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Targeting curcusomes to inflammatory dendritic cells inhibits NF-κB and improves insulin resistance in obese mice.

Yekollu SK, Thomas R, O'Sullivan B - Diabetes (2011)

Bottom Line: 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.Targeting inflammatory DCs is a novel approach for type 2 diabetes treatment.

View Article: PubMed Central - PubMed

Affiliation: University of Queensland Diamantina Institute, Woolloongabba, Queensland, Australia.

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.

Research design and 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.

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Related in: MedlinePlus

Improved insulin signaling in ob/ob mice treated with curcusomes. Fasting blood glucose (A), insulin (B), and HOMA-IR (C) from ob/ob mice injected intraperitoneally with curcusomes for 72 h. ***P ≤ 0.001, **P ≤ 0.01 (one-way ANOVA followed by Bonferroni post hoc test). D: GTT from mice treated in A. **P ≤ 0.01 (one-way ANOVA followed by Bonferroni post hoc test). E: Serum adiponectin levels from mice treated in A. *P ≤ 0.05 (Student t test). F: Fasting HOMA-IR from ob/ob mice injected intraperitoneally with curcusomes for 4 weeks. ***P ≤ 0.001 (one-way ANOVA followed by Bonferroni post hoc test).
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Figure 4: Improved insulin signaling in ob/ob mice treated with curcusomes. Fasting blood glucose (A), insulin (B), and HOMA-IR (C) from ob/ob mice injected intraperitoneally with curcusomes for 72 h. ***P ≤ 0.001, **P ≤ 0.01 (one-way ANOVA followed by Bonferroni post hoc test). D: GTT from mice treated in A. **P ≤ 0.01 (one-way ANOVA followed by Bonferroni post hoc test). E: Serum adiponectin levels from mice treated in A. *P ≤ 0.05 (Student t test). F: Fasting HOMA-IR from ob/ob mice injected intraperitoneally with curcusomes for 4 weeks. ***P ≤ 0.001 (one-way ANOVA followed by Bonferroni post hoc test).

Mentions: Compared with NOB mice, ob/ob mice have increased fasting glucose and insulin, leading to a higher HOMA-IR (Fig. 4A–C). Treatment of ob/ob mice with curcusomes for 72 h reduced fasting glucose, insulin, and HOMA-IR to levels observed in NOB mice (Fig. 4C). GTTs confirmed that insulin resistance was improved after curcusome treatment, with a significant improvement in glucose uptake after glucose challenge (Fig. 4D). The improvement in HOMA-IR with curcusomes correlated with an increase in serum levels of the insulin-sensitizing adipokine adiponectin (Fig. 4E). The increase in adiponectin indicated that adipose tissue function was affected by curcusome delivery.


Targeting curcusomes to inflammatory dendritic cells inhibits NF-κB and improves insulin resistance in obese mice.

Yekollu SK, Thomas R, O'Sullivan B - Diabetes (2011)

Improved insulin signaling in ob/ob mice treated with curcusomes. Fasting blood glucose (A), insulin (B), and HOMA-IR (C) from ob/ob mice injected intraperitoneally with curcusomes for 72 h. ***P ≤ 0.001, **P ≤ 0.01 (one-way ANOVA followed by Bonferroni post hoc test). D: GTT from mice treated in A. **P ≤ 0.01 (one-way ANOVA followed by Bonferroni post hoc test). E: Serum adiponectin levels from mice treated in A. *P ≤ 0.05 (Student t test). F: Fasting HOMA-IR from ob/ob mice injected intraperitoneally with curcusomes for 4 weeks. ***P ≤ 0.001 (one-way ANOVA followed by Bonferroni post hoc test).
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3198103&req=5

Figure 4: Improved insulin signaling in ob/ob mice treated with curcusomes. Fasting blood glucose (A), insulin (B), and HOMA-IR (C) from ob/ob mice injected intraperitoneally with curcusomes for 72 h. ***P ≤ 0.001, **P ≤ 0.01 (one-way ANOVA followed by Bonferroni post hoc test). D: GTT from mice treated in A. **P ≤ 0.01 (one-way ANOVA followed by Bonferroni post hoc test). E: Serum adiponectin levels from mice treated in A. *P ≤ 0.05 (Student t test). F: Fasting HOMA-IR from ob/ob mice injected intraperitoneally with curcusomes for 4 weeks. ***P ≤ 0.001 (one-way ANOVA followed by Bonferroni post hoc test).
Mentions: Compared with NOB mice, ob/ob mice have increased fasting glucose and insulin, leading to a higher HOMA-IR (Fig. 4A–C). Treatment of ob/ob mice with curcusomes for 72 h reduced fasting glucose, insulin, and HOMA-IR to levels observed in NOB mice (Fig. 4C). GTTs confirmed that insulin resistance was improved after curcusome treatment, with a significant improvement in glucose uptake after glucose challenge (Fig. 4D). The improvement in HOMA-IR with curcusomes correlated with an increase in serum levels of the insulin-sensitizing adipokine adiponectin (Fig. 4E). The increase in adiponectin indicated that adipose tissue function was affected by curcusome delivery.

Bottom Line: 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.Targeting inflammatory DCs is a novel approach for type 2 diabetes treatment.

View Article: PubMed Central - PubMed

Affiliation: University of Queensland Diamantina Institute, Woolloongabba, Queensland, Australia.

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.

Research design and 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.

Show MeSH
Related in: MedlinePlus