Estrogen regulation of adipose tissue lipoprotein lipaseÑ
Possible mechanism of body fat distribution
Thomas M. Price, MD,a Susan N. O’Brien, PhD,b Brenda H. Welter, MT(ASCP),b Richard
George, MD,b Jyoti Anandjiwala, PhD, b and Michael Kilgore, PhDb
Greenville and Clemson, South Carolina
OBJECTIVE: The purpose of this study was to evaluate the regulation of lipoprotein lipase activity, protein
mass, and messenger ribonucleic acid by estradiol.
STUDY DESIGN: Premenopausal women not taking exogenous sex steroids had transdermal 17b-estradiol
and placebo patches placed in the gluteal region during the early follicular phase of the menstrual cycle.
Adipose biopsies were performed from beneath the patches. Adipose tissue lipoprotein lipase activity was
determined by a radiometric assay, protein mass was determined by enzyme-linked immunosorbent assay,
and messenger ribonucleic acid level was determined by Northern analysis. Comparisons between the
treated and placebo sides were analyzed by nonparametric statistics.
RESULTS: Adipose tissue from beneath the 17b-estradiol patch had significantly decreased lipoprotein lipase activity and extracellular protein mass than did adipose tissue from beneath the placebo patch. There
was no difference in lipoprotein lipase messenger ribonucleic acid levels.
CONCLUSION: Estrogen decreases lipoprotein lipase activity by a posttranscriptional modification of protein
levels. A hypothesis of sex steroid regulation of body fat distribution is proposed. (Am J Obstet Gynecol
1998;178:101-7.)
Key words: Lipoprotein lipase, estrogen, body fat distribution
Regional adipose distribution in women is an important determinant of disease risk. Premenopausal women
typically have a lower body adipose distribution (gynoid)
characterized by fatty tissue deposition in the gluteofemoral region. With obesity, especially in women
with androgen excess, an upper body adipose distribution (android) develops that is characterized by fatty tissue deposition in the abdominal subcutaneous and intraperitoneal regions. Compared with gynoid adiposity,
android adiposity is a significant health risk for women; it
is associated with increased incidences of hypertension,
adult-onset diabetes,1 arteriosclerotic coronary disease,2
endometrial cancer,3 and possibly breast cancer.4
Sex steroids regulate body fat distribution, and, in
turn, circulating levels of sex steroids are influenced by
adipose distribution. Before puberty there is little difference in body fat distribution between boys and girls.
From the Department of Obstetrics and Gynecology, Greenville Hospital
System,a and Greenville Hospital System/Clemson University
Biomedical Research Cooperative.b
Supported in part by the National Heart Foundation, a program of the
American Health Assistance Foundation.
Charles Hunter Award Paper, presented at the Fifteenth Annual Meeting
of the American Gynecological and Obstetrical Society, Asheville, North
Carolina, September 5-7, 1996.
Received for publication July 1, 1997; accepted July 8, 1997.
Reprint requests: Thomas M. Price, MD, Division of Reproductive
Endocrinology, Department of Obstetrics and Gynecology, Greenville
Hospital System, Greenville, SC 29605.
Copyright © 1998 by Mosby, Inc.
0002-9378/98 $5.00 + 0 6/1/84558
With the onset of puberty, healthy females have an increase in total body fat percentage and gynoid adiposity
develops. Females with androgen excess, such as that
seen in polycystic ovarian syndrome, have a greater tendency for upper body adiposity.5 Circulating sex steroid
levels in women with android adiposity are altered; they
contain increased concentrations of free testosterone, androstenedione, and free estradiol and decreased levels of
sex hormone binding globulin compared with levels in
women with gynoid adiposity.6
The mechanism whereby sex steroids regulate body
adipose distribution remains undefined. Adipose distribution is influenced primarily by two factors: the number
of adipocytes in a given region and the size of adipocytes
in a region. For example, premenopausal women not
only have a greater number of adipocytes in the gluteofemoral region but also have larger adipocytes in this
area7 than men do. Although many processes may affect
the size of an adipocyte, the enzyme lipoprotein lipase
has a major role in this function. Lipoprotein lipase is responsible for the conversion of circulating triglycerides
into free fatty acids, which may pass into adipocytes.
Activity differs with sex, age and location of adipose tissue. Premenopausal women have higher levels of lipoprotein lipase activity than men do and regional variation
with increased activity levels in gluteofemoral adipose tissue compared with abdominal subcutaneous adipose tissue independent of cell size. In contrast, males have
higher lipoprotein lipase activity in subcutaneous abdom-
101
102 Price et al.
inal adipose tissue compared with gluteal adipose tissues.8, 9 This regional variation in women appears regulated by sex steroids, as evidenced by the decrease in gluteofemoral lipoprotein lipase activity with menopause
and also during lactation.10 Adipocyte size correlates
with these changes in lipoprotein lipase activity.
Lipoprotein lipase is localized both intracellularly in
adipocytes and extracellularly on the surface of adjacent
vascular endothelial cells. Separate activity studies measure these two compartments. Measurement of extracellular activity is referred to as heparin releasable because
heparin is used to dissociate the enzyme from its binding
with heparin sulfate on the cell surface. Total activity is
referred to as extractable because homogenization in the
presence of detergent and heparin is used to recover
both intracellular and extracellular activity. This study investigates the regulation of lipoprotein lipase by estrogen
through analysis of messenger ribonucleic acid (mRNA),
protein levels, and activity studies.
Material and methods
Subjects and adipose biopsy. Premenopausal, nonsmoking women with regular cyclic menses receiving no type of
sex steroid therapy were recruited for this study. Before
the study informed consent was obtained; the protocol
had been approved by the hospital Institutional Review
Board. Transdermal 17b-estradiol patches (Estraderm 0.l
mg) were applied to one side of the upper gluteal region
of each subject and placebo patches (Estraderm placebo
patch) were applied to the opposite gluteal region. Two
patches of each type were applied to each side between
cycle days 3 and 7 for a period of 2 to 9 days. For exposures >48 hours the 17b-estradiol patches and the placebo
patches were replaced with new patches that were placed
back into the same location every 72 hours. After various
times of exposure the patches were removed and adipose
biopsies were performed from beneath both the 17bestradiol patches and the placebo patches.
For adipose biopsies, the skin was prepared with povidone-iodine (Betadine) and alcohol, and local anesthesia with 1% lidocaine was administered subdermally and
subcutaneously. Aspiration of adipose tissue was performed with a hand-held syringe fitted with a specially tapered 15-gauge needle. Adipose tissue was placed on ice
until processing for the analysis of estrogen levels,
lipoprotein lipase enzyme-linked immunosorbent assay
(ELISA), and lipoprotein lipase Western assays. For
lipoprotein lipase activity studies adipose tissue was
placed into cold Krebs’ Ringer phosphate buffer,
whereas for Northern analysis adipose tissue was immediately frozen in liquid nitrogen. Careful attention was paid
so that the process was identical for aspiration from both
the treated side and the placebo side. Each subject had
both biopsies performed, so each subject acted as her
own control.
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Am J Obstet Gynecol
Estradiol and estrone levels. In 13 subjects estradiol
and estrone levels were measured in oil rendered from
the adipose tissue beneath the treated and placebo
patches with use of a radioimmunoassay (RIA) that has
been previously described.11 Of these 13 subjects, 2 were
treated for 2 days, 9 for 6 days, and 2 for 9 days. For this
process adipose tissue was heated in a double boiler to
96° C and the rendered oil collected in Qorpak environmentally clean glass bottles. Each adipose sample was assayed in duplicate. An accurately weighed amount of oil
was dissolved in hexane at 55° C for 15 minutes. Steroids
were then extracted from the hexane with methanol/
water (80:20) and centrifugation at 1000g. The
methanol-water fraction was dried at 55° C under a
steady stream of filtered air. Dried residues were resuspended in deionized water and further purified with extraction through octadecyl C18 columns (Baker SPE-21
extraction system). Eluted samples were dried and resuspended in phosphate-buffered saline solution with
merthiolate and gelatin buffer for RIA. Tritiated steroids
include [2,4,6,7-3H(N)] estradiol and [2,4,6,7-3H(N)] estrone (NEN, Boston), with specific antiserum to each
compound (gift of Eli Lilly, Indianapolis). Results were
reported as concentration (in picograms per gram) of estrogen per weight of rendered oil. The assay is sensitive
to 6 pg of estrogen, with an intraassay coefficient of variation of 9%.
Lipoprotein lipase activity studies. Lipoprotein lipase
activity was determined in seven subjects after exposure
to the 17b-estradiol patches or the placebo patches for 2,
6, or 9 days. The enzyme activity studies used have been
described in detail12 and are briefly summarized. This radiometric assay involves the enzymatic conversion of carbon 14–labeled triolein (trioleoylglycerol) to 14C-labeled
oleic acid. The fatty acid product was separated from the
triglyceride precursor by extraction with a carbonate-borate buffer. Pooled human serum was used as the source
of a necessary cofactor, apolipoprotein C-II, whereas albumin was used as an acceptor for free fatty acid. Skim
milk prepared from unpasteurized bovine milk was used
as a standard for lipoprotein lipase activity.
For the heparin-releasable assay, 50 mg of adipose tissue was incubated in a shaking water bath at 37° C for 30
minutes in an elution solution containing 0.05 mg/ml
heparin, 25% serum in Krebs-Ringer phosphate buffer.
At the end of the incubation period an aliquot of the
buffer was assayed for enzyme activity. For detergent extraction 50 mg of adipose tissue was homogenized at
room temperature in an all-glass tissue grinder in a detergent solution containing 2 mg/ml sodium deoxycholate, 0.08 mg/ml Nonidet P-40, 0.05 mg/ml heparin,
10 mg/ml bovine serum albumin, and 0.25 mol/L sucrose in Tris buffer. The homogenate was centrifuged at
4° C at 12,000g for 15 minutes and an aliquot was removed for assay of enzyme activity. For both the heparin-
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Am J Obstet Gynecol
releasable and extractable assays four samples from each
patient were analyzed, with each sample assayed in quadruplicate. The intraassay coefficients of variation for the
heparin-releasable and extractable procedures are 14.6%
and 6.4%, respectively. The interassay coefficient of variation as determined by the repeated measure of the skim
milk standard was 13%. Activity results are expressed as
nanomoles per minute · gram of wet tissue.
Lipoprotein lipase Northern analysis. Northern analyses were performed in adipose tissue after 2 and 9 days of
exposure to the 17b-estradiol patches or the placebo
patches. Adipose total RNA was isolated by the guanidinium–thiocyanate–cesium chloride method,13 separated in a 1.25% formaldehyde gel electrophoresis, and
electrophoretically transferred to Zeta probe. Human
partial lipoprotein lipase complementary deoxyribonucleic acid (cDNA)14 was labeled with random primers, aphosphorus 32–deoxycytidine triphosphate (ICN 3000
Ci/mmol). After prehybridization at 65° C for a minimum of 6 hours, hybridization was performed overnight
at 55° C in a solution of 50% formamide, 5´ saline–
sodium citrate buffer, 50 mmol/L sodium phosphate
buffer, 10´ Denhardt’s solution, 250 µg/ml salmon
sperm DNA, 1% sodium dodecyl sulfate, and 0.1%
sodium pyrophosphate. Washings of increasing stringency of saline–sodium citrate/sodium dodecyl sulfate
were performed at room temperature until appropriate
background radioactivity was achieved. Lipoprotein lipase mRNA species of 3.5 and 3.7 kb8 were identified and
quantified by laser densitometry. Visualization of total
RNA on ethidium-stained formaldehyde gels and
Northern analysis of 18S ribosomal RNA was used to verify equal loading and integrity of RNA. Northern analysis
of 18S ribosomal RNA was performed with use of a g32P–end-labeled oligonucleotide probe, as previously
published.15
Lipoprotein lipase Western analysis. To establish the
specificity of the chicken antihuman lipoprotein lipase
antibody used in the ELISA, Western analysis after heparin-sepharose purification was performed, in a modification of a previously published method16 with use of abdominal adipose tissue and authentic lipoprotein lipase
(Sigma, St. Louis). For the heparin-sepharose purification, 1 gm of adipose tissue was homogenized in 2 ml of
buffer (0.5% deoxycholate, 0.02% NP-40, 0.73% sucrose,
125 mg/ml heparin, 25 mmol/L Tris, pH 8.3) plus protease inhibitors (1 mmol/L phenylmethylsulfonyl fluoride, 10 mg/ml leupeptin, 1 mmol/L ethylenediaminetetraacetic acid (EDTA), 1 mmol/L benzamidine, and 0.05
mmol/L aprotinin). After centrifugation the aqueous
layer was added to low-salt buffer (25% glycerol, 5
mmol/L sodium barbital, pH 7.4, 1 mmol/L EDTA, 0.5
mol/L sodium chloride) and incubated with heparinsepharose CL-6B beads (Pharmacia Biotech, Piscataway,
N.J.) for 60 minutes at 4° C. After centrifugation at 1000g
Price et al. 103
for 5 minutes the supernatant was removed and the
beads washed in low-salt buffer. Lipoprotein lipase was
eluted from the beads with 40 ml of high-salt buffer (25%
glycerol, 5 mmol/L sodium barbital, pH 7.4, 1 mmol/L
EDTA, and 1.5 mol/L sodium chloride). Three micrograms of lipoprotein lipase standard was added to lowsalt buffer and extracted in the same manner. For the
Western blot, extracted adipose tissue and standard
lipoprotein lipase were electrophoresed in a 10% polyacrylamide gel and electrophoretically transferred to
polyvinylidene difluoride. After overnight blocking in triethanolamine-buffered saline solution with 0.5% Tween20 and 5% nonfat dry milk at 4° C, the membrane was incubated with chicken antihuman lipoprotein lipase
antibody (1:1000 in triethanolamine-buffered saline solution with 0.5% Tween-20) for 2 hours at room temperature. After washing with triethanolamine-buffered
saline solution with 0.5% Tween-20, the secondary antibody, peroxidase-conjugated rabbit antichicken immunoglobulin G (IgG) (Organon Teknika, Durham,
N.C.) diluted 1:2000, was added for 2 hours at room temperature. Membrane was developed with use of ECL
Western blotting detection reagents per the manufacturer’s directions (Amersham, Arlington Heights, Ill.)
and exposed to film.
Lipoprotein lipase ELISA. ELISA was performed to determine lipoprotein lipase protein mass in seven subjects
after 6 days of exposure to the 17b-estradiol patches or
the placebo patches. A two-antibody sandwich ELISA was
developed with modifications of a previously published
technique.17 ELISA was performed with use of both the
heparin-releasable fraction and the extactable fraction
with the following preparation. For the heparin-releasable fraction 1 gm of adipose tissue was placed in 2 ml
of phosphate-buffered saline solution with 13 mg/ml heparin and protease inhibitors and incubated in a shaking
water bath at 37° C for 30 minutes. After centrifugation at
100g, the aqueous solution was removed and frozen at
–80° C until assay. For the extractable assay the same tissue was added to 2 ml of homogenization buffer plus protease inhibitors and homogenized with Dounce for 30
strokes. After centrifugation as above, the aqueous layer
between the cell pellet and floating lipid cake was removed and frozen until assay. The heparin-releasable fraction represents extracellular protein. Unlike the activity
assay where the extractable fraction represents both extracellular and intracellular activity, the extractable fraction for the ELISA represents only intracellular protein
because the tissue has been first treated with heparin.
For the ELISA procedure, 96-well microtiter plates
were coated overnight at 4° C with 50 ml per well of 10
mg/ml M40 (mouse antibovine lipoprotein lipase that
cross-reacts with human lipoprotein lipase) as the capture antibody. After washing with phosphate-buffered
saline solution, 0.1% bovine serum albumin, and 0.05%
104 Price et al.
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Am J Obstet Gynecol
Fig. 1. Estradiol (E2) and estrone (E1) levels (mean ± SD) in adipose tissue from beneath 17b-estradiol or placebo patches. Both
estradiol (p = 0.003) and estrone (p = 0.006) levels were higher
in adipose tissue from beneath treated patch compared with
placebo patch.
Tween-20, plates were blocked for 2 hours at room temperature with phosphate-buffered saline solution with
3% bovine serum albumin, and samples were diluted in
phosphate-buffered saline solution, 0.1% bovine serum
albumin, and 0.05% Tween-20 or lipoprotein lipase standard were added and incubated overnight at 4° C. After
washing, the primary antibody, chicken antihuman
lipoprotein lipase or preimmune serum at 7.5 mg/ml in
phosphate-buffered saline solution, 0.1% bovine serum
albumin, and 0.05% Tween-20 was added for 1 hr at
room temperature. After washing, biotin-labeled goat antichicken IgG (Kirkegaard & Perry, Gaithersburg, Md.)
diluted 1:666 in phosphate-buffered saline solution,
0.1% bovine serum albumin, and 0.05% Tween-20 was
added for 1 hour. After washing, the plates were incubated for 30 minutes at room temperature with ABC
reagents in phosphate-buffered saline solution (Pierce
ImmunoPure Ultra-Sensitive ABC Staining Kit,
Rockford, Ill.) according to the manufacturer’s directions. The wells were then developed with peroxidase
substrate (BioRad’s peroxidase ABTS substrate kit,
Hercules, Calif.) and read in an ELISA plate reader at
405 nm. Frozen aqueous samples were assayed in triplicate in two different ELISAs performed on different
days. The intraassay coefficient of variation was 11%,
whereas the interassay coefficient of variation was 38%
for the heparin-releasable assay and 26% for the extractable assay.
Statistical analyses were performed with the Wilcoxon
signed-rank test or the Kruskal-Wallis test. A p value <0.05
was considered statistically significant.
Fig. 2. Heparin-releasable (HR) and extractable (EXT) lipoprotein lipase (LPL) activity assays in adipose tissue from beneath
treated and placebo patches. Estradiol (E2) treatment resulted
in 25% decrease in heparin-releasable lipoprotein lipase activty
(p = 0.028) and 26% decrease in extractable lipoprotein lipase
activity (p = 0.028).
Results
To ensure a concentration gradient of estrogen between the treated and untreated sides, free estradiol and
estrone levels were measured in the oil rendered from
the adipose tissue beneath each patch. Significantly
higher mean levels of both estrone (2407 ± 636.3 vs 683.7
± 99.7 pg/gm oil) and estradiol (2775 ± 834.4 vs 165.4 ±
30.5 pg/gm oil) were measured in the adipose tissue beneath the 17b-estradiol patch than in adipose tissue beneath the placebo patch (Fig. 1). There was no significant difference between the estrogen levels beneath the
patches according to the length of exposure to transdermal estradiol. The ratio of estrone/estradiol also differed
between the treated and placebo sides. For the treated
side this ratio was 1.74 ± 1.55 (mean ± SD) compared
with 4.75 ± 2.01 for the placebo side, p = 0.003. Thus it is
clear that adipose tissue from beneath the patch was
being exposed to significantly more estradiol than was
adipose tissue from beneath the placebo patch.
Fig. 2 illustrates the heparin-releasable and extractable
lipoprotein lipase activity studies of adipose tissue be-
Price et al. 105
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Fig. 3. Northern analysis for lipoprotein lipase mRNA from adipose tissue beneath treated and placebo patches for 2 and 9
days. Bands at 3.7 and 3.5 kb representing lipoprotein lipase
mRNA are seen. RNA integrity and loading equivalency are verified by Northern analysis of 18S ribosomal RNA (rRNA) levels.
No difference in lipoprotein lipase mRNA levels was seen with
estradiol treatment.
neath the patches. Heparin-releasable activity reflects
that of extracellular lipoprotein lipase, whereas extractable activity reflects both extracellular and intracellular lipoprotein lipase activity. Compared with placebo,
estradiol treatment resulted in a decrease in both heparin-releasable and extractable activity by 25% and
26%, respectively. The difference between treatment and
placebo tended to increase with longer exposure for
both heparin-releasable (r = 0.49, p = 0.33) and extractable (r = 0.26, p = 0.58), but this trend was not statistically significant. In regard to individual datum points,
six of the seven subjects showed a decrease in lipoprotein
lipase activity with treatment, whereas one subject
showed no difference.
Fig. 3 demonstrates the lipoprotein lipase Northern
analysis showing no difference in lipoprotein lipase
mRNA levels with estradiol treatment. Transcripts at 3.5
and 3.7 kb are evident, whereas 18S ribosomal RNA levels
are shown to demonstrate RNA integrity and equivalent
loading.
Fig. 4 illustrates a Western analysis of lipoprotein lipase
protein after extraction with heparin-sepharose beads
with use of the primary chicken antihuman lipoprotein
lipase antibody. A single band at 56 kd identified in adipose tissue is identical in size to authentic lipoprotein lipase extracted in the same manner. This demonstrates
Fig. 4. Western analysis for lipoprotein lipase (LPL) protein
after extraction and purification with heparin-sepharose beads.
Single protein band at 56 kd is seen in abdominal (Abd) adipose
tissue that is identical in size to authentic lipoprotein lipase protein processed in the same manner.
that the chicken anti–lipoprotein lipase antibody appears
specific for this protein.
Fig. 5 shows the results of the lipoprotein lipase ELISA
for the heparin-releasable and extractable fractions. The
heparin-releasable fraction relates to extracellular protein. The extractable fraction represents intracellular
protein, in contrast to the activity assay where the extractable fraction represents both extracellular and intracellular activity. Heparin-releasable protein levels were
significantly decreased with estradiol treatment by 40%,
whereas no significant effect was seen with extractable or
intracellular lipoprotein lipase levels. In regard to individual datum points, all subjects showed a decrease in heparin-releasable lipoprotein lipase protein mass.
Comment
In this study we have investigated the effect of transdermal estrogen administration on lipoprotein lipase activity, protein levels, and mRNA levels in premenopausal
women. Because of the large individual differences in
lipoprotein lipase levels, each subject served as her own
control. To ensure that the patch itself had no effect, a
placebo patch, identical in composition to the treatment
patch except lacking estrogen, was applied to the con-
106 Price et al.
Fig. 5. Heparin-releasable (HR) and extractable (EXT) lipoprotein lipase (LPL) protein mass analysis by ELISA in adipose tissue from beneath treated and placebo patches. Estradiol (E2)
treatment resulted in 40% decrease in heparin-releasable
lipoprotein lipase protein mass (p = 0.018) but no significant
change in extractable lipoprotein lipase protein mass (p =
0.735).
tralateral side. Each subject had the patches applied early
in the follicular phase to minimize the endogenous estrogen and progesterone levels. Estrogen appears primarily to affect extracellular or heparin-releasable
lipoprotein lipase. Although decreases were seen in both
heparin-releasable and extractable activity, this is understandable because the heparin-releasable activity contributes approximately 20% to 30% to the extractable activity. In the protein analysis only heparin-releasable or
extracellular lipoprotein lipase appeared to be influenced by estrogen. The mechanism responsible for this
regulation remains to be determined.
The effects of estrogen and progesterone on adipose
tissue have been thought to be indirect because of researchers’ inability to identify either an estrogen receptor or progesterone receptor in human fat.18 Recently,
both the mRNA19 and protein20 for the estrogen receptor have been identified in human adipose tissue. In addition, we now have evidence for the progesterone transcript in human adipose tissue (unpublished data). The
estrogen receptor also has both cell-specific and regional
January 1998
Am J Obstet Gynecol
distribution in women. Estrogen receptor transcript levels are greater in adipocytes than in adipose stromal
cells19 and are greater in abdominal adipose tissue than
in gluteal adipose tissue in premenopausal women.21
The source of estrogen production changes significantly with age. In premenopausal women estradiol is the
predominant circulating estrogen and is secreted primarily by the ovary. In postmenopausal women estrone is the
primary circulating estrogen; it is produced in adipose
tissue from circulating C19 steroids such as androstenedione by the enzyme cytochrome P450 aromatase. P450
aromatase transcript levels in adipose tissue have been
shown to increase with age22 and are also greater in adipose tissue from the gluteal region than from the abdominal region.22 In contrast to estrogen, progesterone
is only significantly secreted by the ovary after ovulation,
with very low circulating levels in postmenopausal
women and men.
Studies of the effects of hormone replacement therapy on lipoprotein lipase activity levels have been somewhat contradictor y and complicated by baseline interindividual differences. In studies by Rebuffe-Scrive et
al.10 the oral administration of a sequential combination
of estradiol valerate and levonorgesterol to postmenopausal women resulted in a significant increase in
adipose tissue lipoprotein lipase activity. In a subsequent
study oral treatment with ethinyl estradiol increased
gluteal adipose tissue lipoprotein lipase activity levels,
whereas the addition of norethindrone reversed this effect. Percutaneous 17b-estradiol applied to the upper
back and shoulders had no effect on gluteal body adipose tissue lipoprotein lipase activity. 23 In contrast,
other data suggest that estrogen inhibits adipose tissue
lipoprotein lipase. Iverius and Brunzell24 have shown an
inverse correlation between serum estradiol levels and
adipose tissue lipoprotein lipase levels in obese women.
Progesterone, on the other hand, appears to increase
lipoprotein lipase activity, although fewer studies exist.
Rebuffe-Scrive et al.25 have shown that percutaneous administration of progesterone cream increases lipoprotein lipase activity and fat cell size in underlying adipose
tissue.
The correlation between lipoprotein lipase activity and
mRNA levels is also regionally dependent. In general,
lipoprotein lipase mRNA levels correlate with enzyme activity and are significantly higher in any region in women
than in men. Yet in premenopausal women the gluteal
adipose activity is greater than that of the abdominal adipose tissue, whereas mRNA levels are significantly higher
in the abdominal adipose tissue compared with those in
gluteal adipose tissue.8 This observation suggests a posttranscriptional regulation of lipoprotein lipase to increase activity levels in gluteal adipose tissue. Other hormones, including growth hormone and insulin, regulate
lipoprotein lipase by a posttranslational mechanism.
Price et al. 107
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With the design of this experiment it is not possible to
determine whether the effect on lipoprotein lipase by estrogen is a direct effect or mediated through an estrogen-induced pathway. Yet, because estrogen is an irreversible end product of steroidogenesis, it is clear that
the regulation of lipoprotein lipase is the result of an
estradiol or estradiol metabolite.
With the information known at this time, we propose
the following hypothesis for one mechanism whereby sex
steroids affect lipoprotein lipase activity and influence
body fat distribution. In premenopausal women progesterone increases lipoprotein lipase activity, which is
greater in the gluteofemoral than in the abdominal region. Regional variations in the progesterone receptor
remain to be investigated, but higher levels in gluteofemoral adipose tissue would correlate with greater
lipoprotein lipase activity. In postmenopausal women
progesterone production is lost, and localized production of estrone predominates, with a decrease in lipoprotein lipase activity. Because localized production of estrone is greater in the gluteofemoral region, lipoprotein
lipase activity in this area decreases to a greater extent
than does activity in the abdominal region. This change
in activity is associated with a decrease in gluteofemoral
adipocyte size and a shift from lower body to upper body
adiposity.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
We thank the following individuals: Dr. P. Iverius for
technical assistance with the lipoprotein lipase activity
assay, Dr. L Chan for providing the lipoprotein cDNA
and chicken antihuman lipoprotein antibody, and Dr. L.
Smith for providing the M40 mouse antibovine lipoprotein antibody. We also thank Ms. Dawn Blackhurst for statistical analysis and Ms. Nancy Taylor for editorial review.
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