enhances mitochondrial biogenesis. Also a significant inhibition of gluconeogenesis in primary mouse hepatocytes was observed. The treatment with CNX-010-49 resulted in a significant decrease in fasting glucose, improved insulin sensitivity and glucose tolerance. Treatment also resulted in a significant decrease in serum triglycerides levels and a complete inhibition of body weight gain without affecting feed consumption. A significant reduction in the serum biomarkers like Plasminogen activator inhibitor-1 (PAI-1), interleukin 6 (IL-6) and Fetuin-A with CNX-010-49 treatment was observed indicating a potential to modulate processes implicated in cardiovascular benefits.

Conclusions: These results indicate that inhibition of 11β-HSD1 with CNX-010-49 can give a potential benefit in the management of metabolic dysregulations that are seen in type 2 diabetes.

Show MeSH
Related in: MedlinePlus