Neuregulin-4 is an adipocyte-derived angiogenic factor that is essential in the maintenance of adipose tissue vasculature

Adipose tissue (AT) contains well-developed vascular networks. Pathological AT expansion often accompany the reduction in AT blood vessels, which further exacerbates adipocyte dysfunction due to hypoxia; however, it remains unclear whether AT vascular rarefaction is simply secondary to adipocyte hypertrophy, or if there is an actively regulated pathway that mediates impaired AT angiogenesis in obesity. Here we show previously undescribed mechanism in the regulation of AT angiogenesis, which could be causally implicated in obesity-associated AT vascular rarefaction. To identify factors involved in the impaired adipose tissue angiogenesis in obesity, we performed microarray analysis using RNAs prepared from WAT of lean or obese mice. We found several growth factors that are down-regulated in WAT of obese mice, and identified Nrg4, the newest member of neuregulins belonging to the EGF family of extracellular ligands, as a candidate growth factor that induces AT vascular rarefaction in obesity. Nrg4 angiogenic and its targeted activation in adipocytes enhanced white AT angiogenesis and improves in Targeted blockade of endothelial Nrg4-ErbB4 signaling in white AT using prohibitin binding peptide-conjugated nanocarrier the angiogenesis and abrogated the ameliorated obesity-related metabolic disorders induced by Nrg4-overexpression in adipocytes. of Nrg4 reduction in and