Angiogenic Adipokine Neuregulin 4 Ameliorates Obesity Associated With Adipocyte Dysfunction by Regulating Adipose Tissue Angiogenesis

Adipose tissue angiogenesis plays an important role in the maintenance of adipocyte function, impairment of which causes systemic metabolic disorders. Although adipocytes produce various angiogenic factors, the interactive communications between endothelial cells (EC) and mature adipocytes in the regulation of adipose tissue homeostasis remain to be elucidated. We searched for genes that is highly expressed in adipose tissue, and the expression of which is regulated by EC. Microarray analysis using RNAs prepared from mature adipocytes treated with EC conditioned medium revealed several genes with unknown functions; one of which encodes neuregulin 4 (Nrg4), a latest member of neuregulin family that belong to the EGF family proteins. Here, we demonstrate that Nrg4 is a paracrine-acting adipokine that regulates adipose tissue angiogenesis through a signaling crosstalk between EC and mature adipocytes. Nrg4 is highly and preferentially expressed in mature adipocytes, while its receptor is expressed in EC but not in adipocyte. Nrg4 enhanced endothelial angiogenic functions and angiogenesis but its expression in adipocytes was negatively regulated by EC and/or blood vessels, constituting a negative-feedback loop for adipose Nrg4. Genetic loss of Nrg4 caused overweight and impaired metabolic homeostasis even while consuming normal chow, whereas targeted activation of Nrg4 (aP2 Nrg4 Tg) in adipocytes enhanced insulin sensitivity and protected mice from obesity-related metabolic disorders. Mechanistically, Nrg4 modulated energy expenditure, adipose tissue inflammation and adipokine expression by regulating adipose tissue angiogenesis. These data provide new insights in the 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.