A DEL-1/αvβ3 integrin axis promotes brown adipocyte progenitor proliferation and cold-induced brown adipose tissue adaptation

Cold-triggered adaptation of the brown adipose tissue (BAT) promotes increased non-shivering thermogenesis and helps maintain body temperature. Here, we demonstrate that the secreted protein developmental endothelial locus-1 (DEL-1) acts as a regulator of cold-induced BAT adaptation. DEL-1 was expressed in the vascular endothelium of the BAT and its expression was upregulated upon cold exposure. By interacting with αvβ3 integrin on brown adipocyte progenitor cells, DEL-1 promoted their proliferation in a manner dependent on AKT signaling and glycolysis activation. Compared to DEL-1-sufficient mice, DEL-1-deficient mice or mice expressing a non-integrin-binding mutant of DEL-1 carrying an Asp-to-Glu substitution in its RGD motif, displayed decreased cold tolerance. This phenotype was associated with impaired BAT adaptation to cold and reduced brown adipocyte progenitor cell proliferation. Conversely, endothelial-specific DEL-1 overexpression in DEL-1-deficient mice restored the BAT thermogenic response to cold. Together, the DEL-1/αvβ3 integrin-dependent endothelial-brown adipocyte progenitor cell crosstalk promotes cold-stimulated BAT adaptation. This knowledge could be potentially harnessed therapeutically for promoting BAT expansion towards improving systemic metabolism.