CNX-013-B2, a unique pan tissue acting rexinoid, modulates several nuclear receptors and controls multiple risk factors of the metabolic syndrome without risk of hypertriglyceridemia, hepatomegaly and body weight gain in animal models

Diabetology & Metabolic Syndrome

Madanahalli R Jagannath¹  Marikunte V Venkataranganna¹  Baggavalli P Somesh¹  Yoganand Moolemath¹  Mahesh Kumar Verma¹  Puttrevana M Pallavi¹  Baisani S Naveenkumar¹  Shivakumar Pratibha¹  Aralakuppe S Gopala¹  Chandrashekaran Harish¹  Anilkumar Dandu¹  Talanki Lokesh Pooja¹  Suni K Chacko¹  Sivakumaran Yogeshwari¹  Mudigere N Lakshmi¹  Venkategowda Sunil¹  Mammen O Anup¹  Jaideep Singh¹  Bobbili Madhusudhan Reddy¹  Manoj Kumar Sadasivuni¹ 

[1] Connexios Life Sciences Pvt Ltd, Bangalore, India

关键词: Steatosis;    CHF;    Exercise mimetic;    Insulin sensitizer;    PPAR pan-activator;    Dyslipidemia;    Diabetes;   

Others  :  1115090
DOI  :  10.1186/1758-5996-6-83

 received in 2014-07-22, accepted in 2014-08-06,  发布年份 2014

【 摘 要 】

Background

In addition to their role in growth, cellular differentiation and homeostasis Retinoid X Receptors (RXR) regulate multiple physiological and metabolic pathways in various organs that have beneficial glucose and lipid (cholesterol) lowering, insulin sensitizing and anti-obesity effects. Rexinoids, compounds that specifically binds and activate RXR, are therefore considered as potential therapeutics for treating metabolic syndrome. Apparently many of the rexinoids developed in the past increased triglycerides, caused hepatomegaly and also suppressed the thyroid hormone axis. The aim of this study is to evaluate CNX-013-B2, a potent and highly selective rexinoid, for its potential to treat multiple risk factors of the metabolic syndrome.

Methods

CNX-013-B2 was selected in a screening system designed to identify compounds that selectively activated only a chosen sub-set of heterodimer partners of RXR of importance to treat insulin resistance. Male C57BL/6j mice (n = 10) on high fat diet (HFD) and 16 week old ob/ob mice (n = 8) were treated orally with CNX-013-B2 (10 mg/kg twice daily) or vehicle for 10 weeks and 4 weeks respectively. Measurement of plasma glucose, triglyceride, cholesterol including LDL-C, glycerol, free fatty acids, feed intake, body weight, oral glucose tolerance and non-shivering thermogenesis were performed at selected time points. After study termination such measurements as organ weight, triglyceride content, mRNA levels, protein phosphorylation along with histological analysis were performed.

Results

CNX-013-B2 selectively activates PPARs- α, β/δ and γ and modulates activity of LXR, THR and FXR. In ob/ob mice a significant reduction of 25% in fed glucose (p < 0.001 ), a 14% (p < 0.05) reduction in serum total cholesterol and 18% decrease (p < 0.01) in LDL-C and in DIO mice a reduction of 12% (p < 0.01 ) in fasting glucose, 20% in fed triglyceride (p < 0.01) and total cholesterol (p < 0.001) levels, coupled with enhanced insulin sensitivity, cold induced thermogenesis and 7% reduction in body weight were observed.

Conclusion

CNX-013-B2 is an orally bio available selective rexinoid that can be used as a novel therapeutic agent for management of multiple risk factors of the metabolic syndrome without the risk of side effects reported to be associated with rexinoids.

【 授权许可】

   
2014 Sadasivuni et al.; licensee BioMed Central Ltd.

【 图 表 】

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