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

Autor: Shivakumar Pratibha, Anilkumar Dandu, Bobbili Madhusudhan Reddy, Sivakumaran Yogeshwari, Mudigere N Lakshmi, Mahesh Kumar Verma, Manoj Kumar Sadasivuni, Mammen O Anup, Puttrevana M Pallavi, Madanahalli R Jagannath, Marikunte V Venkataranganna, Jaideep Singh, Chandrashekaran Harish, Baggavalli P Somesh, Yoganand Moolemath, Venkategowda Sunil, Suni K. Chacko, Baisani S Naveenkumar, Aralakuppe S Gopala, Talanki Lokesh Pooja
Rok vydání: 2014
Předmět:
Zdroj: Diabetology & Metabolic Syndrome
ISSN: 1758-5996
DOI: 10.1186/1758-5996-6-83
Popis: 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
Databáze: OpenAIRE
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