RT Journal Article
SR Electronic
T1 ACE2 Pathway Regulates Thermogenesis and Energy Metabolism
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.08.10.455823
DO 10.1101/2021.08.10.455823
A1 Xi Cao
A1 Tingting Shi
A1 Chuanhai Zhang
A1 Wanzhu Jin
A1 Lini Song
A1 Yichen Zhang
A1 Jingyi Liu
A1 Fangyuan Yang
A1 Charles N Rotimi
A1 Amin Xu
A1 Jinkui Yang
YR 2021
UL http://biorxiv.org/content/early/2021/08/10/2021.08.10.455823.abstract
AB Identification of key regulators of energy homeostasis holds important therapeutic promise for metabolic disorders, such as obesity and diabetes. ACE2 cleaves angiotensin II (Ang II) to generate Ang-(1-7) which acts mainly through the Mas receptor. Here, we identify ACE2 pathway as a critical regulator in the maintenance of thermogenesis and energy expenditure. We found that ACE2 is highly expressed in brown adipose tissue (BAT) and that cold stimulation increases ACE2 and Ang-(1-7) levels in BAT and serum. ACE2 knockout mice (ACE2-/y), Mas knockout mice (Mas-/-), and the mice transplanted with brown adipose tissue from Mas-/- mice displayed impaired thermogenesis. In contrast, impaired thermogenesis of db/db obese diabetic mice and high-fat diet-induced obese mice were ameliorated by overexpression of ACE2 or continuous infusion of Ang-(1-7). Activation of ACE2 pathway was associated with improvement of metabolic parameters, including blood glucose, lipids and energy expenditure in multiple animal models. Consistently, ACE2 pathway remarkably enhanced the browning of white adipose tissue. Mechanistically, we showed that ACE2 pathway activated Akt/FoxO1 and PKA pathway, leading to induction of UCP1 and activation of mitochondrial function. Our data propose that adaptive thermogenesis requires regulation of ACE2 pathway and highlight novel therapeutic targets for the treatment of metabolic disorders.Competing Interest StatementThe authors have declared no competing interest.