Adipose Tissue Macrophage Phenotype and Function

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The ability of adipose tissue to efficiently store and release lipid is critical for mammals to maintain metabolic health. In conditions when triglyceride storage by adipocytes is impaired lipid accumulates ectopically in non- adipocytes and is associated with common systemic disorders including type 2 diabetes, non-alcoholic fatty liver disease, susceptibility to infections, atherosclerosis, dementia and autoimmune disorders. Although the pathways that regulate systemic release of lipids via lipolysis and the uptake of fatty acids and carbohydrates for lipogenesis have long been known and are well studied, our understanding of local lipid homeostasis in fat is largely unexplored. Studies originally funded by the grant found that macrophages and other immune cells accumulate in adipose tissue in response to changes in metabolic state and that the adipose tissue macrophages have a unique phenotype and ability to handle and metabolism lipid. In studying the source of lipid in adipose tissue macrophages, we discovered a lipase-independent pathway of lipid release by adipocytes, in which acyl- glycerides are incorporated into extracellular vesicles (AdExos) and released at a high rate that correlates with adipose tissue macrophage content and lipolysis. During the current funding cycle we published these findings and described basic aspects of AdExos biology including their rate of release by adipocytes and regulation by adiposity, uptake by ATMs via macropinocytosis, ability to induce chemotaxis in bone marrow derived macrophages and to activate a program of lipid metabolism typical of authentic ATMs. From these findings we hypothesize AdExos are the key interface between the metabolic and immune systems in fat and a central component of lipid homeostasis in adipose tissue. In the current proposal, we set out to determine whether AdExos regulate the recruitment, differentiation and proliferation of monocyte-derived and resident ATMs, test whether the differential response to AdExo of monocyte derived and resident ATMs account for differences in inflammatory and trophic phenotypes, determine whether a lipolysis per se drives AdExo production and test if ATM hydrolysis of lipids in AdExos contribute to a lipid cycle in adipose tissue.