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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2007-0234
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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 7 2706-2711
Copyright © 2007 by The Endocrine Society

Dissociation between Adipose Nitric Oxide Synthase Expression and Tissue Metabolism

Stefan Engeli, Michael Boschmann, Frauke Adams, Gabriele Franke, Kerstin Gorzelniak, Jürgen Janke, Friedrich C. Luft and Jens Jordan

Franz-Volhard Clinical Research Center, Medical Faculty of the Charité and Helios Klinikum, D-13125 Berlin, Germany

Address all correspondence and requests for reprints to: Jens Jordan, M.D., Franz-Volhard Clinical Research Center, Charité Campus Buch, Wiltbergstrasse 50, 13125 Berlin, Germany. E-mail: jens.jordan{at}charite.de.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Nitric oxide synthase (NOS) expression in adipose tissue is increased in obese subjects. The functional relevance is not known.

Objective: The objective was to compare adipose tissue metabolism between obese men with greater or lower adipose endothelial NOS (eNOS) or inducible NOS (iNOS) expression.

Design: The design was an open-labeled prospective study.

Setting: The study took place at an academic clinical research center.

Patients: The patients included 14 obese (32 ± 0.6 kg/m2) and eight normal-weight (23 ± 2 kg/m2) healthy men.

Intervention: Microdialysis catheters in abdominal sc adipose tissue and in vastus lateralis were perfused with N-{omega}-nitro-L-arginine methyl ester (L-NAME) or N-{omega}-nitro-D-arginine methyl ester (D-NAME). Then, incremental isoproterenol concentrations were added to the perfusate.

Main Outcome Measures: Microdialysate glycerol was the main outcome measure.

Results: Tissue perfusion and microdialysate glycerol concentrations at baseline and during isoproterenol stimulation were similar in obese men with high or low eNOS or iNOS expression during both L-NAME and D-NAME. During D-NAME, basal and maximal isoproterenol stimulated glycerol were similar in lean and in obese men. However, in lean men, the dose-response relationship between isoproterenol and glycerol was shifted towards the left (P < 0.0001). NOS inhibition with L-NAME had no effect on basal or isoproterenol-stimulated glycerol in the obese group in skeletal muscle or in adipose tissue. In contrast, L-NAME augmented the lipolytic response in lean subjects in both tissues.

Conclusions: Differences in eNOS and iNOS mRNA expression at the adipose tissue level may have a limited effect on lipolysis and tissue perfusion. The lower resting lipolysis in adipose tissue of obese compared with nonobese subjects cannot be explained by a tonic nitric oxide effect.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
NITRIC OXIDE (NO) is produced by three isoforms of NO synthase, namely endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), and neuronal nitric oxide synthase. iNOS and eNOS expression has been demonstrated in human sc adipose tissue, mainly in adipocytes (1, 2, 3). eNOS is the predominant isoform in human adipose tissue. iNOS is expressed at much lower levels than eNOS (2, 3). Neuronal NOS is either not expressed or expressed at very low levels (2). eNOS mRNA expression is consistently increased in obese subjects (2, 3). The increased eNOS gene expression is associated with a profound increase in eNOS protein in most but not all populations (2, 4). In one study, iNOS mRNA and protein expression in adipose tissue were similar in nonobese and obese subjects (2). In another study, iNOS mRNA expression was increased in the obese group (3). The functional relevance of the increase in NOS expression and protein content is not known. In human microdialysis experiments, NOS inhibition with either N-{omega}-nitro-L-arginine methyl ester (L-NAME) or NG-monomethyl-D-arginine increased lipolysis in healthy lean subjects. The increase in lipolysis was evident at rest (1) and during local ß-adrenoreceptor stimulation (5). The effect was in part mediated by an increase in interstitial norepinephrine (5). Thus, we hypothesized that NOS inhibition with L-NAME should result in excessive lipolysis both at baseline and during ß-adrenergic stimulation in obese patients with greater eNOS and/or iNOS expression in adipose tissue compared with obese patients with lower expression. Given the central role of NO in the regulation of vascular tone (6), we suspected that the effect of NOS inhibition on tissue blood flow may also be increased in patients with higher eNOS and iNOS expression. Finally, we hypothesized that all of these responses should be increased in obese patients compared with normal-weight controls.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

We studied 14 obese (age, 35 ± 1.6 yr; body mass index, 32 ± 0.6 kg/m2) and eight normal-weight (age, 26 ± 2 yr; body mass index, 23 ± 2 kg/m2) otherwise healthy male subjects. The protocol was approved by the Humboldt University Institutional Ethics Committee, and written informed consent was obtained from all subjects before commencement of the study.

Microdialysis

All microdialysis studies were performed after an overnight fast. Two microdialysis catheters each were inserted into sc abdominal adipose tissue at the level of the umbilicus and in the right vastus lateralis muscle as described previously (5, 7). Before insertion of the catheters, the respective areas were anesthetized with either EMLA creme (Astra, Wedel, Germany) for adipose tissue or with cutaneous and sc injection of 1% lidocaine without epinephrine (Astra) for muscle. Perfusion of the catheters was begun at a flow rate of 2 µl/min with Ringer’s solution (Serumwerk Bernburg, Bernburg, Germany) containing 50 mM ethanol (Braun Melsungen, Melsungen, Germany). After a baseline period of 45 min, either 100 µM L-NAME or N-{omega}-nitro-D-arginine methyl ester (D-NAME) (Clinalfa, Läufelfingen, Switzerland) was added to the perfusion medium. Then, incremental isoproterenol concentrations (0.01, 0.1, and 1.0 µM) were added to the perfusate. Each perfusion step lasted 45 min. Microdialysates were sampled in 15-min intervals.

Assays

Ethanol concentrations in the perfusate and dialysate were measured using a standard enzymatic assay (8). Dialysate concentrations of glycerol were measured on a CMA/600 analyzer (CMA Microdialysis, Solna, Sweden). Changes in blood flow were determined using the ethanol dilution technique that is based on Fick’s principle (9, 10). A decrease in the ratio between ethanol in the dialysate and perfusate corresponds to an increase in blood flow and vice versa. Changes in dialysate glycerol concentration were used to assess changes in lipolysis and/or lipid mobilization.

Adipose tissue gene expression analysis

We obtained abdominal sc adipose tissue samples (0.5–1.0 g) by needle biopsy from the periumbilical region only in the obese group. Specimen were washed twice in 0.9% NaCl and separated from blood cells and blood clots by centrifugation at room temperature for 5 min at 200 x g as described previously (11). Adipose samples were then snap frozen in liquid nitrogen. Total RNA was isolated from adipose tissue by the Qiagen RNeasy Mini kit (including the RNase-free DNase set; Qiagen, Hilden, Germany), followed by determination of quality and quantity with the Agilent 2100 Bioanalyzer and the RNA 6000 Nano Chip (Agilent Technologies, Waldbronn, Germany). Two micrograms of total RNA were reverse transcribed in 20 µl final volume for 1 h at 37 C using 100 U Superscript Reverse Transcriptase, 5.4 µg random primer, 0.5 mM dNTPs, 10 mM dithiothreitol, and 1x RT buffer (all reagents by Invitrogen, Karlsruhe, Germany). Relative quantitation of gene expression was performed with the ABI 5700 sequence detection system for real-time PCR using the standard curve method. The human 18S ribosomal RNA gene was chosen as the endogenous control ("housekeeping gene") to normalize gene expression data (presented in arbitrary units). PCRs were performed with the TaqMan Universal Master Mix and the TaqMan assay reagent for glyceraldehyde-3-phosphate dehydrogenase in a total volume of 25 µl. Primers and fluorescently labeled probes for eNOS and iNOS were reported previously (TaqMan technology, all machines, software, and chemicals by PE Biosystems, Weiterstadt, Germany) (3). The two-step PCR conditions were 2 min at 50 C, 10 min at 95 C, 45 cycles with 15 s at 95 C, and 1 min at 62 C. All primer pairs were spanning exon-intron boundaries. Interassay coefficients of variation were 0.9% for the 18S ribosomal RNA gene, 1.3% for eNOS, and 1.9% for iNOS.

Statistics

If not otherwise indicated, data are given as mean ± SD. Group differences were compared using paired t tests. Individual variables were correlated with by linear regression. Dose-response curves were compared using ANOVA testing. A value of P < 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Responses in obese patients with lower and higher eNOS expression

We stratified obese patients according to eNOS expression in a group with lower and a group with higher eNOS expression. The cutoff value was median eNOS expression in this group. Clinical characteristics and iNOS expression were similar in the group with lower and in the group with higher eNOS expression (Table 1Go). eNOS expression was not correlated with age (r2 = 0.1, P = 0.26). In adipose tissue, ethanol ratio at baseline and during isoproterenol stimulation were virtually identical in both groups with D-NAME and L-NAME (Fig. 1Go, top row). Isoproterenol induced a dose-dependent increase in dialysate glycerol. The lipolytic response was identical in patients with lower and higher eNOS expression with D-NAME and L-NAME (Fig. 1Go, bottom row). We calculated individual differences between adipose glycerol concentration with 1 µM isoproterenol with D-NAME and L-NAME. The difference was not correlated with eNOS expression (r2 = 0.13, P = 0.2).


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  		TABLE 1. Obese patients with higher and with lower eNOS expression

 

Figure 1
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  		FIG. 1. Changes in ethanol ratio and dialysate glycerol in adipose tissue in obese patients with lower and in obese patients with higher eNOS mRNA expression. Isoproterenol was applied during NOS inhibition with L-NAME (right) or with the inactive isomer D-NAME (left). Data are given as mean ± SEM.

 
Responses in obese patients with lower and higher iNOS expression

In a similar manner, we stratified obese patients according to iNOS expression. Clinical characteristics and expression data are given in Table 2Go. Patients with greater iNOS expression were slightly older than patients with lower iNOS expression. However, within the obese group, the relative change in microdialysate glycerol with 1 µM isoproterenol was not related to age (r2 = 0.08, P = 0.34). Furthermore, individual differences in adipose tissue glycerol with L-NAME and D-NAME during 1 µM isoproterenol stimulation were not correlated with age (r2 = 0.1, P = 0.4). Finally, iNOS expression was not correlated with age (r2 = 0.1, P = 0.24). Otherwise, both groups were well matched. Ethanol ratio and glycerol at baseline and during isoproterenol stimulation were similar in the group with lower and in the group with higher iNOS expression with both D-NAME and L-NAME (Fig. 2Go). Differences between adipose glycerol concentration with 1 µM isoproterenol with D-NAME and L-NAME were not correlated with iNOS expression (r2 = 0.0, P = 0.96).


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  		TABLE 2. Obese patients with higher and with lower iNOS expression

 

Figure 2
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  		FIG. 2. Changes in ethanol ratio and dialysate glycerol in skeletal muscle in obese patients with lower and in obese patients with higher eNOS mRNA expression. Isoproterenol was applied during NOS inhibition with L-NAME (right) or with the inactive isomer D-NAME (left). Data are given as mean ± SEM.

 
Comparison between obese and lean subjects

In adipose tissue, basal ethanol ratio during D-NAME perfusion was 0.69 ± 0.11 in obese and 0.20 ± 0.08 in lean men (P < 0.0001). The group difference was maintained during isoproterenol perfusion (Fig. 3Go). NOS inhibition did not have a major effect on adipose ethanol ratio in either group. During D-NAME, basal and maximal isoproterenol-stimulated glycerol were similar in lean and obese men (Fig. 3Go). However, in lean men, the dose-response relationship between isoproterenol and glycerol was shifted toward the left (P < 0.0001 by ANOVA between groups). NOS inhibition with L-NAME had no effect on basal or isoproterenol-stimulated glycerol in the obese group. In contrast, L-NAME augmented the lipolytic response in lean subjects.


Figure 3
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  		FIG. 3. Changes in ethanol ratio and dialysate glycerol in adipose tissue in obese patients (left) and in lean control subjects (right). Isoproterenol was applied together with the NOS inhibitor L-NAME or with the inactive isomer D-NAME. **, P < 0.01 by ANOVA. Data are given as mean ± SEM.

 
Responses in skeletal muscle to L-NAME and D-NAME in lean and obese subjects

In skeletal muscle, basal ethanol ratio during D-NAME perfusion was 0.18 ± 0.05 in obese vs. 0.07 ± 0.09 in lean men (P = 0.001). With isoproterenol, ethanol ratio decreased in a dose-dependent manner in both groups, although the group difference was maintained (Fig. 4Go, top row). The response was attenuated with L-NAME. Basal dialysate glycerol concentrations were substantially increased in obese men (62 ± 13 µM in obese vs. 25 ± 17 µM in lean men, P = 0.0002) (Fig. 4Go, bottom row). The maximal isoproterenol-induced glycerol response during D-NAME was also increased in the obese group (P < 0.05). L-NAME augmented the isoproterenol response in lean but not in obese men.


Figure 4
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  		FIG. 4. Changes in ethanol ratio and dialysate glycerol in skeletal muscle in obese patients (left) and in lean control subjects (right). Isoproterenol was applied together with the NOS inhibitor L-NAME or with the inactive isomer D-NAME. *, P < 0.05 and **, P < 0.01 by ANOVA. Data are given as mean ± SEM.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
We compared the effect of local NOS inhibition applied through a microdialysis catheter on tissue perfusion and metabolism in obese patients with lower and obese patients with higher eNOS or iNOS expression. Adipose tissue metabolism and perfusion at baseline and during isoproterenol stimulation was virtually identical in the group with higher eNOS and the group with lower eNOS expression in adipose tissue both with or without NOS inhibition. Similarly, patients with higher and lower iNOS expression showed identical metabolic responses. We hypothesized that the NOS inhibition has a greater effect on lipolysis in obese compared with lean men. We found the opposite. Our data challenge the functional relevance of NOS expression data reported in previous studies (2, 3).

In adipose tissue and in skeletal muscle, basal blood flow was decreased in obese men compared with normal-weight men. NOS inhibition did not change basal blood flow or isoproterenol-mediated vasodilatation in adipose tissue. In skeletal muscle, NOS inhibition attenuated isoproterenol-induced vasodilatation in both groups. NOS inhibition also attenuated isoproterenol-induced vasodilatation in previous studies (5, 12). The phenomenon is probably explained by ß-2 adrenoreceptor-mediated NO release (13, 14), yet a difference in skeletal muscle perfusion was maintained during NOS inhibition. Thus, differences in basal tissue blood flow between normal weight and obese men are probably not explained by differences in interstitial NO production.

Changes in dialysate glycerol concentrations can be caused by changes in lipolytic activity or in glycerol clearance. Glycerol clearance from the interstitial space is strongly influenced by tissue blood flow. Given the marked blood flow reduction in obese men, interstitial glycerol should accumulate in adipose tissue. Instead, glycerol tended to decrease. The finding is consistent with a profound reduction in basal and isoproterenol-stimulated adipose lipolysis in obese men (15).

Differences in NO production could contribute to the variability in lipolytic activity. NO may influence lipolysis through different pathways involving both direct effects on adipocytes and indirect effects through modulation of neurotransmitter release and uptake. In human isolated adipocytes, NO attenuates lipolysis and NOS inhibition increases lipolysis (1). Gaudiot et al. (16) reported that NO exogenously added to isolated rat adipocytes can stimulate or attenuate basal lipolysis through cGMP-independent mechanism that is tightly linked to the redox state of NO. NO attenuates norepinephrine release from postganglionic adrenergic neurons in vitro (17) and in vivo (5, 18). Moreover, NO may modulate norepinephrine uptake through the neuronal norepinephrine transporter via a cGMP-independent mechanism (19). The net effect of NO on human adipose tissue appears to be a reduction in lipolysis. This effect may restrain lipid mobilization from abdominal adipose tissue. In our study, NOS inhibition did not attenuate the difference in lipolytic rate between lean and obese men. Indeed, NOS inhibition solely increased isoproterenol-induced lipolysis in lean men. Moreover, the lipolytic response was identical in obese men with lower and higher eNOS or iNOS expression. Our data challenge the concept that increased NOS expression leads to increased NO production, which in turn tonically inhibits lipolysis in obese individuals.

Skeletal muscle data are more difficult to interpret given the NOS inhibition-induced change in isoproterenol-mediated vasodilatation. In obese men, glycerol remained unchanged during NOS inhibition, although skeletal muscle blood flow and, thus, glycerol clearance had decreased. The finding is consistent with a reduction in skeletal muscle lipolysis. In normal-weight men, glycerol increased during NOS inhibition. The increase may be explained by glycerol accumulation, increased lipolysis, or a combination of both mechanisms. Thus, the contribution of NO to skeletal muscle lipolysis may differ quantitatively and qualitatively between lean and obese men.

The main limitation of our study is the age difference between obese and lean subjects. Within the obese group, age did not influence iNOS or eNOS expression, but we cannot exclude completely that differences in the response to NOS inhibition between both groups are confounded by the age difference. However, we are confident that the comparison between obese patients with higher and lower iNOS expression is valid. Within the obese group, isoproterenol-stimulated lipolysis or the change in lipolysis with NOS inhibition were not related to age.

We conclude that differences in eNOS and iNOS mRNA expression at the level of the adipose tissue may have a limited effect on lipolysis and tissue perfusion. The lower resting lipolysis in adipose tissue of obese compared with nonobese subjects cannot be explained by a tonic NO effect. mRNA expression data can be quite misleading in the absence of functional data.


   Acknowledgments
 
We thank Henning Damm for expert technical help.


   Footnotes
 
This study was supported in part by the Deutsche Forschungsgemeinschaft and a grant in aid from Sanofi Synthelabo.

Disclosure Statement: The authors have nothing to disclose.

First Published Online April 24, 2007

Abbreviations: eNOS, Endothelial nitric oxide synthase; iNOS, inducible nitric oxide synthase; D-NAME, N-{omega}-nitro-D-arginine methyl ester; L-NAME, N-{omega}-nitro-L-arginine methyl ester; NO, nitric oxide.

Received January 31, 2007.

Accepted April 18, 2007.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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