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Endocrinology Vol. 138, No. 3 1092-1096
Copyright © 1997 by The Endocrine Society

Articles

Influence of Estrogenic Status on the Lipolytic Activity of Parametrial Adipose Tissue in Vivo: an in Situ Microdialysis Study1

Christian Darimont, Rémi Delansorne, Jacques Paris, Gérard Ailhaud and Raymond Negrel

Centre de Biochimie (C.D., G.A., R.N.) (UMR 6543 CNRS), Université de Nice-Sophia Antipolis, Faculté des Sciences, Parc Valrose, 06108 Nice cedex 2, France; and Laboratoire THERAMEX (R.D., J.P.), Preclinical R & D Department, BP 59, MC 98000 Monaco cedex

Address all correspondence and requests for reprints to: Prof. Raymond Negrel, Centre de Biochimie (UMR 6543 CNRS), Université de Nice-Sophia Antipolis, Faculté des Sciences, Parc Valrose, 06108 Nice cedex 2, France. E-mail: Negrel{at}unice fr.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Ovarian hormones have been shown to modulate the metabolism of adipose cells obtained from adipose tissue of different animals. The aim of this study was to better understand the short- and long-term influences of estrogens on the in vivo lipolytic response of rat parametrial fat pads, determined by measurement of extracellular glycerol concentrations using in situ microdialysis. Possible direct effects of estrogens on lipolysis were studied by perfusion of a potent estrogenic analogue such as moxestrol. Moxestrol (10-6 M) failed to increase glycerol concentrations in estrus, diestrus, or 8-day ovariectomized animals. However, the basal glycerol concentrations and the lipolytic responses stimulated by 10-6 M isoproterenol were decreased in parametrial fat pads of diestrus, compared with estrus, rats. Greater decreases in basal and stimulated glycerol concentrations were observed in rats that had been ovariectomized for 8, 15, or 30 days. In ovariectomized rats, isoproterenol-induced lipolysis was restored to the levels observed in diestrus animals by a daily injection of 17ß-estradiol for a period of 7 days. These results implicate estrogens as long-term modulators of in vivo basal and stimulated lipolytic responses of rat parametrial fat pad.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
OVARIECTOMY (OVX) has been extensively studied as a model of fat accumulation in adult female rats (1, 2, 3, 4, 5, 6). Estradiol (E2) has been identified as the main physiological ovarian factor responsible for maintaining a normal level of fat storage in intact animals because substitutive treatments with E2 were able to prevent fat weight gain of OVX rats (1, 3, 4, 7, 8). With long-term administration, E2 also has been shown to reduce fat deposits of intact females (9, 10, 11). Progesterone, the other steroid hormone of ovarian origin, was found to increase fat accumulation only in vivo (5, 7, 10), despite some direct lipolytic properties in vitro (12, 13).

The inhibition of lipoprotein lipase activity, which results in a decrease in circulating fat uptake by adipose tissue, has been demonstrated clearly in vivo to be one of the mechanisms by which E2 is able to shift the balance between lipogenesis and lipolysis towards fat store depletion (2, 3, 10, 11, 14, 15), even in obese Zucker rats (16). On the other hand, the influence of E2 on lipolytic properties has been studied exclusively in ex vivo/in vitro experiments on adipocytes isolated from adipose tissues of E2-treated animals. They all pointed to indirect mechanisms that involved potentiation of catecholamine-stimulated lipolysis (8, 17, 18, 19) or regulation of adenylate cyclase catalytic activity (8), except one that reported a direct stimulation of glycerol release from isolated male epididymal adipocytes after 1 h of incubation with E2 (20).

In situ microdialysis of fat deposits has provided considerable insights into the regulation of lipolysis through in vivo measurements of local glycerol release in both human and animal adipose tissues (21, 22, 23). The aim of the present study was to reappraise the influence of the estrogenic status on lipolysis in vivo in female rats by using this technique. To do so, we investigated lipolysis at two opposite stages of the estrous cycle, estrus and diestrus, when estrogenic receptivity are maximal and minimal, respectively, and in OVX animals that were or were not given estrogen supplements. In addition, infusion through the microdialysis probe was used to determine whether there was a direct estrogenic effect on lipolysis.

For all of these studies, the parametrial adipose tissue was chosen as the fat pad of choice because lipoprotein lipase activity (10); catecholamine-, ACTH-, or cAMP-induced lipolysis (19, 24); adenylate cyclase activity (24); and densities of both ß-adrenoreceptors (24) and estrogen receptors (15, 18, 25) all have been shown to be maximal in this tissue. The fact that, under physiological conditions, it is exposed to high local concentrations of ovarian steroids because of its anatomical location (26, 27) was another reason to choose to study its responsiveness to estrogens.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals
Female Wistar rats (200–250 g; 45–55 days old) were kept at constant room temperature with a 12-h dark-light cycle. The stage of the estrous cycle was evaluated by daily vaginal smears, and only the animals showing two consecutive regular cycles were used in the study.

OVX were performed under anesthesia with ketamine (Imalgene, Rhône Mérieux, France) and xylazine (Rompun, Bayer, France) by ip injections of 70 and 5 mg/kg, respectively. Microdialysis experiments were carried out 8, 15, or 30 days later.

Estrogen treatment of OVX rats consisted of daily sc injections of 17ß-E2 (1 µg/kg) for 7 days, beginning the day after the surgery. E2 was dissolved in a small volume of ethanol before being diluted 1:1000 (vol/vol) in olive oil; control OVX animals received daily sc injections of olive oil containing 0.1% ethanol.

Microdialysis of adipose tissue and glycerol determination
Anesthesia of the animals was initiated by an ip injection of chloral hydrate (0.2 g/kg BW) and maintained throughout the experiments by a continuous ip perfusion (20 µl/min) with 0.25% chloral hydrate. Body temperature was maintained at 37 C with a heating blanket that was controlled by a rectal thermometer.

The probes (CMA/20 from Carnegie Medicin, Stockholm, Sweden; molecular cut-off at 20,000 Da, 0.5 mm od, and 4 mm long) were implanted into parametrial adipose tissues. After connection to a microinfusion pump (CMA 100, Carnegie Medicin), the probes were prewashed quickly for 10 min by perfusion of deionized water at a rate of 10 µl/min. They were then equilibrated for 60 min at 1 µl/min with Ringer’s solution. Constant values for the glycerol concentrations were obtained in the dialysate after 60 min of equilibration, which indicated that a steady state was achieved.

At that time point, the lipolytic challenge was initiated by simultaneously perfusing the two parametrial fat pads of the same animals at the same rate of 1 µl/min: one was perfused with Ringer’s solution alone or containing 10-6 M moxestrol (Mox = R2858), an estrogenic analogue that is more potent than E2 (28), and the other was perfused with 10-6 M isoproterenol (Iso) diluted in Ringer’s solution. Successive fractions of 20 µl were collected in a microfraction collector (CMA/40, Carnegie Medicin) and immediately frozen at -20 C for subsequent glycerol determinations on 5-µl aliquots using a radiometric assay (29).

The dialysis yield of Mox was quantitated in vitro by perfusion of the tritiated molecule (1 nM; 84 nCi/ml) at a rate of 1 µl/min through a probe immersed in a Ringer’s solution maintained at 37 C. Counting of the radioactivity present in the surrounding solution allowed us to calculate, at steady state, a microdialysis yield of 61.3 ± 10.3% (n = 4).

Statistical analysis
All statistical comparisons were performed on absolute values by ANOVA using the StatView software package.

Materials
Iso and E2 were purchased from Sigma Chemical Co. (St. Louis, MO). Tritiated and unlabeled Mox were obtained from Du Pont de Nemours (Les Ulis, France). The source of all other chemicals has already been given (22).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Lipolytic response to Iso but not to moxestrol
Experiments were first designed to look for a short-term effect of estrogens on the lipolytic response of parametrial adipose tissue. For this purpose, the potent estrogenic analogue, Mox (28), has been used in microdialysis experiments intended to measure glycerol in the interstitial fluid. After 60 min equilibration with Ringer’s solution, Mox was perfused locally at 10-6 M through the microdialysis probe in one parametrial fat pad. In parallel, in the contralateral pad of the same animal, the standard ß-adrenergic agonist, Iso, also was perfused at 10-6 M, a concentration that is known to maximally stimulate lipolysis (21).

Mox failed to induce any significant changes in parametrial glycerol concentrations during 2 h of perfusion in animals either in estrus (Fig. 1AGo), in diestrus (Fig. 1BGo), or after OVX (Fig. 1CGo). By contrast, Iso was able to elicit a clear lipolytic response as early as the first hour of perfusion in all three experimental conditions (Fig. 1Go).



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  		Figure 1. Effect of moxestrol and Iso on the lipolytic response of parametrial adipose tissue in estrus, diestrus, and after OVX. Ringer’s solution perfused from time zero was supplemented at time 60 min (arrow) with either 1 µM Iso (•) in one parametrial fat pad or 1 µM moxestrol ({circ}) in the contralateral one. The experiments were performed using female rats in estrous (A), and diestrous phases (B), and bilaterally OVX since 8 days (C). Glycerol collected in the dialysate (20-min fractions) was measured as described in Materials and Methods. The values are the mean ± SEM of six separate experiments under each condition. Values statistically different from the glycerol level measured at time 60 min (steady state) are indicated by * (P < 0.05) or ** (P < 0.01).

 
Dependence of basal and Iso-stimulated lipolysis on estrogenic status
The steady-state level of extracellular glycerol concentration at 60 min (basal level) was slightly higher in estrus than in diestrus: 110 ± 3.1 vs. 87 ± 11.0 µM (n = 6); in OVX animals, basal glycerol levels (55 ± 9.0 µM; n = 6) were significantly lower than those observed in rats either in diestrus (P < 0.05) or in estrus (P < 0.01).

The Iso-induced increase in the extracellular glycerol concentrations was even more sensitive to the estrogenic status of the animals: the total amounts of glycerol released during 2 h of perfusion were approximately 3-fold higher in estrus than in diestrus (Fig. 1Go, B vs. A). The lipolytic response to 10-6 M Iso was further slightly attenuated 8 days after OVX (Fig. 1CGo).

Effects of OVX duration and estrogen treatment on the lipolytic response
To investigate a further lowering of the lipolytic response to 10-6 M Iso, in situ microdialysis experiments were performed using OVX animals for 8, 15, and 30 days. As shown in Fig. 2Go, as early as 8 days after OVX, both basal and Iso-stimulated glycerol levels were minimal. No significant changes were observed when the post-OVX period was extended to 30 days.



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  		Figure 2. Influence of the duration of OVX on the lipolytic response of Iso. After 60 min equilibration, parametrial fat pads of rats OVX since 8 (•; n = 6), 15 ({blacktriangleup}; n = 6), or 30 ({blacksquare}; n = 3) days were perfused with 1 µM Iso. The values of glycerol in the collected dialysate fractions are the means ± SEM of the values obtained from at least three animals used under each condition as indicated above in parenthesis. Values statistically different from the glycerol level measured at time 60 min (steady state) are indicated by * (P < 0.05) or ** (P < 0.01).

 
The possibility that estrogenic treatment could restore the lipolytic properties of parametrial adipose tissue was investigated in OVX animals treated by daily sc injections of E2 (1 µg/kg) for 7 days after surgery. The body weight gain measured in OVX rats was reduced almost by 50% in E2-treated animals: 38.3 ± 1.9 vs. 20.3 ± 3.5 g (P < 0.01; n = 6). Glycerol concentrations measured during control perfusion with Ringer’s solution alone were not significantly affected by estrogenic treatment (Fig. 3Go). By contrast, the lipolytic response to Iso, which remained low in control OVX animals that received only the vehicle (Fig. 3AGo), reached a level similar to that observed in the diestrus phase of normally cycling female rats after supplementation with E2 at this dosage (Fig. 3BGo).



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  		Figure 3. Influence of a 7-day 17ß-E2 treatment of ovariectomized animals on the lipolytic response induced by Iso. At time 60 min (arrow), 8-day OVX rats daily injected during 7 days with: A, olive oil containing 0.1% ethanol ({triangleup}, {blacktriangleup}); and B, 1 µg 17ß-E2/kg/day ({square}, {blacksquare}) were perfused with either 1 µM Iso (black symbols) in one parametrial fat pad or Ringer’s solution (empty symbols) in the contralateral one. The values of glycerol measured in the dialysate fractions (20 min) were obtained from six separate animals and presented as the mean ± SEM. Statistical comparison with the basal glycerol level measured at time 60 min is indicated as * (P < 0.05) or ** (P < 0.01).

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The effect of OVX on the lipolytic tone of the parametrial adipose tissue is the most striking observation of the present study. Both basal and Iso-stimulated lipolysis were markedly reduced to 50% and 25%, respectively.

A reduction in the lipolytic response of isolated parametrial adipocytes to Iso and other ß-adrenergic agonists, during in vitro incubations, has already been shown to occur either 3 months (30) or 3 weeks (24) after OVX. Under our experimental conditions, using in situ microdialysis, there was no difference in lipolytic deficiency 8, 15, or 30 days post-OVX. Eight days was also a sufficient period to observe a reduction in Iso-stimulated lipolysis in pooled epididymal and perirenal isolated adipocytes from males after orchidectomy (31). Thus, it can be concluded that castration impairs the lipolytic response to Iso in both male and female rat adipose tissues within only 1 week.

The lower level of basal glycerol release after OVX observed in our study, using in situ microdialysis, is an original finding because basal lipolytic activity in adipocytes isolated from tissues of castrated rats has not been shown previously to differ from that of intact animals in either males (31, 32) or females (24, 30). This difference might be explained by the fact that complex cellular interactions are relatively preserved in the surroundings of the microdialysis probe, whereas they are obviously destroyed by collagenase digestion during the process of adipocyte isolation.

Differences in norepinephrine-stimulated lipolysis from isolated parametrial adipocytes, according to estrous stages, already have been reported, with maximal glycerol release obtained in proestrus and estrus (33). In agreement with these observations, the in situ response to Iso was higher in estrus than in diestrus. Therefore, the microdialysis technique seems to be sensitive enough to detect subtle variations in lipolytic tone during the physiological estrous cycle.

E2 is the ovarian factor responsible for regulating lipolytic tone in female rats: its levels are high in proestus and estrus, low in diestrus, and negligible after OVX (27, 34, 35, 36). Treatment of intact female (or even male) rats with E2 has been consistently reported to increase the lipolytic responsiveness of white adipocytes to catecholamines (17, 33, 37, 38). Treatment of OVX rats with a high dosage of E2 benzoate (25 µg/kg·day for 4 days by im injection) already has been shown to increase both basal and Iso-stimulated glycerol release from pooled parametrial and perirenal isolated adipocytes (8). In the present study, it is interesting to note that the low dosage of 1 µg/kg·day E2 sc, starting 1 day after OVX, was sufficient to reduce body weight gain and to partially maintain the lipolytic response of the parametrial tissue to Iso when tested 7 days later.

The major differences in lipolytic properties of adipose tissue from rats in various hormonal states (e.g. estrus, diestrus, OVX, or OVX + substitutive E2 treatment) that we observed in vivo, using in situ microdialysis, confirm the physiological relevance of previous results obtained in vitro with adipocytes isolated from normally cycling, OVX, or E2-treated rats.

In the rat, almost every mechanism directly involved in the stimulation of lipolysis is dependent on the estrogenic status of the animal. Maximal lipolytic activity is reduced after OVX, not only in response to catecholamines such as Iso, epinephrine, or norepinephrine (8, 24, 30), but also to ACTH (24) and forskolin (8, 30). All seem to involve altered activity of the catalytic subunit of adenylate cyclase (8, 24, 30). Stimulation of triglyceride lipase activity by cAMP or isobutylmethylxanthine (IBMX) also is reduced after OVX (30). These mechanisms, which result in altered lipolytic stimulation, probably also play a role in the decrease in basal glycerol levels observed after OVX or in diestrus. By comparison, OVX or E2 treatment seem not to affect indirect modulations of lipolysis; that is to say, they do not influence the antilipolytic pathways that are under the control of insulin, or {alpha}2-adrenergic, nicotinic, or adenosine agonists (24, 30). Altered phosphodiesterase activity also does not seem to be involved in the lipolytic changes induced by OVX (24) or by E2 (8). From these observations, one can conclude that, in female rats, an appropriate estrogenic environment is necessary to maintain both basal lipolytic activity and its responsiveness to direct stimulatory mechanisms.

The dependence of ß-adrenoreceptor density on estrogenic status in parametrial adipocyte membranes is controversial: there was no change in receptor density in one study (24) but a 50% decrease in another one (30). However, the lipolytic response to ß-adrenergic agonists such as Iso was markedly impaired in both studies, which suggested that this parameter was not of crucial importance. Moreover, treatment of OVX rats with testosterone (T) was able to fully normalize the ß-adrenoreceptor numbers in parametrial adipocytes but remained ineffective in reversing the diminished lipolytic response to catecholamines and also to forskolin; only cAMP- and IBMX-induced stimulations of glycerol release were restored to normal levels (30).

Thus, although T has been reported to exert some effect at the hormone-sensitive lipase level (32), only E2 has been shown to be able to restore the catalytic activity of adenylate cyclase of isolated parametrial adipocytes from OVX rats (8). A recent study has identified the stimulating G protein {alpha}-subunit (G{alpha}s) as an estrogenic target potentially involved in the regulation of lipolysis in the female rat: its level of expression is decreased after OVX and restored by E2 but not by T treatment (39).

Similarly, in the male rat (31, 32, 40), orchidectomy altered the lipolytic responses of epididymal adipocytes to catecholamines, forskolin, and cAMP and reduced the catalytic activity of adenylate cyclase. T treatment successfully restored all these properties. The main difference from that observed in female parametrial adipose tissue after OVX, with or without E2 treatment, was that G{alpha}S levels did not change in male epididymal adipose tissue after orchidectomy, with or without T treatment (32). It is tempting to speculate that the dependence of G{alpha}s on E2, but not on T, is the likely explanation of differences between male and female rats in lipolysis deficiency and restoration after castration.

Finally, when membrane components involved in cAMP production are considered as putative direct targets of E2, rapid nongenomic mechanisms of estrogen action come to mind (for review, see Ref.41). The hypothesis that a membrane estrogen receptor controls a cAMP-signaling pathway has received renewed interest from studies with breast, uterine, or pituitary cells (42, 43) to support the pioneer observations by Szego and Davis (44). With respect to lipolysis, Mitznegg et al. (20) reported stimulation of cAMP production and glycerol release by isolated male epididymal adipocytes within 1 h of incubation with a very high concentration (10-3 M) of E2. This finding could not be reproduced, although lower concentrations of E2 were used: 5 x 10-5 M (45) or 10-5 M on female parametrial adipocytes (12). In the present in vivo study, Mox (10-6 M) did not stimulate glycerol release during 2 h of perfusion of adipose tissue. One may argue that the membrane estrogen receptor might not have the same molecular specificity or that synthetic Mox might not be an agonist in this system. However, immunological analysis (43) and preliminary structure-activity relationships (42) strongly suggest that the membrane-bound and intracellular forms of estrogen receptors are very similar. One may also add that 10-6 M is too low a concentration to exert this other type of estrogenic mediation. However, this new pathway is characterized by a much lower EC50 than the classical intracellular one: 10 pM vs. 1 nM (42).

In conclusion, lipolysis, despite its strong link with cAMP levels, did not seem to be a direct immediate target of nongenomic cAMP-mediated estrogenic action. On the other hand, classical genomic regulation by ovarian estrogens of G{alpha}s (39) and of catalytic components of adenylate cyclase (8, 24) may explain the marked in vivo dependence of both basal and catecholamine-stimulated lipolysis on the estrogenic status of female rats.


   Acknowledgments
 
We thank P. Saint-Marc and G. Oillaux for technical and secretarial assistance, respectively. A. Lanquetin and Dr. F. Puccio (Théramex, Monaco) are gratefully acknowledged for helpful technical discussions. We are grateful to Dr. M. Murphy (Halifax, Canada) for careful reading of the manuscript.


   Footnotes
 
1 The present microdialysis study has been approved by the Comité Consultatif de Protection dans la Recherche Biomédicale de l’Université de Nice-Sophia Antipolis. This work was supported by both the Centre National de la recherche Scientifique (UMR 6543) and Laboratoire Théramex. Back

Received August 1, 1996.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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