Angiotensin II (Ang II) is the main active product of the renin-angiotensin system (RAS), mediating its action via two major receptors, namely, the Ang II type 1 (AT1) receptor and the type 2 (AT2) receptor. Recent results also implicate several other members of the renin-angiotensin system in various aspects of brain functions. The first aim of this paper is to summarize the current state of knowledge regarding the properties and signaling of the AT2 receptor, its expression in the brain, and its well-established effects. Secondly, we will highlight the potential role of the AT2 receptor in cognitive function, neurological disorders and in the regulation of appetite and the possible link with development of metabolic disorders. The potential utility of novel nonpeptide selective AT2 receptor ligands in clarifying potential roles of this receptor in physiology will also be discussed. If confirmed, these new pharmacological tools should help to improve impaired cognitive performance, not only through its action on brain microcirculation and inflammation, but also through more specific effects on neurons. However, the overall physiological relevance of the AT2 receptor in the brain must also consider the Ang IV/AT4 receptor.

This study was aimed at establishing whether specific activation of angiotensin II (ANG II) type 2 receptor (AT2R) modulates adipocyte differentiation and function. In primary cultures of subcutaneous (SC) and retroperitoneal (RET) preadipocytes, both AT2R and AT1R were expressed at the mRNA and protein level. Cells were stimulated with ANG II or the AT2R agonist C21/M24, alone or in the presence of the AT1R antagonist losartan or the AT2R antagonist PD123,319. During differentiation, C21/M24 increased PPAR␥ expression in both RET and SC preadipocytes while the number of small lipid droplets and lipid accumulation solely increased in SC preadipocytes. In mature adipocytes, C21/M24 decreased the mean size of large lipid droplets. Upon abolishment of AT2R expression using AT2R-targeted shRNAs, expressions of AT2R, aP2, and PPAR␥ remained very low, and cells were unable to differentiate. In Wistar rats fed a 6-wk high-fat/highfructose (HFHF) diet, a significant shift toward larger adipocytes was observed in RET and SC adipose tissue depots. C21/M24 treatments for 6 wk restored normal adipocyte size distribution in both these tissue depots. Moreover, C21/M24 and losartan decreased hyperinsulinemia and improved insulin sensitivity impaired by HFHF diet. A strong correlation between adipocyte size area and glucose infusion rate during euglycemic-hyperinsulinemic clamp was observed. These results indicate that AT2R is involved in early adipocyte differentiation, while in mature adipocytes and in a model of insulin resistance AT2R activation restores normal adipocyte morphology and improves insulin sensitivity.angiotensin type 2 receptor; adipocyte; differentiation; PPAR␥; highfat/high-fructose diet SEVERAL RECENT REVIEWS clearly implicate the renin-angiotensin system (RAS) in various aspects of adipose tissue physiology and dysfunction, linking RAS abnormalities with the development of insulin resistance and type 2 diabetes (7,25,36,50). Classically, the hormone angiotensin II (ANG II) mediates its action via two major receptors, namely the ANG II type 1 receptor (AT1R) and the type 2 receptor (AT2R). AT1R is closely associated with the regulation of blood pressure and hydro-mineral balance, with long-term ANG II-induced AT1R activation playing a well-documented role in hypertension, type 2 diabetes, and cardiovascular diseases (7,25,36,50). In contrast, AT2R is highly expressed in fetal life, while in the adult its expression is much more variable, according to tissues and pathophysiological situations (for recent reviews see Refs. 25,45,46,51,56). In conditions of insulin resistance, several studies, although not all (38), suggest that AT1R blockade provides end-organ protection independently of its antihypertensive effect by decreasing the size of adipocytes in visceral adipose tissue and by reversing the profile of adipokine secretion associated with obesity and type 2 diabetes (13,17,34,48,61) (for review see Refs. 20,25). Therapeutic responses to angiotensin receptor blockers (ARBs) may result from enhanced AT2R...

Our study unrevealed a new mechanism by which PKC-β activation promotes EC dysfunction caused by the de-regulation of the IL-18/IL-18BP pathway, leading to increased VCAM-1 expression, monocyte/macrophage adhesion, and accelerated atherosclerotic plaque formation in diabetes.

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