Credit: pjludlow/Getty

Impaired adipose tissue insulin signalling is a major feature of insulin resistance, but the precise mechanisms behind this impairment were unclear. Now, in a new study published in Nature Metabolism, Dominique Langin and colleagues have described a novel hormone-sensitive lipase–ChREBP interaction that constitutes a previously undescribed gateway between lipid and glucose metabolism.

“I started working on hormone-sensitive lipase in the 1990s during my post-doc at University of Lund, Sweden,” adds Langin. “The initial period was devoted to cloning the human gene and characterization of various isoforms.” Langin and his team have now described a new role for hormone-sensitive lipase, one that is independent of its enzymatic activities. In their study, Langin and colleagues describe a direct protein–protein interaction between a lipase and the transcription factor ChREBP. The authors found that this interaction controls the intracellular localization and transcriptional activity of ChREBP.

To decipher the mechanisms involved in improvements in glucose metabolism mediated by hormone-sensitive lipase inhibition, the authors used human adipocytes and mouse transgenic models. They also used a number of techniques, including surface plasmon resonance assays, to investigate protein–protein interactions. Once Langin and colleagues had characterized this new pathway, they provided translational relevance through experiments on adipose tissue samples from different clinical studies.

Langin and colleagues describe a direct protein–protein interaction between a lipase and the transcription factor ChREBP

“To combat obesity-associated insulin resistance and the development of type 2 diabetes mellitus, there is currently no strategy targeting adipose tissue (thiazolidinediones worked that way but were withdrawn several years ago for adverse effects unrelated to the control of fat metabolism),” explains Langin. “Disrupting the hormone-sensitive lipase–ChREBP interaction constitutes such a strategy that would be specific for adipose tissue as the lipase is only expressed at very low levels in the liver.” Therefore, the authors are currently working towards improving the characterization of the domains of interaction in the two proteins with the aim of developing molecules to disrupt that interaction.