CD36: the common soil for inflammation in obesity and atherosclerosis?

Insulin resistance, a decreased metabolic responsiveness of peripheral organs and tissues to insulin, is considered the central mechanism of metabolic syndrome, a cluster of cardiovascular risk factors, including abdominal obesity, hypertension, a pro-atherogenic lipid profile, a pro-thrombotic, pro-inflammatory state, and dysglycemia. Studies in recent years have revealed the causal role of chronic low-grade inflammation in development of obesity-associated insulin resistance in animal models. Since chronic inflammation also plays a pivotal role in atherosclerotic cardiovascular disease, it is therefore considered to be the fundamental mechanistic link between insulin resistance and increased cardiovascular prevalence in obesity. Compelling evidence from numerous studies in animal models demonstrates that monocytes are recruited to adipose tissue during obesity and become macrophages through interaction with dysfunctional adipocytes. Moreover, resident adipose tissue macrophages may switch their phenotype from the anti-inflammatory ‘alternative’ (M2) to pro-inflammatory ‘classical’ (M1) macrophages during expansion of adipose tissue in obesity. Accumulation of macrophages and phenotypic switch from M2 to M1 macrophages has been suggested to play a determinant role in insulin resistance in obesity at least in mouse models. Increased adipose tissue inflammation and macrophage infiltration have been confirmed in human obesity. However, subset macrophage accumulation in human adipose tissue in obesity requires further characterization. There is much interest in the question of what are the microenvironmental changes in adipose tissue in obesity that initiate and regulate adipose tissue inflammation. Adipocytes are highly active in secretion of numerous bioactive hormones called adipokines that exert profound endocrine and/or paracrine effects on different types of cells including macrophages and vascular wall cells, i.e. endothelial cells or smooth muscle cells. It is proposed that adipocyte dysfunction reflected by imbalanced secretion of pro-inflammatory and anti-inflammatory adipokines contributes to insulin resistance, metabolic disorders, and cardiovascular disease. Crosstalk between perivascular adipocytes and the vascular wall or adipocytes and macrophages through paracrine secretion of adipokines has been reported in many studies in recent years. It has been demonstrated that adipocytes or perivascular adipose tissues release relaxing factors causing vascular smooth muscle relaxation, and secrete smooth muscle cell growth inhibitors such as adiponectin as well as growth promoters, which could play a role in vascular remodelling under disease conditions. Moreover, increased perivascular adipose tissue inflammatory cell infiltration in atherosclerosis has also been demonstrated in patients, which is similar to the phenomenon in obesity. To what extent the perivascular adipose tissue inflammation contributes to cardiovascular disease remains to be determined. Also, regulatory mechanisms of crosstalk between adipocytes and macrophages and other cells in obesity and cardiovascular disease are largely unknown. The study by Kennedy et al. explored the crucial role of CD36 in mediating crosstalk between adipocytes and macrophages in vitro and also in vivo in mouse models of obesity. CD36, first discovered in platelets 30 years ago, is now characterized as a membrane glycoprotein that is widely expressed on the surface of a variety of cell types, including cardiomyocytes, vascular endothelial cells, smooth muscle cells, macrophages, adipocytes, and hepatocytes. CD36 functions as a class B scavenger receptor and fatty acid translocase that binds long-chain fatty acids and facilitates their transport into cells. CD36 also binds and scavenges a wide spectrum of endogenous molecules, including oxidized lipids from LDL, advanced glycated proteins, components of apoptotic cells, and cell-derived microparticles. It seems not surprising that the previous work of this research group and others demonstrated multiple cellular functions of CD36. For example, CD36 functions as a negative regulator of angiogenesis and promotes endothelial apoptosis; it promotes oxidative stress by down-regulation of antioxidant enzymes peroxiredoxin-2 and haem oxygenase-1 in vascular smooth muscle cells under conditions of vascular injury; it renders platelets hypersensitive to aggregation stimuli and thereby promotes platelet aggregation and secretion; it promotes lipid uptake in macrophages and facilitates foam cell formation. It appears that CD36-mediated effects on a variety of cell types are through similar signal transduction pathways, i.e. activation of the non-