Angiotensin type 2 receptor activation promotes browning of white adipose tissue and brown adipogenesis

Abstract

Brown adipose tissue dissipates energy in the form of heat. Recent studies have shown that adult humans possess both classical brown and beige adipocytes (brown-like adipocytes in white adipose tissue, WAT), and stimulating brown and beige adipocyte formation can be a new avenue to treat obesity. Angiotensin II (AngII) is a peptide hormone that plays important roles in energy metabolism via its angiotensin type 1 or type 2 receptors (AT1R and AT2R). Adipose tissue is a major source of AngII and expresses both types of its receptors, implying the autocrine and paracrine role of AngII in regulating adipose functions and self-remodeling. Here, based on the in vitro studies on primary cultures of mouse white adipocytes, we report that, AT2R activation, either by AngII or AT2R agonist (C21), induces white adipocyte browning, by increasing PPARγ expression, at least in part, via ERK1/2, PI3kinase/Akt and AMPK signaling pathways. It is also found that AngII–AT2R enhances brown adipogenesis. In the in vivo studies on mice, administration of AT1R antagonist (ZD7155) or AT2R agonist (C21) leads to the increase of WAT browning, body temperature and serum adiponectin, as well as the decrease of WAT mass and the serum levels of TNFα, triglycerides and free fatty acids. In addition, AT2R-induced browning effect is also observed in human white adipocytes, as evidenced by the increased UCP1 expression and oxygen consumption. Finally, we provide evidence that AT2R plays important roles in hormone T3-induced white adipose browning. This study, for the first time, reveals the browning and brown adipogenic effects of AT2R and suggests a potential therapeutic target to combat obesity and related metabolic disorders.

Angiotensin receptor subtypes regulate adipose tissue renewal and remodelling

“…Interestingly, AT 1 R receptor deletion suppresses in vitro adipocyte differentiation, with reduced expression of thermogenic genes. These data indicate that both receptors are involved in the regulation of adipogenic differentiation and likely the initiation of AT 2 R‐dependent activation of PI3‐kinase/Akt and AMPK signalling cascades and downregulation of ERK1/2 phosphorylation requires the formation of a heteromeric complex with AT 1 R . Furthermore, AT 2 R, acting as a partner for heterooligomerisation with β‐adrenoceptors, may exert additional indirect effects on WAT browning.…”

lncRNA MIAT suppression alleviates corneal angiogenesis through regulating miR-1246/ACE

“…AngII is consisted of AT1R and AT2R receptors, AT1R mainly conducted cell proliferation and smooth muscle contraction, while AT2R mainly modulates cell apoptosis and smooth muscle relaxation [23]. It has been reported that AngII is mediated in various diseases, such as renal disease [24], energy metabolism [25], and myocardial disease [26]. The previous study identified that AngII is involved in angiogenesis [27].…”

AMPK: a balancer of the renin–angiotensin system

“…Studies on the relationship between AT2R and AMPK extended mainly in adipose tissue and lungs. One investigation revealed that in white adipocytes, AT2R may activate AMPK independent of AngII [119]. AT2R induced white adipocyte browning by increasing peroxisome proliferator-activated receptor (PPARγ) expression in primary cultures of mouse white adipocytes, which at least partially passes through AMPK, PI3k/Akt and ERK1/2 signaling pathways [119].…”

“…One investigation revealed that in white adipocytes, AT2R may activate AMPK independent of AngII [119]. AT2R induced white adipocyte browning by increasing peroxisome proliferator-activated receptor (PPARγ) expression in primary cultures of mouse white adipocytes, which at least partially passes through AMPK, PI3k/Akt and ERK1/2 signaling pathways [119]. Another research demonstrated that AngII adjusts the relationship of AMPKβ1/2 between Cdk4, leading to the hyperphosphorylation of retinoblastoma protein (Rb) and induction of E2F1(E2F is a group of genes that encodes a family of transcription factors in higher eukaryotes, E2F1 is one activator of the family)-dependent Bim gene activation in pulmonary artery endothelial cells (PAECs) [120,121].…”