Saturated Fatty Acids and Inflammation: Who Pays the Toll?
Since the discovery that obesity is associated with macrophage accumulation in adipose tissue,1,2 mechanisms by which adipose tissue becomes inflamed, resulting in insulin resistance, have remained elusive. Several studies have demonstrated that saturated fatty acids (SFAs) stimulate adipose tissue inflammation by a process that involves Toll-like receptor 4 (TLR4), a receptor that binds bacterial lipopolysaccharide (LPS). TLR4 is a pattern recognition receptor that plays a key role in the innate immune response. The observation that TLR4 deficiency protected against insulin resistance in obesity induced by a diet high in SFAs3 suggested that TLR4 was the link between diet excess and insulin resistance.3 Attenuation of diet-induced insulin resistance4,5 and adipose tissue inflammation6 also have been observed in C3H/HeJ mice with a loss of function mutation in TLR4.
See accompanying article on page 802
In vitro studies have shed light on how SFAs lead to adipose tissue inflammation. TLR4 activation by SFAs increases the expression of a number of inflammatory genes in adipocytes by a nuclear factor κB–dependent mechanism,7–11 similar to TLR4 activation by LPS. SFAs also stimulate inflammatory molecules in macrophages.3,10–12 TLR4’s critical role has been demonstrated by silencing TLR4 expression with short …