norbixin and Insulin-Resistance

The increased prevalence of cardio-metabolic disorders worldwide prompted the exploration of new strategies for its treatment. Peroxisome Proliferator activated receptor (PPAR) play major role in regulation of lipid as well as glucose metabolism and thus, natural PPARγ activators seem to be drug of choice.. In the present work, we studied norbixin which is a natural apocarotenoid derivative for its agonistic activity for PPAR γ followed by in vivo studies for amelioration of cardio-metabolic syndrome (CMetS).. The methods include computational studies, TR-FRET binding analysis and in vivo studies on high fat diet induced rats.. Molecular docking and molecular dynamics (MD) simulation studies showed that norbixin could be embedded into hydrophobic pocket of PPARγ and stable hydrogen bonding interactions were found with residues Glu273, Tyr327, Ser289, His323, His449 and Tyr473 of PPARγ. These results were substantiated by significant in vitro PPAR agonistic activity of norbixin in TR-FRET binding assay studies. The experimental results of norbixin in high fat diet induced CMetS in rats further confirmed that norbixin decreased insulin resistance (IR), hyperglycemia and dyslipidemia. These results were accompanied by reduced inflammatory marker hs-CRP as well as decreased oxidative stress and arterial pressure. The histopathology of heart sections also showed that norbixin could prevent the abnormal fibrotic changes in heart. Furthermore, PPARγ protein expressions were increased, whereas NF-κB expression was decreased by norbixin treatment in western blot studies.. These results validate norbixin as a novel PPARγ agonist and prove therapeutic potential of norbixin in treatment of CMetS.

Topics: Animals; Cardiovascular Diseases; Carotenoids; Computer Simulation; Diet, High-Fat; Hyperglycemia; Insulin Resistance; Male; Metabolic Syndrome; Molecular Docking Simulation; PPAR gamma; Rats; Rats, Wistar

Insulin resistance is partly due to suppression of insulin-induced glucose uptake into adipocytes. The uptake is dependent on adipocyte differentiation, which is controlled at mRNA transcription level. The peroxisome proliferator-activated receptor (PPAR), a ligand-regulated nuclear receptor, is involved in the differentiation. Many food-derived compounds serve as ligands to activate or inactivate PPAR. In this study, we demonstrated that bixin and norbixin (annatto extracts) activate PPARgamma by luciferase reporter assay using GAL4-PPAR chimera proteins. To examine the effects of bixin on adipocytes, 3T3-L1 adipocytes were treated with bixin or norbixin. The treatment induced mRNA expression of PPARgamma target genes such as adipocyte-specific fatty acid-binding protein (aP2), lipoprotein lipase (LPL), and adiponectin in differentiated 3T3-L1 adipocytes and enhanced insulin-dependent glucose uptake. The observations indicate that bixin acts as an agonist of PPARgamma and enhances insulin sensitivity in 3T3-L1 adipocytes, suggesting that bixin is a valuable food-derived compound as a PPAR ligand to regulate lipid metabolism and to ameliorate metabolic syndrome.

Topics: 3T3-L1 Cells; Adipocytes; Adipogenesis; Animals; Carotenoids; Genes, Reporter; Glucose; Insulin; Insulin Resistance; Lipid Metabolism; Luciferases; Mice; PPAR gamma; RNA, Messenger