monash_81602.pdf (11.68 MB)
Lipid induced macrophage inflammation: implications for obesity induced insulin resistance
Version 2 2017-05-18, 02:51
Version 1 2017-01-31, 05:28
thesisposted on 2017-05-18, 02:51 authored by Nicholls, Hayley Tenielle
The fatty acid translocase (FAT) and scavenger receptor CD36 is important in the recognition and uptake of lipids as well as the initiation of immune responses to pathogens and altered self components. Accordingly, we hypothesised that it plays a role in saturated fatty acid-induced macrophage lipid accumulation and pro-inflammatory activation. Inhibition of CD36 in RAW264.7 macrophages using the putative CD36 inhibitor sulfosuccinimidyl oleate (SSO) markedly reduced saturated fatty acid-induced lipid accumulation and inflammation in macrophages. Mice harbouring a CD36 specific deletion in haematopoietic derived cells fed a HFD for 20 weeks, displayed improved insulin signalling and reduced macrophage infiltration in adipose tissue compared with WT mice. However, this did not translate into protection against HFD-induced whole body insulin resistance. Contrary to our hypothesis and results gained using SSO, neither saturated fatty acid-induced lipid accumulation nor inflammation was reduced when comparing CD36KO with WT bone marrow-derived macrophages. While CD36 is not essential for saturated fatty acid induced macrophage lipid accumulation, we provide evidence that CD36 plays an important role in macrophage activation and migration to adipose tissue in obesity. The activation of Toll Like Receptors (TLR) by saturated fatty acids is recognised to play a key role in the induction of metabolic inflammation. It is supposed that saturated fatty acids act as extracellular ligands for TLR, however, this has not been clearly demonstrated. Primary bone marrow derived macrophages from mice which lack 2 critical TLR downstream adaptor molecules, MyD88 and TRIF, are protected from saturated fatty acid induced inflammation. Unexpectedly, we discovered that these double knockout macrophages are significantly protected from saturated fatty acid induced intracellular lipid accrual, which may result from an elevated oxidative capacity. Understanding how fatty acids regulate inflammatory signalling pathways will enable us to better prevent, manage and treat chronic metabolic diseases.