Interaction between hormone-sensitive lipase and ChREBP in fat cells controls insulin sensitivity.

Nature Metabolism
Pauline MorignyDominique Langin

Abstract

Impaired adipose tissue insulin signalling is a critical feature of insulin resistance. Here we identify a pathway linking the lipolytic enzyme hormone-sensitive lipase (HSL) to insulin action via the glucose-responsive transcription factor ChREBP and its target, the fatty acid elongase ELOVL6. Genetic inhibition of HSL in human adipocytes and mouse adipose tissue results in enhanced insulin sensitivity and induction of ELOVL6. ELOVL6 promotes an increase in phospholipid oleic acid, which modifies plasma membrane fluidity and enhances insulin signalling. HSL deficiency-mediated effects are suppressed by gene silencing of ChREBP and ELOVL6. Mechanistically, physical interaction between HSL, independent of lipase activity, and the isoform activated by glucose metabolism ChREBPα impairs ChREBPα translocation into the nucleus and induction of ChREBPβ, the isoform with high transcriptional activity that is strongly associated with whole-body insulin sensitivity. Targeting the HSL-ChREBP interaction may allow therapeutic strategies for the restoration of insulin sensitivity.

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Methods Mentioned

BETA
transgenic
nuclear translocation
fluorescence recovery after photobleaching
immunoprecipitation
co-immunoprecipitation
proximity ligation assay
proximity ligation
transfection
ChIP
PCR

Clinical Trials Mentioned

NCT01785134

Software Mentioned

Zen Blue software
GraphPad
NoValix
GraphPad Prism

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