A Novel Angiogenic Adipokine Neuregulin-4 Preserves Metabolic Homeostasis by Regulating Adipose Tissue Angiogenesis

Abstract

Adipose tissue angiogenesis is a crucial factor for the maintenance of adipocyte functions, impairment of which causes systemic metabolic disorders. Adipocytes produce various angiogenic factors; however, the interactive communications between endothelial cells (EC) and mature adipocytes in the regulation of adipose tissue homeostasis remains largely unexplored. We searched for genes that are highly expressed in adipose tissue, and the expression of which is regulated by EC. We found several genes with unknown functions; one of which encodes neuregulin-4 (Nrg4), the latest member of neuregulin family that are part of the EGF family proteins. Here, we show that Nrg4 is a paracrine-acting adipokine that regulates adipose tissue angiogenesis through a communication between EC and mature adipocytes. Nrg4 is highly and preferentially expressed in mature adipocytes, while its receptor is expressed in EC but not in the adipocyte. Nrg4 activated endothelial angiogenic functions and enhanced angiogenesis both in vitro and in vivo. Of note, Nrg4 expression was substantially reduced in white adipose tissue during diet-induced obesity. Furthermore, targeted activation of Nrg4 in adipocytes (aP2-Nrg4-Tg) led to significantly improved glucose tolerance and better insulin sensitivity comparing to those in WT mice after a high fat-diet, while their body weight was similar. Adipose tissue angiogenesis was enhanced in aP2-Nrg4-Tg mice, resulting in ameliorated adipose tissue hypoxia and inflammation. Interestingly, expression of Nrg4 in adipocytes was negatively regulated by EC and/or blood vessels, constituting a negative-feedback loop for adipose Nrg4. These data unveiled a significant role of interactive communication between EC and mature adipocytes in the regulation of adipose tissue angiogenesis, and shed light on Nrg4 as a therapeutic target for the treatment of metabolic disorders associated with obesity.