Regulatory, Integrative and Comparative Physiology

Editorial Focus: A fat contribution to RAS activation and blood pressure control: evidence from angiotensinogen conditional null mice. Focus on: “Adipocyte-specific deficiency of angiotensinogen decreases plasma angiotensinogen concentration and systolic blood pressure in mice.”

Justin L. Grobe, Kamal Rahmouni

the renin-angiotensin system (RAS) is well recognized as a critical regulator of blood pressure and a determinant of cardiovascular homeostasis. The RAS was originally described in the circulation, although the presence of many or all components of the RAS has been documented in a variety of individual tissues including kidney, brain, heart, adrenal gland, and blood vessels (4). The importance of these local versions of the RAS in the development and maintenance of hypertension and associated end-organ damage has been firmly established.

Mounting evidence supports the concept that a local RAS is present in the adipose tissue (2). Expression of the angiotensinogen (AGT) gene has been reported in murine adipocyte cell lines as well as in murine and human adipose tissues. Fatty acids, carbaprostacyclin, glucocorticoids, and the sympathetic nervous system appear to positively regulate AGT gene expression in adipocytes by transcriptional mechanisms. The presence in adipose tissue of renin and angiotensin converting enzyme (ACE) expression and activity make possible the local production of angiotensin (ANG) II. Both subtypes of ANG II (AT1 and AT2) receptors are present in adipocytes as demonstrated by the presence of mRNA and protein and also by ligand binding functional and pharmacological studies. In addition to the potential physiological importance of the local adipose RAS, the significance and participation of adipose-derived RAS components, particularly AGT, to the circulating RAS has attracted much attention. The study by Yiannikouris et al. (10) provides convincing evidence that adipose-derived AGT contributes to plasma AGT levels and blood pressure regulation.

The liver is considered the primary site of AGT synthesis and the main source of circulating AGT. Indeed, Stec et al. (7) found that elimination of hepatic AGT expression was associated with a significant decrease in the plasma level of AGT (>90% of control levels). However, some evidence suggests that adipose tissue may contribute significantly to plasma AGT levels. This is based on findings using transgenic mice with AGT gene expression restricted to adipose tissue using an adipocyte-specific promoter (aP2) driving the expression of a rat AGT cDNA in AGT-deficient mice (6). Compared with AGT knockout mice, which have no detectable AGT plasma levels and are hypotensive, transgenic mice re-expressing AGT only in the adipose tissue have some circulating AGT (∼10% of the wild-type controls), are normotensive, and exhibit restored renal function. A major limitation of this previous study, however, stems from the fact that the expression of AGT was not driven by its own promoter, but by an aP2 promoter. Also, there was a dramatic increase in the expression levels of the AGT in the fat explants of transgenic mice. Therefore, it was not clear whether the AGT found in the plasma of the transgenic mice reflected a physiological contribution of adipocytes to the circulating RAS or an abnormal situation in which adipose tissue was dumping the overproduced AGT into the bloodstream.

To test the importance of locally produced adipose AGT to the circulating RAS, Yiannikouris et al. (10) generated mice that lack AGT expression only in adipose tissue. This was achieved by breeding mice carrying floxed alleles of the AGT gene with mice expressing Cre recombinase driven by the aP2 promoter (AGTflox/flox/aP2Cre mice). The efficacy of this strategy was demonstrated by the substantial reduction in the expression of AGT gene in the various fat pads, but not in the nonfat tissues tested (liver, kidney, brain, and heart) of AGTflox/flox/aP2Cre mice. Measurement of plasma AGT revealed that adipose tissue contributes significantly to the circulating pool of AGT. Indeed, both male and female AGTflox/flox/aP2Cre mice exhibited ∼26% reduction in plasma AGT compared with their age- and sex-matched controls. Interestingly, AGTflox/flox/aP2Cre mice also displayed a significant decrease in systolic blood pressure, indicating the relevance of adipose-derived AGT for blood pressure control. Further analysis showed that adipocyte-derived AGT may explain the positive correlation between blood pressure and total fat mass. Thus, the present study establishes adipose tissue RAS as an important determinant of systemic RAS activity and demonstrated its requirement for blood pressure maintenance (Fig. 1).

Fig. 1.

Contribution of adipose-derived angiotensinogen (AGT) to circulating renin-angiotensin system (RAS) in health and disease. In normal state (lean), while most plasma AGT is likely derived from the liver, AGT produced by adipocytes appears to contribute significantly (∼26%) to the circulating pool of AGT and, therefore, blood pressure control. When fat mass increases (obese state), adipocyte-derived AGT may become a major source of circulating AGT leading to activation of systemic RAS and arterial pressure elevation. Such mechanisms may explain the link between obesity and hypertension.

It is interesting to note, in the present study, the lack of effects of adipose AGT deficiency on body mass and metabolism. Indeed, body weight, plasma leptin, adipose mass, and adipocytes morphology evolved normally with age in male and female AGTflox/flox/aP2Cre mice compared with wild-type controls. Fasting blood glucose, plasma insulin, and glucose tolerance were also unaffected by adipose AGT deficiency. Previous investigations into the role of the RAS in metabolic control have demonstrated substantial reductions in adiposity and body mass, altered adipose morphology, increases in metabolic rate, decreased food intake, and/or altered glucose homeostasis in global RAS knockout models (or in wild-type animals following pharmacological inhibition) of renin, AGT, ACE, AT1A receptors, AT2 receptors, and Mas receptors (9). Furthermore, studies investigating the effects of brain versus peripheral RAS signaling have underscored opposing roles for brain versus peripheral RAS in metabolic control (1, 3). Thus, the present study adds to this line of investigation by highlighting a surprisingly minimal role for adipose-derived AGT in RAS-mediated metabolic control. However, it is possible that in AGTflox/flox/aP2Cre mice circulating RAS components, such as ANG II, may be compensating for the lack of locally produced peptide resulting in normal growth and differentiation of adipocytes.

There are some limitations to the present study that are worth mentioning. First, there are lingering concerns in the field about the specificity of the aP2 promoter. Previous studies have documented the expression of aP2 in nonadipose tissues, including the central nervous system, peripheral nervous ganglia, and adrenal medulla (5, 8). Consistent with a possible ectopic Cre expression, there was a trend toward reduced hepatic expression of AGT in the 2- and 12-mo-old aP2-Cre/AGTflox/flox mice in the present study, although this was not statistically significant. Second, because of the relatively small changes in blood pressure with adipose AGT knockout mice (5–10 mmHg), the use of tail-cuff methodology for blood pressure assessment is not ideal, given the sensitivity of this method to psychogenic stress combined with the above-mentioned possible ectopic knockout of AGT within nervous system tissues.

Together with a century of research on the role of the RAS in blood pressure control, the study by Yiannikouris et al. (10) supports the concept implicating adipose-derived AGT as a molecular link between obesity and hypertension. With the expansion of adipose tissue mass due to increased caloric intake, a sedentary lifestyle, or various endocrine disorders leading to a positive energy balance, there is an increase in the expression of AGT gene, which could explain the high plasma AGT levels in obesity (Fig. 1). Such increase in plasma AGT leads to elevated circulating RAS activity, which can increase blood pressure both through direct actions of circulating ANG II on peripheral vasculature and renal function and through actions of brain ANG II to stimulate arginine vasopressin and sympathetic nervous system activity to various tissues. Given that an increase in adipose, and perhaps circulating, ANG II causes adipocyte hypertrophy and increased fat mass, the overall effect of RAS activation not only leads to hypertension, but may also promote weight gain. The mouse model developed by Yiannikouris et al. will be useful to elucidate the pathophysiological role of AGT derived from adipocytes in obesity and associated cardiovascular diseases.


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