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

[Speaker] Dhite B Nugroho:1,3
[Co-author] Koji Ikeda:2, Agian J Barinda:2, Donytra A Wardhana:1, Keiko Yagi:2, Ken-Ichi Hirata:1, Noriaki Emoto:2
1:Department of Internal Medicine, Division of Cardiovascular Medicine, Graduate School of Medicine, Kobe University, Japan, 2:Department of Clinical Pharmacy, Kobe Pharmacy University, Japan, 3:Department of Internal Medicine, Gadjah Mada University, Indonesia

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 was highly and preferentially expressed in healthy adipocytes with substantial reduction in obesity. Nrg4 activated endothelial angiogenic functions and its targeted activation in adipocytes enhanced white AT angiogenesis and improves metabolic health in mice. Targeted blockade of endothelial Nrg4-ErbB4 signaling in white AT using prohibitin binding peptide-conjugated nanocarrier abolished the enhanced AT angiogenesis and consequently abrogated the ameliorated obesity-related metabolic disorders induced by Nrg4-overexpression in adipocytes. Genetic loss of Nrg4 caused reduction in brown and white AT blood vessels, and induced overweight even while consuming normal chow. Conditional knockout of Nrg4 in brown adipocytes caused blood vessels reduction in brown but not in white AT, and was sufficient to induce obese phenotype.

These findings suggest that Nrg4 plays a critical role in maintaining AT vasculature and its metabolic functions, and thus disruption of Nrg4-mediated angiogenesis could be an active mechanism for the obesity-associated vascular rarefaction in AT.

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