title: Targeting curcusomes to inflammatory dendritic cells inhibits NF-κB and improves insulin resistance in obese mice.
abstract: OBJECTIVE
  To determine whether and by what mechanism systemic delivery of curcumin-containing liposomes improves insulin resistance in the leptin deficient (ob/ob) mouse model of insulin resistance.
  
  
  METHODS
  Insulin resistant ob/ob mice with steatosis were injected intraperitoneally with liposome nanoparticles, entrapping the nuclear factor-κB (NF-κB) inhibitor curcumin (curcusomes), and uptake in liver and adipose tissue was determined by flow cytometry. The effects of curcusomes on macrophage NF-κB activation and cytokine production were assessed. Transfer experiments determined the role of hepatic tumor necrosis factor (TNF)/inducible nitric oxide synthase-producing dendritic cells (Tip-DCs) and adipose tissue macrophages (ATMs) in inflammation-induced insulin resistance, determined by homeostatic assessment of insulin resistance.
  
  
  RESULTS
  Phagocytic myeloid cells infiltrating the liver in ob/ob mice had the phenotypic characteristics of Tip-DCs that arise from monocyte precursors in the liver and spleen after infection. Targeting Tip-DCs and ATMs with curcusomes in ob/ob mice reduced NF-κB/RelA DNA binding activity, reduced TNF, and enhanced interleukin-4 production. Curcusomes improved peripheral insulin resistance.
  
  
  CONCLUSIONS
  Both hepatic Tip-DCs and ATMs contribute to insulin resistance in ob/ob mice. Curcusome nanoparticles inhibit proinflammatory pathways in hepatic Tip-DCs and ATMs and reverse insulin resistance. Targeting inflammatory DCs is a novel approach for type 2 diabetes treatment.
authors: University of Queensland Diamantina Institute, Woolloongabba, Queensland, Australia.
authors: Suman Kumar
authors: SK
authors: Yekollu
authors: Ranjeny
authors: R
authors: Thomas
authors: Brendan
authors: B
authors: O'Sullivan
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003474:Curcumin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D016503:Drug Delivery Systems; D005786:Gene Expression Regulation / Q000187:drug effects; D007333:Insulin Resistance; D020738:Leptin / Q000235:genetics; D008081:Liposomes; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D053758:Nanoparticles / Q000008:administration & dosage / Q000627:therapeutic use; D009765:Obesity / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D013047:Specific Pathogen-Free Organisms; D014018:Tissue Distribution
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D020738:Leptin; D008081:Liposomes; D016328:NF-kappa B; D012333:RNA, Messenger; D003474:Curcumin