Adipose Tissue Macrophages Promote Myelopoiesis and Monocytosis in Obesity

Obesity is associated with infiltration of macrophages into adipose tissue (AT), contributing to insulin resistance and diabetes. However, relatively little is known regarding the origin of AT macrophages (ATMs). We discovered that murine models of obesity have prominent monocytosis and neutrophilia, associated with proliferation and expansion of bone marrow (BM) myeloid progenitors. AT transplantation conferred myeloid progenitor proliferation in lean recipients, while weight loss in both mice and humans (via gastric bypass) was associated with a reversal of monocytosis and neutrophilia. Adipose S100A8/A9 induced ATM TLR4/MyD88 and NLRP3 inflammasome-dependent IL-1β production. IL-1β interacted with the IL-1 receptor on BM myeloid progenitors to stimulate the production of monocytes and neutrophils. These studies uncover a positive feedback loop between ATMs and BM myeloid progenitors and suggest that inhibition of TLR4 ligands or the NLRP3-IL-1β signaling axis could reduce AT inflammation and insulin resistance in obesity. [Display omitted] •Obesity-associated monocytosis is caused by myeloid progenitor cell proliferation•Adipose tissue-derived S100A8/A9 induces IL-1β expression via TLR4/MyD88 pathway•Deletion of NRLP3 or IL-1R reduces obesity-associated monocytosis Adipose tissue macrophages contribute to metabolic dysfunction in obesity. Nagareddy et al. reveal that adipocytes enhance production of IL-1β from macrophages via TLR4/MyD88 and NLRP3, which drives bone marrow myeloid progenitor proliferation. This feed-forward loop further exacerbates inflammation, which can be reversed by weight loss in both mice and humans.