Lena Nowak, Grazyna Sypniewska
Deparment of Laboratory Medicine,
Collegium Medicum in Bydgoszcz,
Nicolas Copernicus University,
Obesity is associated with premature atherosclerosis, as well as
with many metabolic alterations including insulin resistance,
dyslipidemia and hypertension. Visceral fat accumulation,
particularly, is closely associated with the development of
metabolic syndrome. The menopause transition, as well as the early
postmenopausal period, is associated with increase in total and
central obesity. Among adipocytokines secreted by the adipose
tissue adiponectin is the only one that has a protective role in
the development of obesity-related disorders , such as type 2
diabetes and cardiovascular disease.
This review aims to present a role that adiponectin may play
during the progress of menopause in relation to development of
menopausal metabolic syndrome.
Keywords: adiponectin, metabolic syndrome, menopause, sex
The prevalence of obesity has raised dramatically in recent years.
Increased adiposity, particularly, visceral fat accumulation, is
closely associated with premature atherosclerosis and many
metabolic alterations including insulin resistance, dyslipidemia
and hypertension.[1,2,3]. Obesity is one of the most common
disorders in climacteric women and occurs in approximately 65% of
them . Recent data suggested that menopause status is associated
with differences in adipose tissue metabolism in both, the
abdominal and gluteal region . Menopause has been shown to
contribute to the development of central obesity, insulin
resistance and worsening of glucose and lipid metabolism that
increase the risk for cardiovascular disease in women [6,7]. In
obese women higher morbidity and mortality from cardiovascular
disease was observed with the progress of climacterium. The primary
cause for this situation seems to be a menopausal metabolic
syndrome observed in 40% of climacteric women .
Adipose tissue produces and releases hormones and other
biologically active molecules �adipokines- that regulate several
metabolic activites of the human body . Among these adipokines �
adiponectin has been shown to directly or indirectly affect insulin
sensitivity through modulation of insulin signaling and the
molecules involved in glucose and lipid metabolism. Decrease in the
circulating levels of adiponectin by genetic and environmental
factors is associated with the development of diabetes and the
metabolic syndrome [9,10].
The use of adiponectin is suggested as a novel therapeutic tool
for diabetes and the visceral obesity metabolic syndrome but
evaluation of its effectiveness will require further clinical
Adipose tissue metabolism at menopause.
Menopause is associated with a raise in follicle-stimulating
hormone (FSH) and luteinizing hormone (LH ) levels and a fall in
estrogens. The average age of menopause is 51 years (45 to 55 yrs)
[11,12,13,14]. During the transition from the reproductive years
through menopause and beyond, women experience many changes, among
them changes in adipose tissue metabolism that may contribute to
body fat distribution [5,15]. Women have more body fat compared to
men, and there is a gender-specific difference in fat distribution.
In women, adipose tissue is accumulated especially around the hips,
buttocks, and thighs while men have a larger intra-abdominal fat
Among several hormones, estrogens promote, maintain and control
the typical distribution of adipose tissue and its metabolism
through still partly unknown mechanisms. Lipolysis in humans is
controlled through the β-adrenergic (lipolytic) and α2-adrenergic
(antilipolytic) receptors. In visceral adipocytes adrenaline
stimulates lipolysis (high β/α2 receptor ratio) but in subcutaneous
adipocytes it has an adverse effect ((high α2/β receptor ratio)
. Pedersen et al demonstrated that estradiol, only through the
estrogen receptor α, inhibits adrenaline-stimulated lipolysis in
human subcutaneous fat cells by increasing the amount of
α2-adrenergic antilipolytic receptors. This may explain how
estradiol is related to typical female subcutaneous adipose tissue
distribution because this inhibition is not observed in visceral
fat depots. In women, estradiol may shift accumulation of fat from
visceral into subcutaneous depots .
Premenopausal women have significantly lower risk of developing
obesityrelated diseases than men. This difference, abolished after
menopause, suggests that female sex steroid hormones, mainly
estrogens, influence adipogenesis and adipose tissue metabolism
. During postmenopausal period women develop increased amounts
of visceral fat. The redistribution of body fat, after menopause,
may be essential in linking the menopause with metabolic
alterations which confer to cardiovascular disease (CVD) risk
Changes in the hormone levels at menopause, in particular estrogen
deficiency, are associated with an increase in total adiposity,
preferentially at visceral region. Recent data suggested that in
postmenopausal women low estrogen concentrations, compared with
relatively elevated levels of circulating androgens, may explain,
at least in part, the body fat redistribution, loss of subcutaneous
fat and gain of visceral fat [18,19]. Menopause status may
influence adipose tissue metabolism and lipolysis. Lipoprotein
lipase (LPL) from adipose tissue is very important in accumulation
and distribution of fat stores. It was suggested that regional
differences in subcutaneous adipose tissue metabolism are related
to menopause status. LPL in the gluteal and abdominal fat tissue
seems to be more active in postmenopausal compared with
perimenopausal women that, together with concomitant lower
lipolysis, may predispose postmenopausal women to increase body fat
after menopause .
The more atherogenic lipid profile and increased level of the
prothrombotic plasminogen activator inhibitor-1 is observed in
women after menopause. Additionally, circulating cortisol
concentration is increased that is associated with central obesity,
elevated blood pressure, insulin resistance and dyslipidemia .
It has been reported that increased production of adiponectin,
peroxisome proliferator-activated receptor γ (PPARγ) and fatty acid
transporter in adipose tissue from gluteal region may be a
physiological response to preserve systemic insulin sensitivity in
estrogen-deficient women at postmenopause . Among the different
possible mechanisms, some investigators have suggested a link
between sex hormones and adiponectin metabolism
Relationship of adiponectin with sex
Adiponectin seems to be the most interesting and promising
biologically active molecule released from fat cells since it has
profound protective actions in the pathogenesis of diabetes
mellitus and cardiovascular disease. This protein is also called
ADIPOQ, gelatin-binding protein 28, Acrp30 [1,23]. Adiponectin is
secreted from adipose tissue and compared with many hormones, is
very abundant in the plasma. Human plasma adiponectin concentration
is associated with sex and is significantly higher in women than in
men. This sexual dimorphism develops during pubertal development in
relation to serum androgens. Interestingly, sex differences in
circulating adiponectin levels in older adults cannot be explained
by sex hormone regulation [1,24,25].
In healthy women, adiponectin concentration increases
significantly with age. Plasma concentration of adiponectin
inversely relates to visceral fat mass and visceral fat area,
however the correlation is weak in peri- and postmenopausal women
comparing to that in younger women .
The menopausal transition increases serum adiponectin
concentration, however, the data related to its levels and
association with body fat and regulatory factors are contradictory.
FSH in postmenopausal women is undoubtedly significantly and
positively associated with higher adiponectin. Two big studies have
shown a significant inverse correlation of adiponectin with
estradiol that was observed in healthy postmenopausal women, even
after adjustment for age and body mass index (BMI) [27,28].
Laughlin et al assessed the determinants of serum adiponectin in
postmenopausal women and men aged 50-92 yrs  and found positive
association of adiponectin with testosterone, and negative with
bioavailable estradiol in both sexes. This was not explained by
differences in age and adiposity. Recently, it has been reported
that dehydroepiandrosterone sulfate (DHEA-S), a precursor of
androgens and estrogens, may upregulate adiponectin gene expression
in a depot-dependent manner. The effect of DHEA-S was observed only
in visceral adipocytes from fat depots of morbidly obese humans
On the other hand, increased levels of free testosterone, low sex
hormonebinding globulin (SHBG) in postmenopausal women were shown
to be associated with decreased production of adiponectin
The role of adiponectin in physiology and obesity related
Adiponectin is involved in a number of metabolic processes, such
as glucose utilization, fatty acid oxidation in muscles, decreased
insulin resistance in the liver and the metabolism of adipose
tissue, but the physiological role of adiponectin needs further
explanation [32,33,34]. Adiponectin accumulates in injured vascular
walls, bound to collagens I, III and V present in the
subendothelial intima, indicating that it may be involved in the
repair process of damaged vasculature [2,35]. Recently it was shown
that low adiponectin concentration in postmenopausal women was
associated with adverse changes in carotid intima-media thickness
and stiffness that was not dependent on other cardiovascular risk
Adiponectin level is partially determined by inflammatory marker
levels. Most factors with a significant impact on adiponectin
regulation have inhibitory effects. These include proinflammatory
factors such as cytokines ( IL-6, and TNF-α), monocyte chemotactic
protein-1 and C-reactive protein (CRP) . Decreased expression
and plasma levels of adiponectin may serve as a marker of increased
metabolic and inflammatory risk . The association exists
between adiponectin gene expression and its plasma levels which
results from exclusive secretion of this adipokine by adipocytes.
This is not the case for the pro-inflammatory IL-6 or TNF- gene
expression in fat cells because these molecules are also secreted
by a number of other cell types. It was found that plasma
adiponectin levels and hs-CRP correlate inversely what may suggest
that decreased production of adiponectin contributes to the
systemic and vascular inflammation commonly found in obesity
The potential role of adiponectin in obesity and related
pathologies is directed mainly to protection against atherogenesis
and insulin resistance. Some studies suggest that adiponectin could
be a marker of risk for developing menopausal metabolic syndrome
. Adiponectin has been shown to exert anti-inflammatory and
antiatherogenic properties within the arteries and thus may
negatively modulate the process of atherogenesis [1,3,35,37].
Adiponectin increases insulin sensitivity in various models of
insulin resistance and in vitro increases the ability of
sub-physiologic levels of insulin to suppress glucose production in
isolated hepatocytes. This protein intensifies peripheral tissues
sensitivity to insulin and its deficiency can contribute to the
development of insulin resistance in type 2 diabetes and obesity
[3,34,38]. (Figure 1).
Figure 1. Associations adiponectin between
insulin resistance, metabolic syndrome and atherosclerosis
The role of adiponectin in pathogenesis of metabolic
syndrome of menopause
Estrogen deficiency is increasingly being recognized as a cause of
metabolic syndrome, characterized by visceral obesity, insulin
resistance, impaired lipid metabolism  . Adiponectin plays a
role in the pathogenesis of metabolic syndrome. This protein
improves glucose tolerance via increasing insulin sensitivity.
Adiponectin enhances fatty acid oxidation in liver and muscle, thus
reducing triglyceride content in these tissues. Moreover, it
stimulates glucose utilization in muscle and inhibits glucose
production by the liver, consequently decreasing blood glucose
levels. Plasma adiponectin levels are positively correlated with
insulin sensitivity in humans [ 41,42,43].
Recent studies have indicated that adiponectin levels are
significantly lower in obese than in non-obese women at the same
stage of postmenopause and lower in those with metabolic syndrome.
Lobo et al. reported that weight gain and obesity lead to the
increased prevalence of metabolic syndrome in postmenopausal women
and use of transdermal hormonal therapy is beneficial overall for
reducing many of the parameters of metabolic syndrome .
Visceral fat accumulation results in reduced levels of
adiponectin. It was reported that centrally located fat was the
main determinant of variability in adiponectin concentration in
healthy postmenopausal women . From many studies can be
concluded that low plasma adiponectin was associated with all the
components of the metabolic syndrome. The association of the
adiponectin genetic variation with obesity, metabolic syndrome and
diabetes mellitus has been found in a Taiwanese elderly population
. It seems however, that in humans adiponectin gene does not
play a role of the master obesity gene . Decreased adiponectin
concentration is rather a predictor of the development of type 2
diabetes than obesity. Low adiponectin level most likely reflects
obesity-dependent adipose tissue-specific insulin resistance and
mediates the effect of obesity on insulin resistance in the liver
and muscles. Most probably, the adipose tissue-specific insulin
sensitivity rather than general adiposity itself determines the
adiponectin expression in the adipose tissues  (Figure
Fig. 2 Adiponectin functions as the signal from
adipose tissues to the other peripheral tissues to mediate the
favorable metabolic effects and end organ protective effects.
The influence of menopausal status on the relationship between
adiponectin and insulin resistance was studied and it was found
that significant inverse association between adiponectin and
homeostasis model assessment of insulin resistance (HOMAIR)
occurred only after menopause . The authors concluded that
adiponectin may play a role in the improvement of insulin
sensitivity after, rather than before, menopause .
Several counter-regulatory hormones and inflammatory cytokines,
such as TNF-α, that mediate insulin resistance, were shown to
reduce either adiponectin mRNA expression or protein secretion.
High levels of TNF-α and low estradiol play the most important role
in development of insulin resistance. It was suggested that
adiponectin decreases the secretion of TNF-α and antagonizes TNF-α
by influencing on the expression of many adhesion molecules and the
adhesion of monocytes to endothelial cells [41,48]. Recent studies
have indicated that TNF-α level depends more on menopause progress
than obesity. Moreover, estradiol level was found to be inversely
associated with TNF-α . Postmenopausal women had higher TNF-α
than perimenopausal, however postmenopausal non-obese showed
slightly lower TNF-α levels compared with obese women .
The associations between adipocytokines and traditional risk
factors for cardiovascular disease were assessed in women at
postmenopausal stage. The larger decreases in adiponectin over the
menopause transition were associated with greater increase in
systolic blood pressure, insulin and insulin resistance and with
greater decreases in high density lipoprotein (HDL-cholesterol)
Review of the data confirmed positive association of adiponectin
with HDLcholesterol and negative relation with low-density
lipoprotein (LDL-cholesterol) and triglycerides (TG) but not with
high total cholesterol [50,51].
Adiponectin should be regarded as a most important among
adipocytokines. Decreased adiponectin level, caused by
obesity-induced insulin resistance in the adipose tissue, leads to
decreased insulin sensitivity in the liver and skeletal muscle and
in consequence to insulin resistance-related metabolic
Understanding the mechanisms by which sex hormones affect total
and regional body fat distribution and widening our knowledge about
pathophysiology of obesity and insulin resistance will have
important therapeutic and preventive implications for women at
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