ABSTRACT
TGR5 is a member of the G protein-coupled receptor family and is activated by bile acids (BAs). TGR5 is thought to be a promising drug target for metabolic diseases because the activation of TGR5 prevents obesity and hyperglycemia in mice fed a high-fat diet (HFD). In the present study, we identified a naturally occurring limonoid, nomilin, as an activator of TGR5. Unlike BAs, nomilin did not exhibit the farnesoid X receptor ligand activity. Although the nomilin derivative obacunone was capable of activating TGR5, limonin (the most abundant limonoid in citrus seeds) was not a TGR5 activator. When male C57BL/6J mice fed a HFD for 9 weeks were further fed a HFD either alone or supplemented with 0.2%w/w nomilin for 77 days, nomilin-treated mice had lower body weight, serum glucose, serum insulin, and enhanced glucose tolerance. Our results suggest a novel biological function of nomilin as an agent having anti-obesity and anti-hyperglycemic effects that are likely to be mediated through the activation of TGR5.
Subject(s)
Anti-Obesity Agents/administration & dosage , Benzoxepins/administration & dosage , Citrus/chemistry , Hyperglycemia/drug therapy , Hypolipidemic Agents/administration & dosage , Limonins/administration & dosage , Obesity/drug therapy , Receptors, G-Protein-Coupled/agonists , Animals , Benzoxepins/chemistry , Blood Glucose/drug effects , Diet/adverse effects , Dietary Fats/administration & dosage , Dietary Fats/adverse effects , Gene Expression/drug effects , HEK293 Cells , Humans , Hyperglycemia/etiology , Insulin/blood , Iodide Peroxidase/genetics , Ligands , Limonins/chemistry , Male , Mice , Obesity/etiology , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha , Receptors, G-Protein-Coupled/antagonists & inhibitors , Trans-Activators/genetics , Transcription Factors , Iodothyronine Deiodinase Type IIABSTRACT
A search for C(35)-terpenes from non-saponified extracts of 12 non-pathogenic Mycobacterium species was carried out. Octahydroheptaprenyl mycolic acyl esters were isolated from M. chlorophenolicum cells which were also found from M. thermoresistibile, M. vanbaalenii, M. aichiense, M. smegmatis, and M. parafortuitum. This is the first report on a polyprenol esterified by a mycolate. A novel monocyclic C(35)-terpene possessing a ketone, named heptaprenylcycline B, was isolated, which was detected from M. chlorophenolicum and M. vanbaalenii. The biosynthetic pathway to heptaprenylcycline B was investigated with ancymidol which acts as an inhibitor of a P450 monooxygenase. This experiment suggested that the P450 monooxygenase may be responsible for the production of heptaprenylcycline B.
Subject(s)
Esters/chemistry , Esters/isolation & purification , Mycobacterium/chemistry , Mycolic Acids/chemistry , Terpenes/isolation & purification , Biocatalysis , Cytochrome P-450 Enzyme Inhibitors , Cytochrome P-450 Enzyme System/metabolism , Enzyme Inhibitors/pharmacology , Magnetic Resonance Spectroscopy , Mass Spectrometry , Mycobacterium/metabolism , Terpenes/chemistry , Terpenes/metabolismABSTRACT
Prehypertension (PHT) is associated with increased risk of cardiovascular disease and progression to hypertension. Insulin resistance and hyperinsulinemia have been reported among patients with hypertension. In addition, impaired glucose tolerance (IGT) is a strong predictor of not only of type 2 diabetes but also of cardiovascular disease. However, little is known about the impact of insulin resistance on recently defined categories of hypertension and IGT. The aim of this study was to examine associations of surrogate makers of insulin resistance with PHT and IGT. In a total of 102 IGT patients with normotension and PHT (age: 58+/-5 years; mean+/-SD), blood pressure measurement, 75 g oral glucose tolerance testing (OGTT), metabolic analysis and echocardiography were performed. Body mass index was higher in the PHT group than in the normotension group (p<0.05). The fasting immnunoreactive insulin (F-IRI) (p<0.0001), homeostasis model assessment (HOMA) index (p<0.0001), 30 min postload glucose (p<0.05), 60 min postload glucose (p<0.05), 120 min postload glucose (p<0.01), 120 min postload insulin (p<0.0001) and left ventricular mass index (LVMI) (p<0.0005) were higher in the PHT group than in the normotension group. Multivariate logistic analysis revealed that the presence of PHT was independently predicted by F-IRI. Our findings indicate that the presence of PHT was associated with hyperinsulinemia and that the F-IRI was an independent predictor of PHT in these Japanese patients with IGT.
