ACE2 exerts anti-obesity effect via stimulating brown adipose tissue and induction of browning in white adipose tissue

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Abstract

The angiotensin II (ANG II)-ANG II type 1 receptor (AT1R) axis is a key player in the pathophysiology of obesity. Angiotensin-converting enzyme 2 (ACE2) counteracts the ANG II/AT1R axis via converting ANG II to angiotensin 1-7 (Ang 1-7), which is known to have an anti-obesity effect. In this study, we hypothesized that ACE2 exerts a strong anti-obesity effect by increasing Ang 1-7 levels. We injected intraperitoneally recombinant human ACE2 (rhACE2, 2.0 mg kg_1 day_1) for 28 days to high-fat diet (HFD)- induced obesity mice. rhACE2 treatment decreased body weight and improved glucose metabolism. Furthermore, rhACE2 increased oxygen consumption and upregulated thermogenesis in HFD-fed mice. In the rhACE2 treatment group, brown adipose tissue (BAT) mass increased, accompanied with ameliorated insulin signaling and increased protein levels of uncoupling protein-1 (UCP-1) and PRD1-BF1-RIZ1 homologous domain containing 16. Importantly, subcutaneous white adipose tissue (sWAT) mass decreased, concomitant with browning, which was established by the increase of UCP-1 expression. The browning is the result of increased H3K27 acetylation via the downregulation of histone deacetylase 3 and increased H3K9 acetylation via upregulation of GCN5 and P300/CBP-associated factor. These results suggest that rhACE2 exerts anti-obesity effects by stimulating BAT and inducing browning in sWAT. ACE2 and the Ang 1-7 axis represent a potential therapeutic approach to prevent the development of obesity.

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Kawabe, Y., Mori, J., Morimoto, H., Yamaguchi, M., Miyagaki, S., Ota, T., … Hosoi, H. (2019). ACE2 exerts anti-obesity effect via stimulating brown adipose tissue and induction of browning in white adipose tissue. American Journal of Physiology - Endocrinology and Metabolism, 317(6), E1140–E1149. https://doi.org/10.1152/AJPENDO.00311.2019

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