Do adipose macrophages remember obesity? Innate immune memory in weight cycling

Abstract

Abstract Weight loss improves obesity-associated metabolic disease; however, it is difficult to accomplish and even more difficult to maintain. Thus, many individuals regain weight within a few years. Unfortunately, weight cycling worsens the risk of developing diabetes beyond obesity itself. Adipose immune cells contribute to inflammation and diabetes risk with obesity, but less is known about adipose immune cells in weight loss and weight cycling. New data from a mouse model in our lab suggest that weight loss rescues glucose tolerance, but the immune landscape is not restored to a lean state. Adipose memory T cells, lipid handling macrophages, and exhausted T cells remain elevated with weight loss and further increase with weight regain suggesting that immune cells remember the state of obesity. Because immune memory can occur in the myeloid lineage, this project aims to determine if weight cycling induces innate memory in adipose macrophages. We find that adipose macrophages retain their obese phenotype; with increased glycolysis and cytokine production in response to LPS. Interestingly, adipose macrophages from weight cycled mice are even more metabolically active and secrete more basal TNF. We can replicate this phenotype in a cell culture model of innate memory with palmitate or adipose conditioned media, which may be a useful model to determine mechanisms for metabolic memory. Current work is investigating metabolic and epigenetic regulation of both the in vitro and in vivo systems using ATAC-sequencing and metabolic flux analysis. Future studies will explore the contribution of adipose macrophage memory to weight cycling-accelerated metabolic disease and aim to uncover new therapeutic targets to improve metabolic dysfunction. This work was funded by a Veterans Affairs Merit Award (5I01BX002195) to AH and a T32 Training Grant (DK07563) and AHA Postdoctoral Fellowship (20POST35120547) to HC.