This study investigated the role of CD36 expressed in adipose tissue. We showed that CD36 enhances both adipose tissue inflammation and adipocyte cell death in mice in response to high fat feeding. CD36 expression in cultured primary adipocytes was shown to enhance adipocyte inflammatory cytokine expression, indicating that CD36 contributes to inflammatory responses in adipocytes as well as in macrophages. In addition, inflammatory responses in these two cell types are regulated in a synergistic and CD36-dependent manner.
Our studies confirmed earlier reports showing that mice lacking CD36 were significantly protected against HFD-induced obesity associated with increased plasma insulin and glucose levels and reduced glucose tolerance 
. In one study, the CD36 KO phenotype was attributed to elevated leptin secretion and subsequent decreased food intake 
. However, we found no difference in food intake between WT and CD36 KO mice during high fat feeding, in agreement with a more recent study 
. The explanation for why CD36 KO mice show reduced obesity despite having a similar food intake to WT mice is not known. One possibility is that CD36, a fatty acid transporter, may contribute to fatty acid absorption in the small intestine 
. However, CD36 KO mice showed unaltered intestinal fatty acid uptake, except for the very long chain fatty acids 
. A decreased chylomicron secretion with a subsequent delay in fat absorption was observed in CD36 KO mice 
. While such a delay in CD36 KO mice may not affect the overall lipid absorption in chow-fed mice, CD36 may become an important contributor to fatty acid absorption under high fat feeding conditions, a possibility that warrants further study.
Increased adipocyte cell death is commonly observed in obese humans and mice 
. Recent studies indicate that adipocyte apoptosis is a key initiating event for macrophage infiltration into adipose tissue and for insulin resistance 
. Inactivation of the key apoptosis-regulating molecules, Bid or FAS (CD95), resulted in reduced macrophage infiltration and improved systemic insulin sensitivity in mice 
. Importantly, adipocyte apoptosis alone appeared to be sufficient to induce macrophage infiltration in mouse adipose tissue 
. Our findings indicate that CD36 promotes adipocyte and macrophage cell death in adipose tissue during diet-induced obesity.
Interestingly, the increased adipose cell death observed in WT mice on a HFD was evidently not accompanied by decreased cell number. On the contrary, these mice are more obese than their CD36 KO counterparts, despite having adipocytes that do not differ in size from the adipocytes in CD36 KO mice. This may be explained by a continuous remodeling of adipose tissue that involves the elimination and then replacement of adipocytes from progenitor cells 
. Thus, the loss of the adipocytes may be counterbalanced by newly differentiated adipocytes. Interestingly, a high degree of adipocyte death (approximately 80%) was reported in mouse epididymal adipose tissue after 16 weeks of high-fat feeding, while at 20 weeks of feeding only 16% of adipocytes were necrotic 
. These findings support the concept that progression of obesity is associated with an early phase involving adipocyte hypertrophy with subsequent apoptosis and necrosis, and a later stage involving hyperplasia and tissue remodeling 
. Our findings suggest that CD36 is likely to affect adipose tissue remodeling and expansion by promoting adipocyte cell death. As expected, reduced cell death in adipose tissue in CD36 KO mice was accompanied by decreased inflammation and a subsequent reduction in macrophage and T cell infiltration. The reduced cell death and inflammatory responses, as well as reduced obesity in CD36 KO mice were accompanied by improved insulin sensitivity, as recently reported by others 
The contribution of adipocyte CD36 to the inflammatory response has not been previously described. We report that CD36 expression in primary adipocytes markedly exacerbated the pro-inflammatory cytokine response to LPS. In these experiments, adipocytes produced very significant amounts of cytokines in a CD36-dependent manner. Interestingly, adipocytes and macrophages produce distinct patterns of cytokines in response to LPS challenge. IL-6 was predominantly produced by adipocytes while TNFα was mainly produced by macrophages. Importantly, CD36 regulated cytokine production from both cell types, providing strong evidence that CD36 functions as an important regulator of adipose tissue inflammation through its effects in both adipocytes and macrophages.
Adipocyte/macrophage co-culture experiments have shown that these two cell types can act in a synergistic manner to promote a pro-inflammatory response 
. Our finding that CD36 expression in both cell types markedly impacted such a synergistic inflammatory response therefore provides new insight into the etiology of obesity in which interactions between adipocytes and macrophages are important determinants. The signals responsible for triggering inflammatory response in adipocytes during obesity, as well as the mechanism by which CD36 might promote this, are not yet understood. One possibility is that excessive lipid accumulation results in ER stress and a subsequent unfolded protein response (UPR) that activates inflammatory signaling 
. CD36 may promote such a response by enhancing fatty acid and modified lipoprotein uptake into cells and by increasing triglyceride synthesis in cells (Fig. S1
. The interaction of oxidized LDL with CD36 is known to stimulate inflammatory signaling in macrophages and as a consequence suppresses insulin signaling by attenuating AKT and IRS-1 activation 
. Alternatively, CD36-mediated fatty acid uptake may serve to regulate adipocyte function through activation of PPARγ, a nuclear receptor responsible for adipocyte differentiation and adipogenesis 
In summary, the current study provides new understanding of the role of CD36 in adipose tissue function and diet induced obesity. First, CD36 expression influences inflammatory responses in adipocytes as well as in macrophages by promoting pro-inflammatory cytokine expression. Second, adipocytes and macrophages contribute to the regulation of adipose tissue inflammation in a synergistic and CD36-dependent manner. We conclude that CD36 expression in both macrophages and adipocytes plays an important contributory role in diet-induced adipose tissue inflammation and adipocyte cell death.