Abstract
Lipid bodies (LB) are reservoirs of precursors to inflammatory lipid mediators in immunocytes, including mast cells. LB numbers are dynamic, increasing dramatically under conditions of immunological challenge. We have previously shown in vitro that insulin-influenced lipogenic pathways induce LB biogenesis in mast cells, with their numbers attaining steatosis-like levels. Here, we demonstrate that in vivo hyperinsulinemia resulting from high fat diet is associated with LB accumulation in murine mast cells and basophils. We characterize the lipidome of purified insulin-induced LB, and the shifts in the whole cell lipid landscape in LB that are associated with their accumulation, in both model (RBL2H3) and primary mast cells. Lipidomic analysis suggests a gain of function associated with LB accumulation, in terms of elevated levels of eicosanoid precursors that translate to enhanced antigen-induced LTC4 release. Loss-of-function in terms of a suppressed degranulation response was also associated with LB accumulation, as were ER reprogramming and ER stress, analogous to observations in the obese hepatocyte and adipocyte. Taken together, these data suggest that chronic insulin elevation drives mast cell LB enrichment in vitro and in vivo, with associated effects on the cellular lipidome, ER status and pro-inflammatory responses.
Highlights
In adipocytes and hepatocytes, lipid droplets (LD) are structures specialized for lipid storage in support of energy production [1,2,3,4]
We have previously shown that chronic exposure to insulin in vitro causes ectopic lipid accumulation in the RBL2H3, a basophilic model that recapitulates many features of mucosal mast cells, and in primary bone marrow derived mast cells (BMMC) [22]
Bone marrow derived mast cells (BMMC) from high fat diet (HFD) mice treated ex vivo for 6d with sub-optimal concentrations of insulin showed lipid bodies (LB) accumulation relative to controls, as did peripheral blood basophils isolated from HFD fed mice (Fig 1D and 1E)
Summary
Lipid droplets (LD) are structures specialized for lipid storage in support of energy production [1,2,3,4]. The lipid bodies (LB), are found in leukocytes and are specialized as reservoirs of bioactive lipid precursors [5, 6]. Further studies are required to establish whether a similar phenotype is engendered by a positive energy balance and hyperinsulinemia in vivo. This in vitro lipogenesis has been associated with enhanced de novo synthesis of mediators such as LTC4 in response to antigenic stimulation [22]. In the absence of any published lipidomic analysis of these LB, we cannot yet state whether these structures are primarily reservoirs of absorbed dietary lipid (c.f. foam cells) or of de novo synthesized bioactive lipid precursors induced by innate stimuli in granulocytes
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