CCL26 and CXCL12 preserve insulin-sensitizing macrophages in subcutaneous adipose tissue in obesity.

Unlike visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) can protect against insulin resistance and metabolic dysfunction in obesity. Here, we show that, in obesity, subcutaneous adipose tissue macrophages (ATMs) release small extracellular vesicles (sEVs) that can improve insulin sensitivity, opposite to the effect of visceral ATM sEVs. This functional difference is associated with an increase in the proportion of insulin-sensitizing, resident ATMs in SAT. In vivo and in vitro measurements of ATM growth and trafficking combined with single-cell RNA sequencing revealed that higher resident ATM survival and lower blood monocyte immigration along with decreased transition to pro-inflammatory ATMs collectively lead to the relative abundance of resident ATMs in SAT in obesity. These changes are mediated by CCL26 derived from subcutaneous adipocytes and adipocyte progenitors and CXCL12 secreted from resident ATMs. Our results elucidate previously unknown mechanisms for how SAT retains protective functions against metabolic dysfunction in obesity.