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

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

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 4

TLR4 signaling is essential for lipid-induced ceramide accumulation.

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TLR4 signaling is essential for lipid-induced ceramide accumulation. Fol...
Following 6 hours of intravenous infusion of glycerol (white bars) or lard oil (black bars), ceramides (A–C) were enzymatically determined from liver (A), muscle (B), or hypothalamus (C). (D) DAG was simultaneously measured in the same tissues. (E–G) Glucose kinetics were determined during hyperinsulinemic-euglycemic clamps (4 mU/kg/min insulin). (E) The glucose infusion rate required to maintain euglycemia was recorded. (F) Glucose disposal was calculated from 3H-glucose turnover. (G) Hepatic glucose production was calculated during basal and insulin-stimulated conditions and presented as percent suppression by insulin (n = 5–6). *P < 0.05 for lard oil compared with glycerol.