A lipase-independent pathway of lipid release and immune modulation by adipocytes

Abstract

To meet systemic metabolic needs, adipocytes release fatty acids and glycerol through the action of neutral lipases. Here, we describe a secondary pathway of lipid release from adipocytes that is independent of canonical lipolysis. We found that adipocytes release exosome-sized, lipid-filled vesicles (AdExos) that become a source of lipid for local macrophages. Adipose tissue from lean mice released ~1% of its lipid content per day via exosomes ex vivo, a rate that more than doubles in obese animals. AdExos and associated factors were sufficient to induce in vitro differentiation of bone marrow precursors into adipose tissue macrophage–like cells. Thus, AdExos are both an alternative pathway of local lipid release and a mechanism by which parenchymal cells can modulate tissue macrophage differentiation and function.

Adipocyte extracellular vesicles carry enzymes and fatty acids that stimulate mitochondrial metabolism and remodeling in tumor cells

“…EV secreted by primary adipocytes also transfer FA to melanoma cells (Appendix Fig S5A). FA content significantly increased in murine adipocyte EV in obesity (Fig 3E,left panel) and positively correlated with BMI in human samples ( Fig 3E, right panel), although triglyceride content remained unchanged in obesity (Appendix Fig S5B), consistent with recent lipidomic data (Flaherty et al, 2019). FA content significantly increased in murine adipocyte EV in obesity (Fig 3E,left panel) and positively correlated with BMI in human samples ( Fig 3E, right panel), although triglyceride content remained unchanged in obesity (Appendix Fig S5B), consistent with recent lipidomic data (Flaherty et al, 2019).…”

“…To determine whether this FA transfer increases in obesity, we evaluated FA content in EV secreted by primary murine and human adipocytes. FA content significantly increased in murine adipocyte EV in obesity ( Fig 3E, left panel) and positively correlated with BMI in human samples ( Fig 3E, right panel), although triglyceride content remained unchanged in obesity (Appendix Fig S5B), consistent with recent lipidomic data (Flaherty et al, 2019). Since hypertrophic adipocytes internalize less lipids than their smaller counterparts (Frayn, 2001;Hill et al, 2009;Appendix Fig S5C), we could not use the lipid pulse-chase assay described in Fig 3B to compare FA transfer by ND-EV and HFD-EV.…”

“…In accord, elegant studies demonstrated the importance of EV in the dialog between adipocytes and endothelial cells (Crewe et al, 2018), as well as AT macrophages (Flaherty et al, 2019). Here, we show that a metabolic cooperation exists between adipocytes and tumor cells and is amplified in obesity, suggesting that obese cancer patients would likely benefit from FAO inhibitors and/or molecules that inhibit EV uptake.…”

“…F 1205Lu cells were exposed, or not, to adipocyte EV from ND or HFD mice with, or without, Lalistat 2 (Lal). Obese adipocytes do secrete larger quantities of EV compared to lean counterparts, which may further increase their effect in cancer patients (Lazar et al, 2016;Flaherty et al, 2019). pro-tumoral effect.…”

“…Although we did not observe an increased transfer of proteins involved in FAO in obese conditions, we cannot exclude the relevance of these enzymes under physiological conditions. Obese adipocytes do secrete larger quantities of EV compared to lean counterparts, which may further increase their effect in cancer patients (Lazar et al, 2016;Flaherty et al, 2019). In experimental conditions using equal quantities of vesicles, HFD-EV convey higher levels of FA, which increases lipid accumulation in melanoma cells.…”