cAMP-positive regulation of angiotensinogen gene expression and protein secretion in rat adipose tissue

Valérie Serazin,1,2 Marie-Noelle Dieudonné,1,2 Mireille Morot,1,2 Philippe de Mazancourt,1,3 and Yves Giudicelli1,2

1Service de Biochimie et de Biologie Moléculaire de la Faculté de Médecine Paris-Ile-de-France-Ouest, Université René Descartes, F75270 Paris; 2Hôpital de Poissy, F78303 Poissy; and 3Hôpital R Poincaré, F92380 Garches, France

Submitted 25 April 2003 ; accepted in final form 21 October 2003


    ABSTRACT
 TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The adipose renin-angiotensin system (RAS) has been assigned to participate in the control of adipose tissue development and in the pathogenesis of obesity-related hypertension. In adipose cells, the biological responses to {beta}-adrenergic stimulation are mediated by an increase in intracellular cAMP. Because cAMP is known to promote adipogenesis and because an association exists between body fat mass, hypertension, and increased sympathetic stimulation, we examined the influence of cAMP on angiotensinogen (ATG) expression and secretion in rat adipose tissue. Exposure of primary cultured differentiated preadipocytes to the cAMP analog 8-bromoadenosine 3',5'-cyclic monophosphate (8-BrcAMP) or cAMP-stimulating agents (forskolin and IBMX) results in a significant increase in ATG mRNA levels. In adipose tissue fragments, 8-BrcAMP also increases ATG mRNA levels and protein secretion, but not in the presence of the protein kinase A inhibitor H89. The addition of isoproterenol, known to stimulate the synthesis of intracellular cAMP via {beta}-adrenoreceptors, had the same stimulatory effect on ATG expression and secretion. These results indicate that cAMP in vitro upregulates ATG expression and secretion in rat adipose tissue via the protein kinase A-dependent pathway. Further studies are required to determine whether this regulatory pathway is activated in human obesity, where increased sympathetic tone is frequently observed, and to elucidate the importance of adipose ATG to the elevated blood pressure observed in this pathological state.

angiotensinogen expression; cyclic adenosine 5'-monophosphate


IN THE BLOOD COMPARTMENT, angiotensinogen (ATG) is the unique substrate of renin and the precursor of angiotensin II (ANG II), the effector of the renin-angiotensin system (RAS). ANG II plays a crucial role in blood pressure regulation and in fluid volume balance (9). Various tissues express their own RAS, which seems to affect local tissue functions. Besides the liver, white adipose tissue is the second most abundant source of ATG (30). Human and rodent adipose tissues possess a functional RAS (14, 31), and the generated ANG II elicits a variety of physiological effects after its binding to specific membranous receptors, the ANG II receptors (10). Locally produced ANG II has been assigned to participate in the control of adipose tissue development. RAS is a positive regulator of the preadipocyte-adipocyte conversion process in animal models (11, 36).

Different studies have shown that cAMP modulates cellular growth and differentiation either positively or negatively, depending on the cell type (12). In rat adipose precursor cells, the pivotal role of the cAMP pathway in differentiation has been illustrated by proadipogenic effects of cAMP-elevating agents that activate the protein kinase A (PKA) pathway (1) and the transcription factor cAMP response element-binding protein (CREB) (33).

Although most obese patients have high blood pressure, the mechanisms linking obesity to hypertension are still poorly understood. The discovery that adipose tissue expresses and secretes ATG and the finding that obese patients have abnormally high circulating ATG levels (40) have suggested an important role of the adipocyte-derived ATG and the adipose RAS in the pathogenesis of obesity-related hypertension (15). Evidence was provided (4) that the increased sympathetic tone observed in obese subjects could be in part responsible for the obesity-related hypertension. Increased sympathetic activity leads to enhanced secretion of catecholamines, which are known to simulate (via {beta}-adrenoceptors) or reduce (via {alpha}2-adrenoceptors) the intracellular cAMP levels in adipose cells (34).

Because increased ATG secretion, ANG II generation, and cAMP production are characteristic features of fully differentiated preadipocytes (18, 37), and because the rat ATG gene promoter contains a putative cAMP response element (CRE) (6), we have here investigated the possibility that cAMP and isoproterenol (a {beta}-adrenergic receptor agonist) may regulate in vitro the expression and secretion of ATG in rat adipose tissue.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Animals. Adult male Sprague-Dawley rats were kept under controlled lighting conditions (light on at 6 AM, dark at 8 PM) and had free access to a standard diet and water. Animals (242 ± 13.9 g) were killed by decapitation.

Preadipocyte culture conditions. Undifferentiated preadipocytes were obtained from the stroma vascular fraction of epidydimal fat pads, as previously described (38). The preadipocytes were plated at a density of 1-2 x 104 cells/cm2 in cell culture dishes with DMEM (Sigma, St. Louis, MO)-8% fetal bovine serum (ATGC Biotechnology, Noisy Le Grand, France), streptomycin (0.1 mg/ml), and penicillin (100 IU/ml). After 12 h, cells were washed and maintained under the same conditions for 3 more days. Medium was changed every day. Then, cells were allowed to differentiate in DMEM-Ham's F-12 medium supplemented with insulin (5 µg/ml), transferrin (10 µg/ml), 3,5,3'-triiodothyronine (2 nM, Sigma), and antibiotics (0.1 mg/ml streptomycin and 100 IU/ml penicillin). After 6 days, >70% of the cultured cells appeared under the microscope as lipid-filled differentiated adipose cells. Then, these cells were incubated for different times in the presence or absence of effectors, collected in a standard acid guanidinium isothiocyanate solution, and stored at -80°C.

Adipose tissue culture conditions. Epididymal adipose tissue fragments (0.3-1 g), prepared as previously described (25), were placed in cell culture dishes and incubated for different times at 37°C under 5% CO2-95% air atmosphere in 6 ml of DMEM-Ham's F-12 medium containing bovine serum albumin (1.5%), penicillin (100 IU/ml), streptomycin (0.1 mg/ml), and antiproteolytic agents [10 µg/ml 4-(2-amoniethyl)-benzenesulfonylfluoride hydrochloride, or AEBSF (Interchim, Montluçon, France), 2 µM leupeptin, and 25 µg/ml aprotinin (Sigma)]. At the end of incubation, tissue fragments were collected in a standard acid guanidinium isothiocyanate solution, homogenized, centrifuged at 3,000 g for 3 min at 4°C to remove lipids, and kept at -80°C. Simultaneously, culture medium was collected in the presence of 10 µM captopril and stored at -80°C until they were used for ATG assay. To check possible cellular lysis and unviability, lactate dehydrogenase (LDH) activity released into the culture medium and cellular glucose uptake were determined in parallel, but no differences between each incubation set could be recorded.

Total RNA extraction and semiquantitative RT-PCR. Total RNA was extracted and purified by following the guanidinium isothiocyanate procedure described by Chomczynski and Sacchi (7). The yield and quality of extracted RNA were assessed by the 260/280-nm optical density ratio and by electrophoresis under denaturing conditions on 1% agarose gel. The RNA was stored at -80°C until use.

The reverse transcription was carried out in a final volume of 10 µl, as previously described (38), by use of Superscript II RNase H-reverse transcriptase (Life Technologies, Grand Island, NY) with random hexamers and 0.1 µg of total RNA. Controls without reverse transcriptase were systematically performed to detect genomic DNA contamination. The cDNAs were stored at -20°C until use. Reverse transcripts (2 µl) were amplified, as previously described (38), with use of the rat cyclophilin (CYC) gene, a ubiquitous housekeeping gene, as internal standard. The PCR conditions generated 336- and 210-bp cDNA fragments for ATG and CYC, respectively. PCR products (10 µl) were analyzed on a 1.5% agarose gel stained with ethidium bromide, photographed, and analyzed by Bio-Imager software. Semiquantitative data were expressed as the ratio of the ATG to CYC signals.

Assay for ATG protein secretion. ATG protein was indirectly determined by a radioimmunoassay of angiotensin (ANG) I, generated by an excess of hog renin (Sigma) with the REN-CT2 RIA kit (CIS bio International, Gif sur Yvette, France), as previously described (38). The inter- and intra-assay variation coefficients were <10%. The ANG I antibody cross-reactivity was <0.01% for ANG II and ANG III. The sensitivity of the assay was 0.15 ng/ml.

Other determinations. LDH activity and glucose concentrations in the incubation medium were assessed as previously described (38). Glycerol release and accumulation in the culture medium were used as an index of lipolysis and measured enzymatically, as previously described (16).

Statistical analysis. Results are expressed as means ± SE of at least three individual experiments. Statistics were performed using Excel 2000 computer software (Microsoft). Statistical analysis of comparisons among groups was undertaken using Student's t-tests.


    RESULTS
 TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The effect of cAMP on the steady-state level of ATG mRNA was first examined in primary cultured differentiated preadipocytes after exposure to 250 µM of the cAMP analog 8-bromoadenosine 3',5'-cyclic monophosphate (8-BrcAMP; Sigma), 10 µM of the receptor-independent activator of adenyl cyclase forskolin (FSK), or 100 µM of the cAMP phosphodiesterase inhibitor IBMX (Sigma). A 3-h exposure was chosen because previous kinetic experiments revealed that this time gave optimal results for the determination of ATG mRNA levels in rat differentiated preadipocytes. As shown in Fig. 1, exposure to these compunds resulted in a significant increase in ATG mRNA (8-BrcAMP: +74 ± 42%, n = 6; FSK: +143 ± 78%, n = 7; IBMX: +175 ± 63%, n = 3).



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Fig. 1. Stimulation of angiotensinogen (ATG) mRNA levels by 8-bromoadenosine 3',5'-cyclic monophosphate (8-BrcAMP), forskolin (FSK), or IBMX in rat differentiated preadipocytes. Primary cultured rat differentiated preadipocytes were incubated for 3 h in the absence (control, C) or presence of 250 µM 8-BrcAMP, 10 µM FSK, or 100 µM IBMX. Control incubates received the respective vehicle. ATG mRNA levels were analyzed in RNA preparations isolated as described in MATERIALS AND METHODS. The abundance of ATG mRNA relative to that of cyclophilin (CYC) mRNA was expressed as a percentage of control values. Data represent means ± SE of 3-7 separate experiments evaluated by Student's t-test for unpaired data. *P < 0.05, **P < 0.005 vs. control.

 

The following experiments were designed to determine whether the above-described cAMP effects were accompanied by parallel variations in ATG protein secretion. However, because ATG protein secretion from differentiated preadipocytes is largely under the detection limits of the RIA (38), we performed these experiments on adipose tissue fragments exposed or not to 8-BrcAMP. The time of exposure (24 h) was chosen because previous kinetic experiments revealed that this time gave optimal results for the ATG mRNA levels and protein secretion. As shown in Fig. 2 and Table 1, exposure to 250 µM 8-BrcAMP resulted in a significant increase in ATG mRNA levels (+84 ± 29%, n = 6). A similar effect was observed after exposure to 10 nM dexamethasone (Dex; +88 ± 41%, n = 5), confirming a previous report (3) and thus warranting the validity of our experimental conditions. Moreover, we failed to observe any synergism between the effects of 8-BrcAMP and Dex (Fig. 2 and Table 1). ATG secretion was also significantly enhanced by 8-BrcAMP (+41 ± 12%, n = 3) or by Dex (+74 ± 13%, n = 3; Fig. 3 and Table 1). Finally, when the same experiments were repeated in the presence of 10 µM of the PKA inhibitor H89 (Sigma), 8-BrcAMP upregulation of ATG mRNA expression and protein secretion could no longer be observed (n = 4). It is important to note that H89 alone failed to affect ATG expression and secretion (Figs. 2 and 3 and Table 1).



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Fig. 2. ATG and CYC mRNA levels in rat adipose tissue fragments incubated in the absence (control, C) or presence of 8-BrcAMP, dexamethasone (Dex), or a PKA inhibitor (H89). Rat adipose tissue fragments were exposed during 24 h to 8-BrcAMP (250 µM), Dex (10 nM), Dex + 8-BrcAMP, H89 (10 µM), or H89 + 8-BrcAMP. At the end of incubation, total RNA was extracted and subjected to reverse transcription, and cDNAs were amplified as described in MATERIALS AND METHODS. The gel shown is representative of 4 different experiments. Lane 1 represents a RT-PCR control performed without reverse transcriptase. Lane 2 represents the 100-bp ladder.

 

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Table 1. Influence of 8-BrcAMP and/or H89 on ATG mRNA levels (semiquantitative RT-PCR) and protein secretion in rat adipose tissue

 


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Fig. 3. ATG secretion from rat adipose tissue fragments incubated in the absence (control, C) or presence of 8-BrcAMP, Dex, or a PKA inhibitor (H89). Rat adipose tissue fragments were incubated as described in legend to Fig. 2. After 24 h, ATG was assayed in incubation medium, as described in MATERIALS AND METHODS. Data are expressed as percentages of control values and are means ± SE of 3 separate experiments evaluated by Student's t-test for unpaired data. *P <= 0.05, **P <= 0.005 vs. control, {diamondsuit}P <= 0.05 vs. 8-BrcAMP.

 

We also evaluated the effect of {beta}-adrenergic stimulation on ATG mRNA levels and protein secretion under the same experimental conditions described above. Previous kinetic experiments revealed that 6 h of incubation gave optimal results on ATG mRNA levels and protein secretion under these conditions. Figure 4 shows that exposure to 10-7 M isoproterenol (Sigma) resulted in a significant increase in ATG mRNA levels (+92 ± 24%, n = 5) and secretion (+53 ± 13%, n = 6). These results were similar to those obtained after a 6-h exposure to 250 µM 8-BrcAMP [increase in ATG mRNA levels (+59 ± 17%, n = 7) and in ATG protein secretion (+39 ± 9%, n = 5)]. Extracellular glycerol (an index of lipolysis) was measured in parallel in the same preparations. The respective increase in glycerol concentration above control values for isoproterenol was sevenfold (P < 0.05) and for 8-BrcAMP was fivefold (P < 0.05).



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Fig. 4. Effect of isoproterenol (compared with 8-BrcAMP) on ATG mRNA levels (A) and ATG protein secretion (B) in rat adipose tissue fragments which were exposed during 6 h to 8-BrcAMP (250 µM) and isoproterenol (10-7 M). A: ATG mRNA level analysis was the same as in Fig. 1. The abundance of ATG mRNA relative to that of CYC mRNA was expressed as a percentage of control values. Data represent means ± SE of 5-7 separate experiments evaluated by Student's t-test for unpaired data. *P < 0.05 vs. control. B: ATG was assayed in incubation medium, as described in MATERIALS AND METHODS. Data are expressed as percentages of control values and are means ± SE of 5 or 6 separate experiments evaluated by Student's t-test for unpaired data. **P <= 0.005 vs. control.

 


    DISCUSSION
 TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
In the present study, we show for the first time that agents known to increase intracellular cAMP (FSK, IBMX) and the membrane-permeable cAMP analog 8-BrcAMP induce an increase in the ATG mRNA level in differentiated rat preadipocytes. In rat adipose tissue fragments, the same positive effect was observed not only on ATG mRNA but also on ATG protein secretion. We have also reported that treatment of rat adipose tissue fragments with a {beta}-adrenergic receptor agonist (isoproterenol) resulted in a significant increase in ATG expression and secretion. This effect was rapid and reached statistical significance after 6 h.

Regulation of ATG gene expression appears to be species and tissue specific. Our data are in good agreement with results from previous studies. Indeed, ATG mRNA levels were reported to be increased by catecholamines in oppossum kidney cells (41) and by 8-BrcAMP in human hepatoma HepG2 cells (8). In contrast, ATG gene expression decreases in rat hepatocytes after exposure to catecholamines, and in the 3T3-L1 adipocyte model after {beta}-adrenergic stimulation (22, 24). Furthermore, our experiments, failing to reveal any synergism between cAMP and Dex, contrast with other studies showing that cAMP amplifies the stimulatory effect of Dex on ATG gene expression in mouse hepatoma cells and in rat hepatocytes (27, 29). We also showed that, when PKA was inhibited, the promoting effects of 8-BrcAMP on ATG mRNA levels and protein secretion were both abolished, thus indicating that these effects required, at least in part, PKA activation. Such a mechanism makes it appear all the more likely that 1) in general, cAMP-dependent PKA activation results in the translocation of PKA catalytic subunits into the nucleus, where these subunits then phosphorylate the 43-kDa CREB (17), and 2) the rat ATG gene promotor includes a putative CRE, which binds the phosphorylated form of CREB and, by the way, modulates ATG gene expression (32). The phosphorylated CREB might also interact with the activated glucocorticoid receptor complex (GRC), which binds to the glucocorticoid response element in the 5'-flanking region of the rat ATG gene upon stimulation by Dex (19). Such a mechanism could explain why we did not find a synergism between cAMP and Dex. On the other hand, this increase in ATG mRNA by cAMP treatment could also result from increased intracellular free fatty acids as the consequence of cAMP-stimulated lipolysis, as free fatty acids were previously described to enhance ATG gene expression in the Ob 1771 adipocyte cell line (35). Finally, a posttranscriptional mechanism cannot also be excluded, since the rate of synthesis of numerous proteins is regulated by posttranscriptional stabilization or destabilization of their mRNA (28). Further experiments will be necessary to characterize in more detail the molecular mechanism of the cAMP-promoting effect on ATG in rat adipose tissue.

The increase of cAMP production in adipose cells coincides with differentiation commitment and expression of markers of the adipocyte phenotype, such as ATG (18, 37). Different studies strongly suggest a pivotal role for cAMP in the regulation of adipogenesis (1). Our observation that cAMP increases the expression and secretion of adipocyte ATG leads us to postulate that this regulation may account, at least in part, for the role of cAMP in adipose tissue development. Indeed, on the basis of in vivo and ex vivo experiments in rodent adipose tissue, the locally released ANG II induces an adipocyte release of prostacyclin, which in turn stimulates preadipocyte differentiation (11, 36). In rats, oral treatment with an ANG II receptor antagonist reduces the fat mass and adipocyte size independently of changes in food intake (10). Moreover, RAS is a positive regulator of the transcription of key genes involved in lipogenesis control in human adipocytes and 3T3-L1 cells (21). However, ANG II has recently been shown to inhibit in vitro adipogenic differentiation of human preadipocytes (20). Nevertheless, the exact action of ANG II, via the different ANG II receptors, in the adipogenic process appears to depend on the species or models investigated, as well as on the type of experiments (i.e., in vivo, ex vivo, or in vitro) used. Additionnal experiments are needed to clarify the involvement of the local RAS in adipose tissue development.

The adrenoceptors play a major role in the regulation of white fat cell function. Catecholamines stimulate adenylyl cyclase and increase intracellular cAMP in rat adipose cells via {beta}-adrenergic receptors. An increased sympathetic nervous system activity has been observed in obese subjects (4) and is believed to be involved in the pathogenesis of hypertension (2). Obesity is a condition that often occurs in patients with arterial hypertension (23), and weight loss is an important part of the treatment for the hypertensive state (13). In addition, it is important to understand how the adipocyte ATG production is regulated because of the potential role of the adipose tissue RAS in obesity-associated hypertension. A positive correlation between plasma ATG levels and blood pressure has been described not only in humans (5) but also in rat models of hypertension (39). Moreover, a positive correlation between plasma ATG levels and body mass index was found in humans (40). Recently, the ATG-deficient hypotensive mouse model (26) allowed us to demonstrate that adipose tissue represents a source for circulating ATG, although the exact contribution of adipose tissue cannot be quantified precisely. Moreover, once released into ciculation, adipose ATG seems involved in blood pressure regulation, since a partial recovery of plasma ATG levels is sufficient to fully restore normal blood pressure in these ATG-deficient mice (26). However, further studies, performed under more physiological conditions, are required to firmly establish whether smaller variations of adipose ATG expression and secretion can influence plasma ATG and, by the way, blood pressure.

The increased adipocyte ATG expression and secretion by cAMP and isoproterenol suggest that the sympathetic nervous system may have a regulatory role in the activation of the local RAS. Hence, we speculate that the activation of the sympathetic nervous system during obesity may enhance adipocyte ATG release into the circulation and may then be involved in blood pressure regulation.

In summary, we have demonstrated that cAMP and {beta}-adrenergic stimulation increases the ATG expression and secretion in rat adipose tissue. This finding leads us 1) to postulate that this regulation may account, at least in part, for the role of cAMP in adipose tissue development and 2) to establish a link between increased sympathetic tone, elevated plasma ATG levels, and hypertension, all of which characterize the obese state.


    FOOTNOTES
 

Address for reprint requests and other correspondence: V. Serazin, Service de Biologie Médicale, C.H.I. Poissy/St Germain en Laye, 10, rue du Champ Gaillard, F78303 Poissy, France (E-mail: valerie_serazin{at}hotmail.com).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


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 DISCUSSION
 REFERENCES
 

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