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Lipid-induced insulin resistance mediated by the proinflammatory receptor TLR4 requires saturated fatty acid–induced ceramide biosynthesis in mice
William L. Holland, … , Philipp E. Scherer, Scott A. Summers
William L. Holland, … , Philipp E. Scherer, Scott A. Summers
Published April 1, 2011
Citation Information: J Clin Invest. 2011;121(5):1858-1870. https://doi.org/10.1172/JCI43378.
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Research Article Metabolism

Lipid-induced insulin resistance mediated by the proinflammatory receptor TLR4 requires saturated fatty acid–induced ceramide biosynthesis in mice

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Abstract

Obesity is associated with an enhanced inflammatory response that exacerbates insulin resistance and contributes to diabetes, atherosclerosis, and cardiovascular disease. One mechanism accounting for the increased inflammation associated with obesity is activation of the innate immune signaling pathway triggered by TLR4 recognition of saturated fatty acids, an event that is essential for lipid-induced insulin resistance. Using in vitro and in vivo systems to model lipid induction of TLR4-dependent inflammatory events in rodents, we show here that TLR4 is an upstream signaling component required for saturated fatty acid–induced ceramide biosynthesis. This increase in ceramide production was associated with the upregulation of genes driving ceramide biosynthesis, an event dependent of the activity of the proinflammatory kinase IKKβ. Importantly, increased ceramide production was not required for TLR4-dependent induction of inflammatory cytokines, but it was essential for TLR4-dependent insulin resistance. These findings suggest that sphingolipids such as ceramide might be key components of the signaling networks that link lipid-induced inflammatory pathways to the antagonism of insulin action that contributes to diabetes.

Authors

William L. Holland, Benjamin T. Bikman, Li-Ping Wang, Guan Yuguang, Katherine M. Sargent, Sarada Bulchand, Trina A. Knotts, Guanghou Shui, Deborah J. Clegg, Markus R. Wenk, Michael J. Pagliassotti, Philipp E. Scherer, Scott A. Summers

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Figure 1

Lard oil infusion inhibits insulin-stimulated glucose uptake in a ceramide-dependent manner.

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Lard oil infusion inhibits insulin-stimulated glucose uptake in a cerami...
(A) Whole body glucose disposal was assessed by hyperinsulin-euglycemic clamp during infusion with lard oil (black bars), soy oil (white bars), or glycerol (gray bars) following treatment with inhibitors myriocin, cycloserine, or PBS. (B and C) Ceramide (B) and DAG (C) content was enzymatically determined using the DAG-kinase assay from soleus muscle following 6 hours of lipid infusion. Values are expressed as mean ± SEM (n = 8). *P < 0.05 for lard or soy oil versus glycerol within a given treatment.

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