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Immunomodulatory glycan LNFPIII alleviates hepatosteatosis and insulin resistance through direct and indirect control of metabolic pathways

Abstract

Parasitic worms express host-like glycans to attenuate the immune response of human hosts. The therapeutic potential of this immunomodulatory mechanism in controlling the metabolic dysfunction that is associated with chronic inflammation remains unexplored. We demonstrate here that administration of lacto-N-fucopentaose III (LNFPIII), a LewisX-containing immunomodulatory glycan found in human milk and on parasitic helminths, improves glucose tolerance and insulin sensitivity in diet-induced obese mice. This effect is mediated partly through increased interleukin-10 (Il-10) production by LNFPIII-activated macrophages and dendritic cells, which reduces white adipose tissue inflammation and sensitizes the insulin response of adipocytes. Concurrently, LNFPIII treatment upregulates nuclear receptor subfamily 1, group H, member 4 (Fxr-α, also known as Nr1h4) to suppress lipogenesis in the liver, conferring protection against hepatosteatosis. At the signaling level, the extracellular signal-regulated kinase (Erk)-activator protein 1 (Ap1) pathway seems to mediate the effects of LNFPIII on both inflammatory and metabolic pathways. Our results suggest that LNFPIII may provide new therapeutic approaches to treat metabolic diseases.

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Figure 1: LNFPIII increases Il-10 production and improves insulin sensitivity.
Figure 2: Reduced inflammation and enhanced insulin signaling in WAT of LNFPIII-treated mice.
Figure 3: LNFPIII-primed macrophage conditioned medium improves insulin sensitivity in 3T3-L1 adipocytes in an Il-10–dependent manner.
Figure 4: LNFPIII protects against hepatic steatosis induced by high-fat diet.
Figure 5: LNFPIII suppresses lipid synthesis through Fxr-α.
Figure 6: Induction of Fxr-α activity by LNFPIII is mediated by Erk-Ap1 signaling.

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Acknowledgements

We thank E. Hu and S.M. Reilly for technical support and T. Horng (Harvard School of Public Health) for providing reagents. P. Bhargava and K. Stanya were supported by a US National Institutes of Health training grant (T32ES016645). This work was supported by the American Diabetes Association, the American Heart Association and a US National Institutes of Health grant (R01AI056484, D.A.H. and R01DK075046, C.-H.L.).

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P.B. was involved in experimental design and execution, data analyses and manuscript preparation. K.J.S., M.R.G. and C.L. conducted GTTs and ITTs with P.B. D.J. and L.D. provided technical assistance. S.L. assisted in hepatocyte isolations. C.L. provided LNFPIII and SEA preparations. D.A.H. helped with experimental design, data interpretation and manuscript writing. C.-H.L. directed the project, participated in data analyses and interpretation and wrote the manuscript.

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Correspondence to Donald A Harn or Chih-Hao Lee.

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Bhargava, P., Li, C., Stanya, K. et al. Immunomodulatory glycan LNFPIII alleviates hepatosteatosis and insulin resistance through direct and indirect control of metabolic pathways. Nat Med 18, 1665–1672 (2012). https://doi.org/10.1038/nm.2962

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