Credit: Jennie Vallis/Macmillan Publishers Limited

Based on previous evidence, it was thought that Toll-like receptor 4 (TLR4) sensed fatty acids to induce inflammation and metabolic dysfunction in obesity. Now, Graeme Lancaster, Mark Febbraio and colleagues have shed new light on this hypothesis, showing that TLR4 is not a receptor for palmitate, a long-chain saturated fatty acid, in vivo.

“From the mid-to-late 2000s, numerous in vitro and in vivo studies confirmed a major role for TLR4 in lipid-induced inflammation, with the idea being that saturated fatty acids were ligands for TLR4,” explains Lancaster. “However, there are several lines of evidence that argue against saturated fatty acids being direct agonists of TLR4 and that is why we began to explore this area a number of years ago.”

In the present study, Lancaster, Febbraio and colleagues used a number of different approaches to investigate whether palmitate, which has been used previously by investigators to induce cellular inflammation, was an agonist of TLR4. The authors first assessed whether TLR4 undergoes dimerization and endocytosis in the presence of palmitate. They then used a computational technique called molecular dynamics simulations to assess whether palmitate acted in a similar manner to lipopolysaccharide, which is the canonical TLR4 agonist.

The authors report that they were unable to find any evidence that palmitate is a ligand of TLR4. “While our study might appear to fly in the face of over a decade’s worth of previous work, it doesn’t,” adds Febbraio. “We propose that certain signals, for example, obesity-induced increases in circulating concentrations of lipopolysaccharide or perhaps endogenous TLR4 ligands emanating from obese adipose tissue, activate adipose tissue-resident macrophages, stimulating them to adopt the classically-activated, or M1, phenotype.” This TLR4-dependent reprogramming of macrophage metabolism renders the adipose tissue-resident macrophages particularly sensitive to subsequent stimulation with long-chain saturated fatty acids, which induce further inflammatory signalling.

While our study might appear to fly in the face of over a decade’s worth of previous work, it doesn’t

Lancaster, Febbraio and colleagues are now working on trying to identify the receptors that mediate the uptake of fatty acids into macrophages.