title: Novel curcumin derivative CNB-001 mitigates obesity-associated insulin resistance.
abstract: Type 2 diabetes is growing at epidemic proportions, and pharmacological interventions are being actively sought. This study examined the effect of a novel neuroprotective curcuminoid, CNB-001 [4-((1E)-2-(5-(4-hydroxy-3-methoxystyryl-)-1-phenyl-1H-pyrazoyl-3-yl)vinyl)-2-methoxy-phenol], on glucose intolerance and insulin signaling in high-fat diet (HFD)-fed mice. C57BL6 mice (5-6 weeks old) were randomly assigned to receive either a HFD (45% fat) or a low-fat diet (LFD, 10% fat) for 24 weeks, together with CNB-001 (40 mg/kg i.p. per day). Glucose tolerance test revealed that the area under the curve of postchallenge glucose concentration was elevated on HF-feeding, which was attenuated by CNB-001. CNB-001 attenuated body weight gain, serum triglycerides, and IL-6, and augmented insulin signaling [elevated phosphoprotein kinase B (p-Akt), and phosphoinsulin receptor (p-IR)β, lowered endoplasmic reticulum (ER) stress, protein-tyrosine phosphatase 1B (PTP1B)] and glucose uptake in gastrocnemius muscle of HFD-fed mice. Respiratory quotient, measured using a metabolic chamber, was elevated in HFD-fed mice, which was unaltered by CNB-001, although CNB-001 treatment resulted in higher energy expenditure. In cultured myotubes, CNB-001 reversed palmitate-induced impairment of insulin signaling and glucose uptake. Docking studies suggest a potential interaction between CNB-001 and PTP1B. Taken together, CNB-001 alleviates obesity-induced glucose intolerance and represents a potential candidate for further development as an antidiabetic agent.
authors.affiliation: Division of Pharmaceutical Sciences and Center for Cardiovascular Research and Alternative Medicine, University of Wyoming, College of Health Sciences, Laramie, Wyoming (E.P., Y.H., J.R., S.N.); Cedars-Sinai Medical Center, Department of Neurology and Neurosurgery, Burns and Allen Research Institute, Los Angeles, California (P.A.L.); and Chemistry Department, University of Wyoming, Laramie, Wyoming (E.T., T.E.L.).
authors.forename: Evgeniy
authors.initials: E
authors.lastname: Panzhinskiy
authors.forename: Yinan
authors.initials: Y
authors.lastname: Hua
authors.forename: Paul A
authors.initials: PA
authors.lastname: Lapchak
authors.forename: Elena
authors.initials: E
authors.lastname: Topchiy
authors.forename: Teresa E
authors.initials: TE
authors.lastname: Lehmann
authors.forename: Jun
authors.initials: J
authors.lastname: Ren
authors.forename: Sreejayan
authors.initials: S
authors.lastname: Nair
mesh_terms: D050154:Adiposity / Q000187:drug effects; D000818:Animals; D020134:Catalytic Domain; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003474:Curcumin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D004041:Dietary Fats / Q000008:administration & dosage; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D004734:Energy Metabolism; D005234:Fatty Liver / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D018149:Glucose Intolerance / Q000188:drug therapy / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007333:Insulin Resistance; D008297:Male; D008810:Mice, Inbred C57BL; D062105:Molecular Docking Simulation; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D019308:Palmitic Acid / Q000008:administration & dosage; D011485:Protein Binding; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000737:chemistry; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction; D015430:Weight Gain / Q000187:drug effects
chemical_list: C529348:CNB 001; D004041:Dietary Fats; D007004:Hypoglycemic Agents; D018696:Neuroprotective Agents; D011720:Pyrazoles; D019308:Palmitic Acid; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; C516609:Ptpn1 protein, mouse; D003474:Curcumin