Background: White adipose tissue can be classified based on its location as subcutaneous and visceral fat, and the latter accumulation is reported to be more detrimental to metabolism. Endoplasmic reticulum (ER) stress has been demonstrated to regulate lipogenesis. The peptide angiotensin(1-7) [Ang(1-7)], which can be produced from angiotensin II (AngII) by angiotensin-converting enzyme 2 (ACE2), plays its role through Mas receptor, also participates in the regulation of lipid metabolism in adipose tissue, however, whether ER stress is involved in the mechanism remains unclear. Therefore, we aimed to explore the role of Ang(1-7) pathway in regulating visceral adipose tissue expansion and ER stress.
Methods: ACE2 knockout (KO), Mas KO and C57BL/6 J mice were fed with high fat diet. Db/db mice were treated with either normal saline, Ang(1-7) or Ang(1-7) combined with Mas receptor inhibitor A779 using mini osmotic pumps. Fat mass was weighted, fat distribution was evaluated by MRI, and lipid profile and adipokines in epididymal adipose tissue were measured by ELISA kits, and histology of epididymal adipose tissue was also analyzed in multiple animal models. Additionally, differentiated 3T3-L1 cells were pre-loaded with palmitic acid to induce ER stress, then treated with drugs as those administrated to db/db mice. ER stress and lipogenesis related proteins in mice adipose and differentiated 3T3L-1 cells were analyzed by Western blot.
Results: ACE2 or Mas KO mice exhibited increased visceral adipose tissue, adipocyte size and protein expression of lipogenesis and ER stress related markers in epididymal adipose tissue compared to wild-type mice. Db/db mice treated with Ang(1-7) displayed decreased visceral fat mass, adipocyte size and protein expression of lipogenesis and ER stress markers in epididymal adipose tissue compared to those treated with normal saline, while A779 partly attenuated these effects. Additionally, Ang(1-7) improved ER stress and lipogenesis markers in differentiated 3T3-L1 cells pre-loaded with palmitic acid.
Conclusions: Our findings indicated that Ang(1-7) attenuated visceral adipose tissue expansion and lipogenesis by suppression of ER stress via Mas receptor. The present study provides a potential perspective for Ang(1-7) for the therapeutics of obesity and related disorders.
Keywords: ACE2; Ang(1–7); Endoplasmic reticulum stress; Lipogenesis; Mas; Visceral adipose tissue expansion.
© 2022. The Author(s).