Mast Cell Responses to Insulin

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 DESCRIPTION (provided by applicant): Obesity and the metabolic syndrome affect the health of millions of individuals. Systemic hyperinsulinemia is associated with elevated adiposity and the pancreatic beta cell dysfunction that precedes the development of Type II diabetes, but is an understudied pathological state in its own right The central premise of our current work is that the systemic effects of hyperinsulinemia extend to the regulation of lipid body (LB) numbers in pro-inflammatory cells, with concomitant effects on cellular function and consequences for our understanding of the immunological impact of hyperinsulinemia. Insulin's regulation of mast cells has been speculated upon since the 1960s. Mast cells (MC) are professional pro-inflammatory cells that express insulin receptors and contain cytosolic LB and, while not previously recognized as targets for insulin signaling, these LB are specialized reservoirs of precursors for pro-inflammatory lipid mediators. Our recently published data establish that LB numbers in mast cells are dynamically regulated under in vitro, ex vivo and in vivo conditions of hyperinsulinemia. This insulin-driven hyper-accumulation of LB results in gain- and loss- of-function for the mast cell, enhancing antigen-driven release of bioactive lipids such as leukotriene C4 and, remarkably, compromising antigen-induced histamine and matrix-active protease release from secretory granules (SG). Our data provide a possible mechanism for the documented protective effects of insulin deficiency on mast cell-driven pathologies, suggest that insulin regulates mast cell functional phenotype, and establish mast cell LB as central arbiters of the impact of metabolic dysfunction on pro-inflammatory responses. Our findings raise new questions that will be addressed in three Specific Aims: Specific Aim 1. Does insulin transcriptionally program the LB:SG ratio in mast cells? We hypothesize that insulin regulates the ratio of LB and SG in these cells. Specific Aim 2. Are the stored and released mast cell LB lipidomes remodeled in response to cellular activation? We hypothesize that the expanded pool of LB present in insulin-exposed mast cells provides precursors for bioactive lipid synthesis, which modifies mast cell activation outcomes. Specific Aim 3. Are there important non-lipid storage roles for MC LB? We hypothesize that by acting as previously undefined calcium storage compartments, LB provide non-lipid storage-related functions in mast cells that are dysregulated when the LB population expands under hyperinsulinemic conditions. We predict that this study will reveal (1) that insulin is determinant of the relative abundance of SG and LB, and contributes to the generation of mast cell heterogeneity in vivo; (2) the functional contribution made by mast cell LB to inflammation; (3) LB as novel Ca2+ sinks that alter fundamental patterns in second messenger signaling following antigen stimulation of MC. These data will provide evidence that the systemic effects of hyperinsulinemia extend to regulation of LB numbers in pro-inflammatory cells, with concomitant effects on cellular function and cellular signaling. We will contribute to a new understanding of the immuno-pathological consequences of systemic hyperinsulinemia.