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Aneta Mankowska, Grazyna Sypniewska
Dept.of Laboratory Medicine, Collegium Medicum in Bydgoszcz,
Nicolas Copernicus University, Torun, Poland
Head: Prof. Grazyna Sypniewska Ph.D, MD.
Abstract
Adipose tissue plays essential
metabolic roles, not only serving as massive energy reservoir but
also producing and releasing hormones and other biologically active
molecules that regulate several metabolic activities. Adipocytes
secrete a variety of factors, referred to as adipokines. Current
research has identified over 50 adipocyte-secreted factors, and
more are yet to be discovered. In obesity, increased production of
pro-inflammatory adipokines and diminished synthesis of
anti-inflammatory factors impacts on multiple functions such as
appetite and energy balance, immunity, insulin sensitivity,
angiogenesis, blood pressure and lipid metabolism. All are linked
with higher risk for cardiovascular disease. Various
adipocyte-released compounds profoundly affect insulin sensitivity
and might potentially link obesity-related diseases, including
atherosclerotic cardiovascular disease, type 2 diabetes mellitus,
hypertension, dyslipidaemia and insulin resistance.
This review aims to present some of
the recent topics of selected adipokine research that may be of
particular
importance.
Introduction
Abdominal fat accumulation has been
shown to play essential role in the development of metabolic
syndrome [1]. The metabolic syndrome, a cluster of metabolic
disorders often associated with visceral obesity, increases
cardiovascular mortality and morbidity. As the body's largest
endocrine organ, adipose tissue not only stores excess energy, but
also synthesizes and releases several bioactive molecules named
"adipokines" [1,2]. The term "adipokines" is restricted to peptides
and proteins secreted from adipocytes, excluding signals released
only by the other cell types (such as macrophages) in adipose
tissue [3].
Obese patients, particularly those with visceral fat accumulation,
have diminished plasma levels of adiponectin, the most
abundant protective adipose-specific adipokine[4].
Visceral fat accumulation is closely related to the
development of cardiovascular disease and obesity-related
disorders such as hypertension, hyperlipidemia, diabetes mellitus
[1,2] as shown on Figure 1 [5].
Figure 1. Visceral fat relations to the metabolic
syndrome (5).
Adipose tissue has long been
regarded as an organ the sole purpose of which was to store excess
energy as triglycerides, and release energy as free fatty acids,
which itself is an essential self-defense system for survival
during starvation [6,7,8]. This point of view has now
changed, fat tissue has emerged as an endocrine and secretory organ
affecting more than one metabolic pathway [3,9,10]. Its major
endocrine function is secreting several hormones, notably leptin
and adiponectin. Also adipose tissue releases adipokines
involved in inflammation and hemostasis : growth factors ( TNFα,
transforming growth factor-beta, nerve growth factor, VEGF),
cytokines ( IL-1β, IL-6, IL-10), chemokines (IL-8),
acute-phase proteins (haptoglobin, serum amyloid A) and
prothrombotic factor (plasminogen activator inhibitor-1) [3,9].
It is now well acknowledged that the
consequences of obesity, particularly diabetes and cardiovascular
diseases, are influenced to a great extent by the actions of
adipokines. Production of pro-inflammatory adipokines
is increased in obesity which has led to the view that
chronic low-grade inflammation is a characteristic feature in the
obese subjects and that this links causally to insulin resistance
and the metabolic syndrome [3,11].
Among various adipocyte-secreted
factors adiponectin and visfatin appear as insulin-sensitising
adipokines, whereas TNF-α, IL-6 and resistin are considered
as compounds increasing insulin resistance. Moreover, leptin
regulates apetite and energy balance [4,8,12].
Adiponectin
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. It was discovered in 1995, at about the same time as
leptin, as a product of the adipose tissue most abundant gene
transcript [11,13].
Adiponectin, a protein synthesized almost exclusively by fat cells,
plays an important role in the regulation of whole body
energy homeostasis, glucose and lipid metabolism and
anti-inflammatory responses in the vascular system [14,15,16].
Human plasma adiponectin concentration is about 1000 times higher
than those of any other hormone and is higher in women than in men.
Adiponectin levels are decreased in obesity, subjects with
insulin resistance, type 2 diabetes and dyslipidemia and are
particularly low in subjects with coronary artery disease.
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
[14,16,17].
The most important feature of adiponectin is its lower
expression in the adipose tissue and lower
concentration in plasma in overweight, obese and diabetic
patients.
Plasma adiponectin is negatively correlated with the BMI, visceral
fat volume, waist/hip ratio, fasting plasma insulin, plasma glucose
and triglyceride concentrations [16,18,19]. Furthermore, it
positively correlates with HDL-cholesterol level [20].
Adiponectin is also involved in the regulation of energy balance
and body weight and it reduces weight gain. Weight loss leads to
increased levels of that adipokine in plasma. Obese patients
who received gastric partition surgery (gastric stapling) showed a
21% reduction in mean BMI that was accompanied by 46%,
in average, increase in plasma adiponectin values.
Adiponectin plays an important role in the regulation of lipid
metabolism (increases fuel oxidation) and carbohydrate metabolism
(improves hepatic insulin sensitivity).
Adiponectin has been shown to exert anti-inflammatory and
anti-atherogenic properties within the arteries and thus may
negatively modulate the process of atherogenesis
[6,8,9,11,16,18,19]. The importance of adipokines, especially
focusing on adiponectin, is discussed with respect to
cardiovascular disease. High concentrations of adiponectin are
found in the bloodstream inside the vascular walls. Matsuzawa et
al. have shown that adiponectin can enter the vascular
walls, bind specifically to collagen types I, III, V and VIII
present in the vascular intima and selectively accumulate in
injured vessel walls, indicating that it may be involved in the
repair process of damaged vasculature [6].
Recent studies suggest that adiponectin may play a role in the
modulation of inflammatory vascular response by supressing the
expression of adhesion molecules on endothelial cells, inhibiting
endothelial cell NF- B signaling and suppressing macrophage
function (foam cell formation). In doing so, adiponectin
inhibits the development of atherosclerotic plaques
[8,9,11,16].
It was also suggested that adiponectin gene variations are
associated with risk of myocardial infarction and ischemic stroke;
in particular selected gene variants were found to be associated
with diminished cardiovascular risk in subjects with or without
diabetes [21].
Engeli et al. suggest that decreased expression and plasma
levels of adiponectin may serve as a marker of increased metabolic
and inflammatory risk [22]. 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
that 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. Regional differences may exist in
adiponectin expression and production in human adipose tissue
[22].
Korner et al. have reported that adiponectin levels are
significantly reduced in patients with breast, endometrial and
prostate cancer. Adiponectin has been shown not only to have
anti-atherogenetic, anti-angiogenic and anti-proliferative
properties, but may also play a role in cancer development
[11].
Many studies support the protective role of adiponectin in the
development of obesity-related disorders and the metabolic
syndrome, particularly in the pathogenesis of type 2 diabetes and
cardiovascular disease. It has been found that in the obese
subjects but not in the lean higher adiponectin plasma
concentration was connected with more favorable lipid profile
(lower triglycerides, LDL-cholesterol and apolipoprotein B, higher
HDL-cholesterol) and decreased inflammation (lower CRP and IL-6) [
20].
Further elucidation of the mechanisms of action of adiponectin,
particularly the identification of inhibitors of adiponectin
expression in obesity, has the potential to create novel and
powerful targets for developing intervention strategies for
obesity-related disorders [4,9,23].
Resistin
The invention of resistin as a novel
factor secreted by fat cells with an impact on insulin sensitivity
was proposed as a new mechanism to explain the pathogenic sequence
of adipocyte-obesity-insulin resistance. Resistin is a
cysteine-rich 12.5 kDa polypeptide, with unclear role in the
pathogenesis of obesity- mediated insulin resistance and type 2
diabetes mellitus. Recent studies in murine models suggest that
resistin (also called Fizz3), secreted by adipocytes, may represent
the long-sought link between obesity and insulin resistance
[9,11]
Many studies are still unravelling
the functionality of resistin in human biology in respect to
glucose metabolism and insulin signaling. The possible involvement
of resistin in obesity and insulin resistance in humans is largely
controversial. Resistin is considered to be a substance increasing
insulin resistance, however the exact mechanisms are not
well-known. Resistin plasma concentrations are increased in obese
subjects and correlate with the inflammatory state that underlies
the initiation and progression of atherosclerotic lesions.
Correlation between resistin concentration and the extent of
atherosclerotic plaques in the coronary vessels has also been
found. All these findings suggest that resistin is directly
involved in the pathogenesis of atherosclerosis. It has been showed
that resitin can be induced by endotoxin and cytokines
[9,11,24].
The data on association of resistin
with obesity or insulin resistance are controversial, some
have reported positive correlations while others did not find
a relationship. Recently, Al-Harithy et al. assessed
the relationship between serum resistin concentrations and insulin
resistance in lean, overweight and obese Saudi women with or
without diabetes [23]. They have shown that resistin concentrations
are elevated in patients with type 2 diabetes and are associated
with obesity and insulin resistance, indicating the involvement of
this adipokine in the development of diabetes in humans [23].
Another study has shown that
resistin is associated with the disorders of glucose and lipid
metabolism in type 2 diabetes [25].
Vendrell et al. suggested
coordinated roles of adiponectin, resistin, and ghrelin in the
modulation of the obesity proinflammatory environment. They
found that resistin levels before surgery treatment are
predictive of the extent of weight loss after bypass surgery. Like
many other adipokines, resistin may possess a dual role in
contributing to metabolic disease: first through its direct effects
on substrate metabolism and second, through regulating inflammation
and the development of endothelial dysfunction [24,26].
Visfatin
In 2004, Fukuhara et al. identified
a molecule that is expressed at much higher levels in visceral fat
than in subcutaneous fat which was named visfatin [27]. This
adipokine is highly expressed in the visceral adipose tissue of
both humans and rodents. Visfatin was found to be identical to a
cytokine expressed by lymphocytes - the pre-B cell colony-enhancing
factor (PBEF). Visfatin binds to the insulin receptor at a site
distinct from insulin and exerts hypoglycemic effect by reducing
glucose release from hepatocytes and stimulating glucose
utilization in peripheral tissues. Since insulin-mimetic actions of
visfatin may be part of the feedback regulation of glucose
homeostasis, a hypothesis may be raised that visfatin
concentrations are influenced by glucose or insulin blood levels in
humans. This possibility offers new therapeutic options for
diabetics [9,11,27].
Brendt et al. examined whether
visfatin plasma concentration and mRNA expression in visceral and
subcutaneous fat correlates with anthropometric and metabolic
parameters in subjects with a wide range of obesity, body fat
distribution, insulin sensitivity, and glucose tolerance [28]. They
have found correlations between visfatin plasma concentrations and
visceral visfatin mRNA expression and measures of obesity but
not with visceral fat mass or waist-to-hip ratio. Surprisingly,
they did not found differences in visfatin mRNA expression
between visceral and subcutaneous adipose tissue [28].
Haider et al. have shown that
elevated plasma visfatin concentrations in morbidly obese subjects
are reduced after weight loss. This may be related to changes in
insulin resistance over time [29].
Further study of visfatin's
physiological role may lead to new insights into glucose
homeostasis and its dysregulation in obesity-related diseases, such
as diabetes mellitus and cardiovascular disease [1,11,27].
Apelin
A novel adipokine apelin,
produced and secreted from fat cells, was discovered
recently. This bioactive peptide is the endogenous ligand of
the orphan G protein-coupled receptor, APJ. Apelin may act as
a potent vasodilator, thus lowering blood pressure, and exerting
positive inotropic effects in rats and humans. Furthermore, the
apelin system may modulate pituitary hormone release and food
and water intake, regulate insulin sensitivity, play a
role in stress activation [30]. This neuropeptide is
involved in the regulation of body fluid homeostasis and
cardiovascular functions. Moreover, recent study showed that apelin
acts as an angiogenic factor for endothelial cells and exerts
potent diuretic effects through inhibition of arginine vasopressin
(AVP) neuron activity and AVP release [11,31,32].
Heinonen et al. investigated basal
plasma levels of apelin, orexin-A, and leptin in morbidly obese
patients [33]. They have shown positive correlations of apelin,
orexin-A, and leptin plasma levels with the BMI. The results of
this study also demonstrated that one year after
gastric banding with significant loss in BMI basal plasma levels of
leptin decreased, while orexin-A remained unchanged [33].
Apelin as a multipotential adipokine
has attracted much interest as a target for novel therapeutic
research and drug design.
Eotaxin
Eotaxin is a chemokine produced by
fat tissue. The eotaxin family comprises three distinct peptides
(eotaxin, eotaxin-2 and eotaxin-3) which have been implicated in
eosinophilic inflammation.Eotaxin binds with high affinity and
specificity to the chemokine receptor CCR3 and plays an important
role in the pathogenesis of allergic disease.Eotaxin belongs to CC
chemokines with selective activity for eosinophils and basophils
and it is important in extrinsic asthma, an inflammatory disorder.
Asthma is often more severe in the obese subjects. Eotaxin and
cytokines produced by adipose tissue may possibly directly
influence airways hyperresponsiveness, leading to an increased
prevalence and severity of asthma symptoms in obese
individuals.
Circulating eotaxin levels are
increased in diet-induced obesity in both mice and humans, and
eotaxin mRNA levels were high in visceral adipose tissue in both
species. Diet-induced weight loss in humans led to a reduction in
plasma eotaxin levels [34,35,36].
The other study showed that reduced
level of circulating eotaxin-3 may represent a potentially powerful
biochemical marker for predicting future adverse cardiac events in
patients with coronary artery disease (CAD). In vitro and clinical
studies suggest that eotaxins could play a role in vascular
inflammation, but no data are available on their prognostic
significance in patients with angiographically documented coronary
artery disease[36,37].
This adipokine may be regarded as a
potential non-invasive marker for assessing airways inflammation in
asthmatics and predicting cardiac events in patients with CAD
[36,37].
We aimed to provide a concise
summary of actual knowledge on the important
adipokines, and to give an update on the latest findings and
current fields of adipokine research in association to obesity and
obesity-related diseases. The molecular effects of adipokines are a
challenging area of research and their in-depth understanding
will undoubtedly lead to the discovery of effective therapeutic
interventions. The disturbances in expression, synthesis and
release, function and balance of adiponectin, resistin and eotaxin
may be considered not only as a link between visceral adiposity and
cardiovascular risk but also as independent risk factors of
coronary heart disease. Elucidation of the mechanisms linking
obesity, diabetes and atherosclerosis is fundamental for developing
the new ways of therapeutic interventions.
References
1. Matsuzawa Y: Therapy
insight: adipocytokines in metabolic syndrome and related
cardiovascular disease. Natl Clin Pract Cardiovasc Med: 2006, 3,
35-42
2. Matsuzawa Y: The metabolic syndrome and adipocytokines.
FEBS Lett: 2006, 22;580,2917-21
3. Trayhurn P, Wood IS: Adipokines: inflammation and the
pleiotropic role of white adipose tissue. Br J Nutr.
2004;92,347-55
4. Okamoto Y, Kihara S, Funahashi T et al.: Adiponectin: a key
adipocytokine in metabolic syndrome. Clin Sci:
2006,110,267-78
5. www.phoenixpeptide.com/Catalog/Adiponectin/adiponectin.htm
6. Matsuzawa Y, Shimomura I, Kihara S, Funahashi T: Importance
of adipocytokines in obesity-related diseases. Horm Res , 2003,
60(suppl 3), 56-59
7. Schaffler A, Scholmerich J, Buchler C: Mechanisms of
disease: adipocytokines and visceral adipose tissue-- emerging role
in intestinal and mesenteric diseases. Nat
Clin Pract Gastroenterol Hepatol. 2005;2,103-11
8. Kopff B, Jegier A: Adipokines: adiponectin, leptin,
resistin and coronary heart disease risk. Przegl Lek. 2005; 62
(Suppl 3),69-72
9. Ronti T, Lupattelli G, Mannarino E: The endocrine function
of adipose tissue: an update. Clin Endocrinol. 2006; 644,
355-365
10. Chudek J, Adamczak M, Nieszporek T, Wiecek A: The adipose
tissue as an endocrine organ-a nephrologists' perspective. Contrib
Nephrol. 2006;151,70-90
11. Koerner A, Kratzsch J, Kiess W: Adipocytokines: leptin-the
classsical, resistin-the controversial, adiponectin- the
promissing, and more to come. Best Practice&Clinical
Endocrinology&Metabolism 2005; 19, 525-546
12. Kralisch S, Klein J, Bluher M et al.: Therapeutic
perspectives of adipocytokines. Expert Opin Pharmacother.
2005; 6, 863-872
13. Szopa M, Malczewska-Malec M, Wybrańska I:
Adiponectin--adipocytokine with a broad clinical spectrum. Przegl
Lek. 2004; 61,109-14
14. Simońska E, Gumprecht J, Skubala A et al.:
Adiponektyna-znaczenie w patogenezie cukrzycy typu 2. Diabetologia
Doświadczalna i Kliniczna 2004; 4,249-254
15. Trayhurn P: Endocrine and signalling role of adipose
tissue: new perspectives on fat. Acta Physiol Scand.
2005,184,285-93
16. Pańkowska E, Szalecki M: Adiponektyna- hormon tkanki
tłuszczowej i jej związek z zespołem metabolicznym i chorobami
układu krążenia. Endokrynologia,Diabetologia i Choroby Przemiany
Materii Wieku Rozwojowego 2005;11,187-190
17. Scherer P.E : Adipose Tissue: From Lipid Storage
Compartment to Endocrine Organ. Diabetes.
2006;55,1537-1545
18. Galvani M, Scarfone A, Granato L et al.: Restoration of
Adiponectin Pulsatility in Severely Obese Subjects After Weight
Loss. Diabetes 2004; 53,939-947
19. Schulze M,B, Grimm E,B, Shai I et al.: Relationship
Between Adiponectin and Glycemic Control, Blood Lipids, and
Inflammatory Markers in Men With Type 2 Diabetes. Diabetes Care
2004; 27,1680-1687
20. Kantarzis K., Rittig K., Balletshofer B. et al.: The
relationship of plasma adiponectin with a favorable lipid profile,
decreased inflammation and less ectopic fat accumulation depend on
adiposity. Clin Chem 2006; 52, 1934-42
21. Hegener H.H., Lee I-M., Cook N.R. et al : Association of
adiponectin gene variations with risk of incident myocardial
infarction and ischemic stroke : a nested case-control study. Clin
Chem 2006; 52, 2021-27
22. Engeli S, Feldpausch M, Gorzelniak K et al.: Association
between adiponectin and mediators of inflammation in obese
women with diabetes. Diabetes 2003; 52, 942-947
23. Al-Harithy RN, Al-Ghamdi S: Serum resistin, adiposity and
insulin resistance in Saudi women with type 2 diabetes mellitus.
Ann Saudi Med. 2005;25, 281-2.
24. McTernan PG; Kusminski CM; Kumar S: Resistin. Curr Opin
Lipidol. 2006;17,170-5
25. Lu HL, Wang HW, Wen Y et al.: Roles of adipocyte derived
hormone adiponectin and resistin in insulin resistance of type 2
diabetes. World J Gastroenterol. 2006;12,1747-51
26. Vendrell J, Broch M, Vilarrasa N et al.: Resistin,
adiponectin, ghrelin, leptin, and proinflammatory cytokines:
relationships in obesity. Obes Res. 2004;12, 962-71.
27. Fukuhara A, Matsuda M, Nishizawa M et al.: Visfatin: a
protein secreted by visceral fat that mimics the effects of
insulin. Science 2005; 307,426-430
28. Brendt J, Kling N, Kralishc S et al.: Plasma Visfatin
concentrations and fat depot-specific mRNA expression in humans.
Diabetes 2005; 54, 2911-2916
29. Haider DG, Schindler K, Schaller G et al.: Increased
plasma visfatin concentrations in morbidly obese subjects are
reduced after gastric banding. J Clin Endocrinol Metab. 2006;
91,1578-81
30. Boucher J, Masri B, Daviaud D et al.: Apelin, a newly
identified adipokine up-regulated by insulin and obesity.
Endocrinology. 2005; 146,1764-71
31. De Mota N, Reaux-Le Goazigo A et al.: Apelin, a potent
diuretic neuropeptide counteracting vasopressin actions through
inhibition of vasopressin neuron activity and vasopressin release.
Proc Natl Acad Sci USA. 2004; 101,10464-9
32. Lee DK, George SR, O'Dowd BF: Unraveling the roles of the
apelin system: prospective therapeutic applications in heart
failure and obesity. Trends Pharmacol Sci. 2006;
27,190-4
33. Heinonen MV; Purhonen AK; Miettinen P et al.: Apelin,
orexin-A and leptin plasma levels in morbid obesity and effect of
gastric banding. Regul Pept. 2005; 130,7-13
34. www.thedoctorslounge.net/chest/articles/obesity_asthma/index.htm
35. Vasudevan AR, Wu M, Xydakis AM, Jones PH et al.: Eotaxin
and obesity. J Clin Endocrinol Metab 2006; 91, 256-261
36. Falcone C; Minoretti P; D'Angelo A et al.: Markers of
eosinophilic inflammation and risk prediction in patients with
coronary artery disease. Eur J Clin Invest. 2006; 36,
211-7
37. Emanuele E, Falcone C, D'Angelo A et al.:Association of
plasma eotaxin levels with the presence and extent of angiographic
coronary artery disease. Atherosclerosis. 2006;186, 140-5
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