2020 Theses Doctoral

Adipocytes Secrete Lipid-Laden Exosomes and Influence Local Macrophage Behavior

Flaherty, Stephen

To meet the body’s metabolic needs, adipocytes release fatty acids and glycerol through the action of neutral lipases. Lipids are also key local regulators of immune function. During obesity, triglycerides accumulate in adipose tissue macrophages and this accumulation is associated with systemic metabolic complications including insulin resistance and atherosclerosis.

While studying the accumulation of lipid in adipose tissue macrophages, we discovered a secondary pathway of lipid release from adipocytes that occurs via exosomes and is independent of canonical lipolysis. Bone-Marrow-Derived Macrophages (BMDMs) cultured with lipase-deficient adipose tissue (as compared to WT) accumulate similar levels of neutral lipid, despite a marked decrease in free fatty acid release from these tissues. Adipocytes release exosome-sized vesicles (AdExos) that contain high levels of neutral lipid, that can be found in both adipose tissue conditioned medium and in circulation. Lean animals release ~ 1% of their adipocyte lipid content per day via exosomes; this rate more than doubles with obesity.

AdExos are taken up almost exclusively by local macrophages and are sufficient to induce the lipid-loading seen in BMDMs co-cultured with adipose tissue. AdExos and associated factors are sufficient to foster differentiation of bone marrow precursors into adipose tissue macrophage-like cells by inducing multinucleation, increased lysosomal program, increased ATM-associated gene expression, and increased lipid content. Our findings suggest both a novel pathway of local lipid release and a mechanism by which parenchymal cells can modulate tissue resident macrophage differentiation and function.