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Introduction
Body fat distribution shows important sex differences. Men are
usually characterized by the android type of obesity with accu-
mulation of fat in the abdominal region, whereas females display
the gynoid type of obesity with a greater proportion of their body
fat in the gluteal and femoral regions. Excessive accumulation of
adipose tissue within the abdominal cavity (visceral or intra-ab-
dominal obesity) has been demonstrated as a strong correlate of
obesity-related metabolic alterations that are known to increase
the risk of cardiovascular disease [1,2]. Accordingly, men are
characterized by higher incidences of cardiovascular disease, at
least before the age corresponding to menopause in women
[3, 4]. These differences suggest a close association between sex
steroid hormones, regional fat distribution, and concomitant al-
terations in risk factors for cardiovascular disease.
Most studies on sex hormones, obesity, and body fat distribution
have focused on plasma levels of testosterone and estradiol [5].
However, steroid metabolism in humans is much more complex
than what can be observed from simple measures of plasma an-
drogen and estrogen levels. Inactive precursor C
19
steroids are
converted into active androgens/estrogens in peripheral target
tissues, a process that depends on the specific expression of ste-
roidogenic enzymes in each of these tissues, thus allowing hu-
mans to regulate locally the amounts of active steroids on a cel-
lular basis. This newly identified mode of hormone synthesis and
action has been termed intracrinology, and adds to the well-
Adipose Tissue Intracrinology: Potential
Importance of Local Androgen/Estrogen
Metabolism in the Regulation of Adiposity
C. BØlanger
1
V. Luu-The
1
P. Dupont
2
A. Tchernof
1, 3
Affiliation
1
Molecular Endocrinology and Oncology Research Center
2
Gynecology Unit
3
Department of Food Sciences and Nutrition, Laval University Hospital Research Center
(CHUL Research Center) and Laval University, Quebec, Canada
Correspondence
A. Tchernof, Ph.D.´ Molecular Endocrinology and Oncology Research Center ´
Laval University Hospital Research Center ´ 2705 Laurier blvd. (T3-67) Quebec, Qc ´ Canada G1V 4G2 ´
Phone: + 1 (418) 654-2296 ´ Fax: + 1 (418) 654-2761 ´ E-Mail: andre.tchernof@crchul.ulaval.ca
Received 7 October 2002 ´ Accepted after revision 15 November 2002
Bibliography
Horm Metab Res 2002; 34: 737±745 Georg Thieme Verlag Stuttgart ´ New York ´ ISSN 0018-5043
Abstract
The present article summarizes some of the studies available on
steroid hormone conversion through the specific expression of
steroidogenic enzymes in adipose tissue (adipose tissue intracri-
nology) and discusses the potential impact of local adipose tissue
steroid metabolism on the regulation of adipocyte function and
other metabolic parameters. Several studies have demonstrated
significant steroid hormone uptake and conversion by adipose
tissues from various body sites and in various cell fractions. Ac-
tivities and/or mRNAs of aromatase, 3b-hydroxysteroid dehydro-
genase (HSD), 3a-HSD, 11b-HSD, 17b-HSD, 7a-hydroxylase,
17a-hydroxylase, 5a-reductase and UDP-glucuronosyltrans-
ferase 2B15 have been detected in adipose tissue or adipose cells.
These studies have demonstrated potentially important roles for
these enzymes in obesity, central fat accumulation, and the me-
tabolic syndrome. Future studies on adipose tissue intracrinolo-
gy will contribute further to our understanding of steroid action
in adipocytes.
Key words
Androgens ´ Estrogens ´ Adipose Tissue ´ Body Fat Distribution ´
Steroidogenic Enzymes
Review
737
known endocrine and paracrine/autocrine modes of hormone
action [6]. Although the absolute amount of extragonadal ste-
roids synthesized through this mode of action is small, local tis-
sue concentrations achieved are thought to be high, exerting sig-
nificant local biological influence [7].
Adipose tissue has been shown to express several steroidogenic
enzymes that enable this tissue to act as a steroid-metabolizing
organ. The modulation of active steroid levels in this tissue
through the activity of steroid-converting enzymes (adipose tis-
sue intracrinology) may contribute to regulate adipocyte metab-
olism at the local level [8]. On the other hand, given the large in-
terindividual variations in body composition, peripheral steroid
metabolism may be altered in the presence of excessive adipose
tissue accumulations. The present review article summarizes
some of the studies available on adipose tissue intracrinology,
and discusses the potential impact of local adipose tissue steroid
metabolism on the regulation of adipocyte function and other
metabolic parameters.
Steroid Reservoir
Following a first report by Twombly et al. [9] in 1967 demon-
strating the presence of estrogens in adipose tissue, studies per-
formed in the early to late seventies [10± 14] showed that ste-
roids are taken up and converted by adipose tissue. Initial studies
[10± 12] observed aromatization of androstenedione to estrone.
Studies using labeled dehydroepiandrosterone injections dem-
onstrated that this steroid was excreted in the urine at slower
rates in obese individuals compared to lean subjects, suggesting
greater distribution volume in obese subjects [13]. These studies
were supported by direct detection of dehydroepiandrosterone
in adipose tissue samples [14]. Around the same time, other in-
vestigators were confirming adipose tissue uptake and conver-
sion of androgens and estrogens both in vitro and in vivo [15 ±17].
Adipose tissue steroid levels have been examined in a relatively
small number of studies [14,18± 21]. The studies by Deslypere et
al. [18] and FehØr et al. [19] were the first detailed analyses to in-
clude several steroids and adipose tissues originating from var-
ious sites. In the study by Deslypere et al. [18], testosterone,
DHEA-S, DHEA, androstenedione, androstenediol, estrone and
estradiol were detected in adipose tissue. The study by FehØr
also detected cortisol, progesterone, and 17-hydroxyprogester-
one [19]. Both studies found a positive tissue/plasma gradient.
The total steroid content of adipose tissue (estimated with a
mean body fat mass of 20 kg) was 40 ± 400 times greater than to-
tal plasma content (assuming a 3 l plasma volume) in one study
[18]. The estimated size of the tissue steroid pool in the other
study was 2 to 87-fold higher than that of plasma [19]. A positive
gradient was also demonstrated for most steroids examined in a
more recent study [20].
Although large interindividual variations seem to exist in adi-
pose tissue steroid levels [14,18± 20], the question of whether re-
gional differences can be detected within the same patient is less
clear. The study by Deslypere detected only minor differences for
most steroids examined [18]. However, in the recent study by
Szymczak et al. [20], statistically significant differences were
noted between breast adipose tissue content and abdominal adi-
pose tissue content in estradiol, estrone sulfate, estradiol sulfate
and androstenediol. The fact that the differences were most ap-
parent with steroid sulfates is consistent with previous studies,
in which regional differences in DHEA-S were noted; this may
suggest depot-specific steroid converting activities. On the other
hand, several correlations were noted between adipose tissue
levels of the various steroids examined in all studies, and steroids
that were present in higher concentrations in the plasma were
also more concentrated in adipose tissue [20].
Measurements of arteriovenous concentration differences also
provided information on the determinants of steroid uptake by
adipose tissue [22]. These studies are based on a cannulation
technique allowing measurement of arteriovenous differences
across human adipose tissues in vivo. Of interest, the plasma
steroid concentration achieved during the test was a strong de-
terminant of the arteriovenous difference across adipose tissue
[22]. While the handling of androstenedione by adipose tissue
was highly variable in both men and women, testosterone was
consistently taken up by adipose tissue in men but consistently
released in women. Both men and women released estradiol. As-
suming all adipose tissue depots to be equally active, these in-
vestigators estimated that adipose tissue steroid conversion
could account for approximately a third of peripheral androgen
production, and suggested that the importance of this route
would become proportionately greater in obesity [22].
In a study performed in rats, Borg et al. [21] recently demonstrat-
ed that highly lipophilic steroid fatty acid esters could be detect-
ed in adipose tissue of male and female rats. In male rats, castra-
tion resulted in the disappearance of testosterone from fat after 6
hours. However, testosterone fatty acid ester levels fell only after
48 h, and were still detected 10 days after castration. The authors
suggested that these long-lived testosterone esters might repre-
sent a testosterone reservoir in adipose tissue [21]. Steroid esters
have been previously detected in humans [23 ± 25], and could
play a similar role. However, more studies are needed to eluci-
date this possibility, since human adipose tissue steroid-ester
content has not yet been examined.
Large inter-individual variations can be observed in body compo-
sition, and more specifically, in the size of the adipose organ. To
illustrate this variability, Fig. 1 shows percentage fat-free mass
and percentage fat mass values in a sample of women according
to BMI values (Fig.1). The smallest fat mass value observed was
6 kg, which corresponded to 13% fat, and the largest fat mass val-
ue observed was 54 kg, which corresponded to 54 % fat. The re-
markable inter-individual differences that can be observed in
the size of the adipose organ (up to around 10-fold differences
in our sample) as well as its rather large size compared to other
peripheral conversion sites suggests a highly variable, but poten-
tially important influence on steroid metabolism.
BØlanger C et al. Adipose Tissue Intracrinology ´ Horm Metab Res 2002; 34: 737 ± 745
Review
738
Steroidogenic Enzymes
As shown in the previous section, adipose tissue steroid conver-
sion is now a well-accepted phenomenon. Steroidogenic en-
zymes for which mRNA, protein, or activity have been detected
in adipose tissues from various origins or in different adipose tis-
sue cell fractions using various experimental approaches are list-
ed in Table 1. In our survey of the literature, we have identified 13
steroidogenic enzyme types in adipose tissue or adipose tissue-
derived cell fractions (Table 1, Fig. 2). Several groups have de-
scribed the aromatization of androstenedione to estrone and of
testosterone to estradiol very well. Aromatase activity and
mRNA has been detected in adipose tissue from several adipose
tissue depots and cultured stromal cells [18, 26 ± 35]. Important
regional differences in aromatase expression have been ob-
served, with the highest values in adipose tissue from the thighs
and buttocks compared to abdominal and breast adipose tissue
[7]. Moreover, consistent with the increase in fractional conver-
sion rates for androstenedione to estrone observed with aging,
adipose tissue aromatase expression increases markedly with
aging (reviewed in [7]). Experiments performed on adipose tis-
sue cell fractions demonstrated that virtually all the activity ob-
served in whole tissue samples could be detected in isolated
stromal cells, while aromatization was undetectable in mature
adipocytes [31].
Estrone-to-estradiol as well as androstenedione-to-testosterone
conversion (17b-HSD activity) has been shown to occur in hu-
man adipose tissue [18,36]. Type 1, 2, 3 and 5 17b-HSD mRNAs
were all detected in both intra-abdominal and subcutaneous adi-
pose tissues [8, 35,37, 38]. However, mRNA for type 1 17b-HSD
appeared to be incompletely spliced and most likely generates
an inactive protein [8]. Type 2 and 3 enzymes were expressed in
both omental and subcutaneous abdominal adipose tissues [8].
More recently, we found that omental and subcutaneous adipose
tissues also express type 5 17b-HSD (Tchernof and Luu-The, un-
published observation). Additional experiments are currently
underway to determine the physiological importance of this en-
zyme in adipose tissue.
Fig. 2 Schematic representation of steroid conversions and steroidogenic enzymes present in adipose tissue. Sources of steroid precursors in
plasma are indicated on the left. Active steroids at the receptor level are boxed. Glucuronide conjugates potentially produced by adipose tissue
are indicated on the right (±G).
Fig. 1 Percent fat mass and fat-free mass values in a sample of lean,
overweight, and obese women illustrating the large inter-individual
variations in adipose tissue accumulation. The smallest fat mass ob-
served was 6 kg and the largest was 54 kg adipose tissue, which corre-
sponds to a ~ 10-fold difference in the mass of the adipose organ.
BØlanger C et al. Adipose Tissue Intracrinology ´ Horm Metab Res 2002; 34: 737 ± 745
Review
739
Another steroidogenic enzyme expressed in adipose tissue, 11b-
HSD type 1, has recently attracted much attention [39± 41]. Ex-
pression and activity of type 1 11b-hydroxysteroid dehydroge-
nase was demonstrated in stromal cells from breast, omental,
and subcutaneous adipose tissue [40, 42]. Contrary to the classi-
cal view that adipose tissue contributes to the deactivation of
cortisol by transforming it to cortisone [43], studies have found
that the predominant activity in omental fat, and to a lesser ex-
tent abdominal subcutaneous fat, was the reduction of inactive
cortisone to active cortisol [40, 44]. As opposed to aromatase
and 17b-HSD expression, which was mostly found in preadipo-
cytes, the expression of type 1 11b-HSD has been shown to be
activated upon adipocyte differentiation, which is thought to
promote lipogenesis [45]. The site-specific regulation of this ac-
tivation may represent an important etiological factor underly-
ing visceral obesity development [45].
Several other enzymes have been identified in human adipose
tissue (Table 1, Fig. 2). Of note, 5a-reductase activity has been de-
tected, which emphasizes the ability of this tissue to generate di-
hydrotestosterone, the most active androgen, from testosterone
[46]. Abdominal subcutaneous adipose tissue also expresses
P450 C17 mRNA (17a-hydroxylase), which is responsible for the
formation of 17-hydroxyprogesterone, adding another possible
pathway for the synthesis of active androgens/estrogens in this
tissue [47].
On the other hand, enzymes that inactivate androgens have also
been detected in adipose tissue. Messenger RNA or activity of
these enzymes, type 3 3a-HSD, 17a-hydroxylase, and UDP-glu-
curonosyltransferase (UGT) 2B15 have been detected in adipose
tissue and stromal cells, and may be responsible for modulating
exposure of adipose cells to active steroids. In support of this no-
tion, we recently found that the glucuronidated form of 5a-an-
drostane-3a,17b-diol (the major product of 3a-HSD and
UGT2B15), was elevated in plasma of overweight men with vis-
ceral obesity [48]. These results suggested that androgen metab-
olism was increased in men with abdominal obesity. Further
support was provided by a study of twins who were submitted
to overfeeding [49]. We induced a 7 % increase in percent fat
that was associated with a 24 cm
2
increase in visceral adipose
tissue cross-sectional area. These changes led to significant in-
creases in plasma levels of androstane-3a,17b-diol glucuronide
[49]. Changes in adipose tissue distribution indices were signifi-
cantly correlated with changes in plasma concentrations of this
androgen metabolite, suggesting that body fat gain is associated
with alterations in local androgen inactivation [49]. A second
glucuronosyltransferase (UGT2B11) was also detected in adipose
tissue [50]. However, no specific substrate has yet been attribut-
ed to this isoform.
Potential Importance of Local Adipose Tissue Steroid
Metabolism in the Regulation of Adiposity
Androgen concentrations are around 5 ±10 times higher in males
than in females [51]. This difference in steroid profile correlates
with the presence of the android pattern of fat distribution in
males. In support of this observation, long-term, high-dose an-
drogen treatment of female-to-male transsexuals leads to a
change in the pattern of fat distribution, with the predominance
of abdominal fat [52]. Within the male physiological range, how-
ever, higher testosterone levels appear to be beneficial to men
[53]. Hence, overall male obesity and overweight have generally
been associated with reduced endogenous plasma testosterone
levels and increased estrogen concentrations [54 ± 56]. Low en-
dogenous testosterone levels also characterize men with visceral
obesity [57,58]. In a previous study [56], we confirmed findings
by other groups [57, 58] showing that abdominal obesity is asso-
ciated with reduced plasma testosterone concentrations. In addi-
tion, adrenal C
19
steroid concentrations (androstenedione, an-
drostenediol, and dehydroepiandrosterone) were also reduced
in abdominal obese men when compared to lean controls [56].
Thus, obesity and excess abdominal adipose tissue accumulation
are not only associated with reductions in plasma levels of gona-
dal steroids, but also with low adrenal C
19
steroid concentrations
in men.
Mechanisms responsible for the complex pattern of associations
among androgens, obesity, and body fat distribution are still un-
clear. Björntorp and colleagues (reviewed in [59]) have suggested
that visceral obesity may arise from an activation of the cortico-
trophin-releasing factor-adrenocorticotrophin-cortisol axis re-
sulting from a variety of causes, including nutritional factors, po-
tential stressors in the psychosocial and socioeconomic environ-
ment, alcohol, smoking, traits of depression, anxiety, and genetic
susceptibility. Activation of the axis would be partly responsible
for alterations in glucose transport, insulin sensitivity and adi-
pose tissue metabolism, which could contribute to an inhibition
of gonadotrophin secretion, and may explain the low androgen
levels found in the plasma of visceral obese men [1,60, 61]. How-
ever, this hypothesis remains to be confirmed. The alternative
view suggests that reduced androgens in male obesity are not a
primary etiologic factor, but the result of an increased clearance
through accelerated conversion in an enlarged adipose tissue or-
gan.
Irrespective of the precise mechanism responsible for reduced
androgen levels in the plasma of abdominal obese men, evidence
is available to suggest that, on a local level, exposure of adipose
cells to less active androgen molecules directly impact on adi-
posity regulation and abdominal adipose cell metabolism. Spe-
cifically, androgens have been shown to enhance the lipolytic ca-
pacity of cultured male rat adipose precursor cells by increasing
the number of b-adrenoceptors and the activity of adenylate cy-
clase [62]. An increased fatty acid turnover has also been ob-
served in human males treated with testosterone [63,64], as
these studies demonstrated that testosterone treatment inhib-
ited the activity of adipose tissue lipoprotein lipase, an important
regulator of lipid uptake by the adipocyte [63, 64]. Evidence of a
direct action by androgens in adipose tissue also comes from
studies that have demonstrated the presence of androgen recep-
tors [65] and androgen binding [66,67] in both human and ro-
dent adipose tissue. Taken together, the available data suggest a
close association between androgens on the one hand and body
fat accumulation and distribution on the other. At the adipocyte
level, androgens directly modulate lipid mobilization and lipid
uptake, presumably by specifically binding to androgen recep-
tors expressed in adipose tissue.
BØlanger C et al. Adipose Tissue Intracrinology ´ Horm Metab Res 2002; 34: 737 ± 745
Review
740
Table 1 Steroidogenic enzymes in human adipose tissue
Enzyme Type Biological Material Studied mRNA Protein Activity Study
Aromatase Abdominal subcutaneous tissue + nd nd McTernan et al., 2000 [26]
Abdominal subcutaneous
and visceral adipose tissue
nd nd (D
4
dione ® E
1
) Deslypere et al., 1985 [18]
Breast adipose tissue + nd nd Price et al., 1992 [27]
Thighs/buttocks/abdomen
subcutaneous adipose tissue
+ nd nd Bulun et al., 1994 [28]
Stromal cells (subcutaneous) nd nd (C19
® C18) McTernan et al., 2000 [26]
nd nd (T
® E
2
) Schmidt et al., 1994 [29],
Schmidt et al., 1998 [30]
+nd(D
4
dione ® E
1
) Simpson et al., 1989 [31],
Zhao et al., 1997 [32]
+nd(T
® E
2
) Schmidt et al., 1998 [30]
nd nd (D
4
dione ® E
1
) Killinger et al., 1990 [33]
Stromal cells (breast) nd nd (D
4
dione ® E
1
) Perel et al., 1986 [34]
Stromal cells (subcutaneous
and visceral)
+nd(D
4
dione ® E
1
) (c) Corbould et al., 2002 [35]
3b-HSD Stromal cells (breast) nd nd (DHEA
® D
4
dione) Killinger et al., 1995 [86]
3a-HSD 3 Abdominal subcutaneous
and visceral adipose tissue
+ nd nd Tchernof and Luu-The
[unpublished observation]
3 Stromal cells (subcutaneous
and visceral)
nd nd (DHT
® 3a-diol) Blouin, Tchernof and Luu-The [unpub-
lished observation], Joyner et al. [68]
11b-HSD 1 Abdominal subcutaneous tissue nd nd (F
® E) Rask et al., 2001 [87]
1 Stromal cells (subcutaneous
and visceral)
+nd(E
® F) Tomlinson et al., 2000 [88]
1 Stromal cells and mature adipocytes nd nd (E
® F) Ricketts et al., 1998 [89]
1 +nd(E« F) Bujalska et al., 2002 [45]
1 Stromal cells nd nd (E
® F) Moore et al., 1999 [90]
1 +nd(E
® F) Bujalska et al., 1999 [91],
Tomlinson et al., 2001 [88]
17b-HSD Abdominal subcutaneous tissue nd nd (E
1
® E
2
) Folkerd et al., 1982 [36]
Abdominal subcutaneous
and visceral adipose tissue
nd nd (E
2
® E
1
) Deslypere et al., 1985 [18]
Breast adipose tissue nd + (E
1
® E
2
) Tait et al., 1989 [92],
Mann et al., 1991[93]
+nd(E
1
« E
2
); (T « D
4
dione) Labrie et al., 1997 [94]
Stromal cells (breast) nd nd (D
4
dione ® T) Perel et al., 1986 [34]
nd nd (DHEA
® D
5
diol) Khalil et al., 1993 [95]
1 Abdominal subcutaneous
and visceral tissues
+ (d) nd nd Corbould et al., 1998 [8]
2 Abdominal subcutaneous
and visceral tissues
+ nd nd Corbould et al., 1998 [8]
2 Abdominal subcutaneous tissue + nd nd Luu-The et al., 1990 [37],
Labrie et al., 1991 [38]
3 Abdominal subcutaneous
and visceral tissues
+ nd nd Corbould et al., 1998 [8]
3 Stromal cells/preadipocytes
(subcutaneous and visceral)
+nd(D
4
dione ® T) Corbould et al., 2002 [35]
5 Abdominal subcutaneous
and visceral tissues
+ nd nd Tchernof and Luu-The
[unpublished observation]
7a-hydroxy-
lase
Stromal cells (breast) nd nd (DHEA
® 7a-OHDHEA) Khalil et al., 1993 [95], Khalil et al.,
1994 [96], Killinger et al., 1995 [86]
17a-hydroxy-
lase
Abdominal subcutaneous tissue + nd (P
® 17a-OHP) Puche et al., 2002 [47]
5a-reductase Adipose tissue (a) nd nd (T
® DHT) Longcope et al., 1985 [46]
Continued
BØlanger C et al. Adipose Tissue Intracrinology ´ Horm Metab Res 2002; 34: 737 ± 745
Review
741
Thus, available data on androgens and body fat distribution ap-
pear to be contradictory. On the one hand, abdominal obesity is
associated with reduced testosterone in plasma; on the other,
androgens directly promote lipid mobilization and inhibit lipid
uptake in adipocytes. Adipose tissue steroid conversion may re-
present an interesting hypothesis to reconciling the available
data. Indeed, an increased elimination of plasma androgens
through accelerated conversion to non-androgenic steroids in
adipose tissue is consistent with a lower exposure of adipocytes
to active androgens at the local level. Accordingly, a recent study
by Joyner et al. [68] indicated that dihydrotestosterone metab-
olism to 3a-diol was significant in preadipocytes, and that this
phenomenon may have led to slight decreases in DHT binding
to its receptor.
In female adipose tissue, estrogens have been shown to exert ac-
tions that are partly similar to those of androgens in males (re-
viewed in [69±71]). Specifically, estradiol may directly inhibit
lipid uptake through inhibition of lipoprotein lipase, and pro-
mote lipid mobilization through stimulation of lipolysis [69]. Ad-
ditional evidence for a role of estrogens in the regulation of adi-
pose tissue accretion and distribution comes from studies that
have demonstrated the presence of both estrogen receptor iso-
forms in this tissue [72± 78]. Human and animal studies have re-
ported evidence for regional differences in adipose tissue estro-
gen receptor levels and regulation [74,76]. Taken together, these
data suggest that adipose tissue is responsive to estrogens, and
that these effects may be depot-specific. Consequently, an in-
creased intracrine conversion of steroid precursors to estradiol
in adipose tissue may contribute to the local regulation of adi-
pose tissue store size and distribution in women. A recent study
by Corbould et al. [35] examined abdominal subcutaneous and
intra-abdominal adipose tissue samples in women. The authors
found a positive correlation between ratio of type 3 17b-HSD to
aromatase in intra-abdominal adipose tissue on the one hand
and waist circumference and BMI on the other, suggesting that
female adipose tissue was substantially androgenic, which in-
creased with obesity or central obesity [35]. Additional indirect
evidence supporting the hypothesis of an important role for adi-
pose tissue-produced estrogens in the regulation of adipocyte
metabolism and obesity-related conditions also comes from
studies on breast adipose tissue aromatase and breast cancer,
which constitute a well-accepted connection [7, 31]. More studies
are needed to firmly establish the physiological relevance of the
intracrine mode of hormonal action in the regulation of adiposity.
The generation of active cortisol through expression of type 1
11b-HSD in abdominal adipose tissue, which has been shown to
increase exposure of omental adipocytes to cortisol, appears to
be of particular importance in the pathogenesis of abdominal
obesity and related metabolic complications. Recent data have
indicated that the dehydrogenase activity of type 1 11b-HSD
was predominant in preadipocytes, and that there was a switch
to oxoreductase activity upon initiation of cell differentiation
[45]. This study suggested that the switch to cortisol production
by type 1 11b-HSD in differentiating adipocytes likely promotes
lipogenesis, which led the authors to propose that the set point
of type 111b-HSD oxoreductase activity may represent an impor-
tant mechanism underlying visceral obesity. Rask et al. per-
formed a study on peripheral cortisol metabolism and the regu-
lation of the hypothalamic-pituitary-adrenal axis [79]. They
found that obese women were characterized not only by in-
creased cortisol activation by subcutaneous adipose tissue 11b-
HSD1 activity, but also by a decreased hepatic activation of corti-
sol from cortisone and increased inactivation of cortisol by A-
ring reductases. This led to increased urine levels of cortisol me-
tabolites such as 5a- and 5b-tetrahydrocortisol. Minimal com-
pensatory activations of the hypothalamic-pituitary-adrenal
axis were noted in obese subjects, and were found to be insuffi-
cient to account for the increased plasma cortisol levels observed
in this condition. These results demonstrated that adipose tissue
11b-HSD1 activity might represent a key contributor to the circu-
lating pool of cortisol [79]. Another study demonstrated that
transgenic mice selectively expressing 11b-HSD type 1 in adipose
tissue develop abdominal obesity, a phenomenon that is exag-
gerated by a high-fat diet [41]. The investigators suggested that
increased expression of 11b-HSD1 in abdominal adipose tissue
might represent a common molecular etiology for visceral obesi-
ty and the metabolic syndrome [41]. These studies dramatically
emphasize the importance of steroid conversions in adipose tis-
sue. The potential impact of other adipose tissue steroidogenic
enzymes that would decrease or increase the exposure of omen-
tal adipocytes to active androgens/estrogens in a manner similar
to 11b-HSD1/cortisol remains to be studied.
Table 1 Continued
Enzyme Type Biological Material Studied mRNA Protein Activity Study
Stromal cells (breast) nd nd (D
4
dione ® D
5
dione) Perel et al., 1986 [34]
Stromal cells nd nd (D
4
dione ® D
5
dione) Killinger et al., 1990 [33]
UGT2B11 Adipose tissue (b) + nd nd Beaulieu et al., 1998 [50]
UGT2B15 Adipose tissue (b) + nd nd LØvesque et al., 1997 [97]
Abdominal subcutaneous
and visceral tissues
+ nd nd Tchernof et al., 1999 [98]
nd: not determined; (a): Arterial venous balance; (b): Not possible to determine biopsy site; (c): low activity detected; (d): incompletely spliced mRNA detected,
most likely leads to inactive protein; UGT: UDP-glucuronosyltransferase; D
4
dione: androstenedione; E
1
: estrone; C
19
: androgens; C
18
: estrogens; T: testosterone;
E
2
: estradiol; DHEA: dehydroepiandrosterone; DHT: dihydrotestosterone; 3a-diol: androstanediol; E: cortisone; F: cortisol; D
5
diol: androst-5-ene-3b,17b-diol;
7a-OHDHEA: 7a-hydroxydehydroepiandrosterone; P: progesterone; 17a-OHP: 17a-hydroxyprogesterone; D
5
dione: androstanedione.
BØlanger C et al. Adipose Tissue Intracrinology ´ Horm Metab Res 2002; 34: 737 ± 745
Review
742
Conclusion
Over the last decade, the incidence of obesity has steadily in-
creased in North America and Europe [80 ± 83]. Recent epidemio-
logical studies showing parallel increases in the incidence of
both obesity and type 2 diabetes have emphasized more than
ever the need for concerted efforts to understand, prevent and
treat these conditions [84,85]. The close relationship between
obesity and plasma sex hormones is well established. However,
steroid metabolism in humans is much more complex than
what can be observed from simple measures of plasma androgen
and estrogen levels. The adipose organ acts as a steroid reservoir
and site of conversion. Local androgen/estrogen synthesis in adi-
pose tissue may account for an important part in steroid action,
and presumably adiposity regulation. Several steroid-converting
activities and steroidogenic enzymes have been detected in adi-
pose tissues, and recent studies have demonstrated potentially
important roles for these enzymes in the metabolic syndrome.
Future studies on adipose tissue intracrinology will contribute
further to our understanding of steroid action in adipocytes.
Acknowledgments
AndrØ Tchernof is the recipient of a Fonds de la Recherche en
SantØ du QuØbec Scholarship. This work was supported by the
Canadian Diabetes Association and the Canadian Institute of
Health Research. Chantal BØlanger is the recipient of a summer
studentship from Human Resources Development Canada.
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