A lipid-rich environment during the development of obesity may represent an important metabolic stressor for ATMs. In general, there are three ways through which ATMs are exposed to lipids; via chylomicrons or VLDLs, by adipocyte lipolysis, or after adipocyte cell death. Hyperlipidaemia seems not to lead to macrophage accumulation in obese adipose tissue [
129], indicating that lipids resulting from adipocyte lipolysis and adipocyte cell death represent the main causes of excessive lipid accumulation in ATMs during obesity. However, the exact contribution of adipocyte lipolysis is also somewhat controversial. On the one hand higher basal rates of lipolysis have been observed in adipocytes of obese individuals [
130]. In line with this, adipocyte hypertrophy and TNFα exposure, which are both elevated in obese adipose tissue, have been linked to increased adipocyte lipolysis [
131‐
133]. On the other hand, decreased basal lipolytic rates [
134] and reduced catecholamine-induced lipolysis by insulin resistant adipocytes in obese adipose tissue [
135,
136] have been reported as well, and are indicative of lower lipolysis rates in obese adipose tissue. Nonetheless, although the exact source is still a matter of debate, macrophages in obese adipose tissue are exposed to excess lipids as illustrated by their lipid-laden appearance. Exposure to FAs is known to influence macrophage phenotype profoundly. Importantly, SFAs induce a proinflammatory macrophage phenotype via Toll-like receptor (TLR)-induced NF-kB activation [
137]. The TLR-family member 4 (TLR4) translates most of the proinflammatory effects of SFAs that trigger TLR4 activation via binding to its adaptor molecule fetuin-A [
138,
139], although some argue that the effects of SFAs are partly TLR-independent [
57,
140]. Another source of proinflammatory signalling finds it origin intracellularly, as an increase in intracellular FAs is associated with endoplasmic reticulum (ER) stress and oxidative stress, enhancing proinflammatory signalling and inducing insulin resistance in vivo [
141]. Moreover, SFAs and their derivatives, including ceramides, are classified as danger-associated molecular patterns (DAMPs) that are recognised by the NLRP3 inflammasome and lead to IL-1β secretion via caspase 1 activation [
142]. However, the response of macrophages upon lipid uptake does not necessarily have to be proinflammatory in nature [
143]. Although it has been suggested that internalised palmitate, a very well-known SFA, promotes lipid metabolism and limits inflammation [
57], in general only unsaturated FAs, particularly
n-3 FAs, are recognised for their anti-inflammatory properties [
139,
144]. Hence, FA species present in adipocytes may for a large part determine the degree of lipid toxicity in macrophages. Alternatively, one might speculate that the metabolic and inflammatory state of macrophages could also be involved in determining its response to different FAs. Overall, mechanisms by which intracellular FAs determine the inflammatory traits of macrophages are relatively unclear. Importantly, lipid-overloaded macrophages in obese adipose tissue [
42] may trigger the production of proinflammatory cytokines such as TNFα and IL-1β, as has been observed in macrophages exposed to FAs in vitro [
138,
145‐
147], and thus contributing to the development of insulin resistance. The type of FAs stored in the adipocyte, the timespan of lipid exposure, the inflammatory phenotype of the macrophage and the presence of various other inflammatory signalling molecules might explain the predominant anti-inflammatory response of ATMs in lean adipose tissue vs the proinflammatory response in obese adipose tissue following lipid exposure.