MICRORNA REGULATION OF ADIPOSE TISSUE IMMUNE RESPONSE IN OBESITY

Project Summary Obesity cultivates complex immune responses in white adipose tissue (WAT), which may contribute to the development of insulin resistance and type 2 diabetes mellitus (T2DM). However, there still exists a gap in knowledge on cellular mechanisms regulating “obesity-specific” immune responses that precludes the development of novel immune therapies to treat obesity and related insulin resistance and T2DM. We were one of the first to report T cells in WAT in obesity. Further studies from us and others showed that WAT conventional T cells promote, and regulatory T cells (Tregs) protect against, insulin resistance in obesity. Nonetheless, the mechanisms underlying WAT Treg homeostasis and mediating their metabolic benefits remain incompletely understood. This application aims to investigate microRNA-30a (miR-30a) regulation of WAT Tregs and its impacts on WAT immune response and metabolism in obesity. This proposal builds on our novel pilot data: 1) miR-30a expression in WAT correlated positively with insulin sensitivity in obese mice and people; 2) enforced miR-30a expression in WAT promoted whole-body insulin sensitivity in obese mice; 3) miR-30a levels were high in WAT Tregs in lean but reduced in obese mice; 4) enforced miR-30a expression in WAT of obese mice increased WAT Treg numbers; 5) specific overexpression of miR-30a in Tregs increased WAT Treg numbers and improved insulin sensitivity in mice fed high-fat diet. Therefore, we hypothesize that miR-30a in WAT stimulates expansion of WAT Tregs and improves Treg functions to increase insulin sensitivity. We will test this hypothesis by pursuing three aims: Aim 1 will define effects of cell (Treg vs adipocyte)-restricted miR- 30a on WAT immune response and metabolism in obesity and establish cell-specific roles of miR-30a; Aim 2 will build on our additional pilot data that miR-30a delivery in WAT suppresses STAT1 (a key inflammatory transcription factor) and establish how miR-30a targeting of Stat1 governs WAT Treg homeostasis in obesity; Aim 3 will build on our novel data that compared to diet high in saturated fat, diet high in unsaturated fat induces higher levels of WAT miR-30a and Tregs in mice and examine dietary regulation of miR-30a and its role in WAT immune response and metabolism. We will accomplish these aims using gain-of-function and loss-of-function approaches in genetically modified animal models, cutting-edge immunophenotyping and transcriptomics, gold standard clamp for insulin sensitivity, and other state-of-the-art tools. Upon completing these aims, we expect to have uncovered a novel mechanism that may help develop new therapies that leverage the immune system to treat obesity and T2DM.