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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 adipocytes differentiation, hypertrophy and lipolysis. Mouse 3T3-L1 preadipocytes were differentiated into mature adipocytes using complete differentiating media (CDM) in the presence and absence of 1 μM of CNX-010-49. The extent of inhibition of adipocytes differentiation was assessed by measuring triglyceride levels (A) and Oil red O staining (B). For inhibition of lipolysis, mature adipocytes were treated with 1 μM isoproterenol and 100 nM cortisone with or without 1 μM of CNX-010-49 for 18 h. Post 18 h, glycerol released into the media was measured (C). For inhibition of adipose hypertrophy, mature adipocytes were treated with GPCI (25 mM glucose, 500 μM palmitate, 1 μM cortisone, 10 ng/ml of inflammatory cytokines (TNFa, IL1 β, IFNγ)) for 48 h with or without 1 μM of CNX-010-49. Post 48 h, triglyceride accumulation was measured (D). All the values are expressed as Mean ± SEM. Statistical comparison was conducted by One-way ANOVA followed by Dunnett’s test (n = 6) (*P < 0.05, **P < 0.01 and ***P < 0.001).
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Figure 4: Effect of CNX-010-49 on adipocytes differentiation, hypertrophy and lipolysis. Mouse 3T3-L1 preadipocytes were differentiated into mature adipocytes using complete differentiating media (CDM) in the presence and absence of 1 μM of CNX-010-49. The extent of inhibition of adipocytes differentiation was assessed by measuring triglyceride levels (A) and Oil red O staining (B). For inhibition of lipolysis, mature adipocytes were treated with 1 μM isoproterenol and 100 nM cortisone with or without 1 μM of CNX-010-49 for 18 h. Post 18 h, glycerol released into the media was measured (C). For inhibition of adipose hypertrophy, mature adipocytes were treated with GPCI (25 mM glucose, 500 μM palmitate, 1 μM cortisone, 10 ng/ml of inflammatory cytokines (TNFa, IL1 β, IFNγ)) for 48 h with or without 1 μM of CNX-010-49. Post 48 h, triglyceride accumulation was measured (D). All the values are expressed as Mean ± SEM. Statistical comparison was conducted by One-way ANOVA followed by Dunnett’s test (n = 6) (*P < 0.05, **P < 0.01 and ***P < 0.001).

Mentions: Conversion of inactive cortisone to active cortisol by 11β-HSD1 favors adipogenesis. CNX-010-49 treatment reduced the differentiation/adipogenesis capacity by 34% as measured by accumulation of triglycerides in adipocytes as well as by oil red O staining (Figure 4A & B). Both cortisone and isoproterenol stimulated lipolysis by 2 fold in mature 3T3-L1 adipocytes as measured by the release of glycerol in the culture medium. CNX-010-49 treatment reduced adipocytes lipolysis by 25% (Figure 4C). Excess metabolic overload and inflammation mediated hypertrophy of adipocytes as measured by enhanced triglyceride accumulation, was reduced by 35% with CNX-010-49 treatment (Figure 4D).


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 adipocytes differentiation, hypertrophy and lipolysis. Mouse 3T3-L1 preadipocytes were differentiated into mature adipocytes using complete differentiating media (CDM) in the presence and absence of 1 μM of CNX-010-49. The extent of inhibition of adipocytes differentiation was assessed by measuring triglyceride levels (A) and Oil red O staining (B). For inhibition of lipolysis, mature adipocytes were treated with 1 μM isoproterenol and 100 nM cortisone with or without 1 μM of CNX-010-49 for 18 h. Post 18 h, glycerol released into the media was measured (C). For inhibition of adipose hypertrophy, mature adipocytes were treated with GPCI (25 mM glucose, 500 μM palmitate, 1 μM cortisone, 10 ng/ml of inflammatory cytokines (TNFa, IL1 β, IFNγ)) for 48 h with or without 1 μM of CNX-010-49. Post 48 h, triglyceride accumulation was measured (D). All the values are expressed as Mean ± SEM. Statistical comparison was conducted by One-way ANOVA followed by Dunnett’s test (n = 6) (*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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getmorefigures.php?uid=PMC4127523&req=5

Figure 4: Effect of CNX-010-49 on adipocytes differentiation, hypertrophy and lipolysis. Mouse 3T3-L1 preadipocytes were differentiated into mature adipocytes using complete differentiating media (CDM) in the presence and absence of 1 μM of CNX-010-49. The extent of inhibition of adipocytes differentiation was assessed by measuring triglyceride levels (A) and Oil red O staining (B). For inhibition of lipolysis, mature adipocytes were treated with 1 μM isoproterenol and 100 nM cortisone with or without 1 μM of CNX-010-49 for 18 h. Post 18 h, glycerol released into the media was measured (C). For inhibition of adipose hypertrophy, mature adipocytes were treated with GPCI (25 mM glucose, 500 μM palmitate, 1 μM cortisone, 10 ng/ml of inflammatory cytokines (TNFa, IL1 β, IFNγ)) for 48 h with or without 1 μM of CNX-010-49. Post 48 h, triglyceride accumulation was measured (D). All the values are expressed as Mean ± SEM. Statistical comparison was conducted by One-way ANOVA followed by Dunnett’s test (n = 6) (*P < 0.05, **P < 0.01 and ***P < 0.001).
Mentions: Conversion of inactive cortisone to active cortisol by 11β-HSD1 favors adipogenesis. CNX-010-49 treatment reduced the differentiation/adipogenesis capacity by 34% as measured by accumulation of triglycerides in adipocytes as well as by oil red O staining (Figure 4A & B). Both cortisone and isoproterenol stimulated lipolysis by 2 fold in mature 3T3-L1 adipocytes as measured by the release of glycerol in the culture medium. CNX-010-49 treatment reduced adipocytes lipolysis by 25% (Figure 4C). Excess metabolic overload and inflammation mediated hypertrophy of adipocytes as measured by enhanced triglyceride accumulation, was reduced by 35% with CNX-010-49 treatment (Figure 4D).

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