The lack of Ang-(1–7) action through Mas receptor increased level

The lack of Ang-(1–7) action through Mas receptor increased levels of serum NEFA and decreased the response of adipocytes

to the antilipolytic effect of insulin. In fat cells, insulin inhibits the mobilization of NEFA by decreasing the rate of lipolysis and/or increasing the lipogenic rate and lipid storage. Insulin resistance in adipose tissue is characterized Sirolimus by decreased suppression of adipose tissue lipolysis by insulin, resulting in elevated circulating NEFA levels [19]. Increased NEFA concentrations leads to serine/threonine phosphorylation of insulin receptor substrate (IRS-1 and IRS-2), subsequently reducing the ability of the IRS to activate phosphatidylinositol (PI) 3-kinase and glucose transport [28]. Recently Giani et al. [14] demonstrated that infusion of Ang-(1–7) in rats resulted in a reversal of fructose-induced insulin resistance through the IR/IRS/PI3 K/Akt pathway in the main target of insulin: skeletal muscle, liver and adipose tissue. These findings are in accordance with the observation that transgenic rats, with chronic elevation of plasma Ang-(1–7), improved

responsiveness to insulin stimulation and increased total and phosphorylated Akt in adipose tissue [24]. In addition, previous work from our group have shown that Mas-knockout mice presented glucose intolerance and reduced insulin sensitivity as well as a decrease in insulin-stimulated glucose uptake by adipocytes and decreased GLUT4 in adipose tissue [25]. Olaparib purchase Previous studies have shown that Mas-deficient mice present lack of several Ang-(1–7) actions, mainly concerning to behavior and cardiovascular regulation [1]. Mas receptor deletion abolished the vasodialator effect of Ang-(1–7) in vitro and also induced a hypertensive state in FVB/N mice. All these data are followed by dysbalance between nitric oxide IKBKE and reactive oxygen species in the vessel wall of Mas-KO. Recently studies have shown that Mas knockout mice presented a prothrombotic profile [12], altered calcium signaling on cardiomyocytes [10] and renal dysfunction

[21]. In conclusion, the absence of Ang-(1–7)/Mas axis induces important alterations in adipose tissue, evidenciated by decreased insulin sensibility in adipocytes, which might be consequent to: (1) decreased mRNA expression of PPARγ; (2) exacerbation of Ang-II action as a consequence of the missing contraregulation by Ang-(1–7), via receptor Mas. EGM – conducted the animal experiments, generation and collection of data, and helped draft and revision of the manuscript. SHSS – participated in the generation and collection of RT-PCR data and helped the revision of the manuscript. AVMF – participated in the generation and collection of RT-PCR data. MB – generated mice lacking the Mas protooncogene. RASS – helped draft and revision of the manuscript, approval of the final version of the manuscript.

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