Adipokines: inflammation and the pleiotropic role of white adipose tissue
British Journal of Nutrition (2004), 92, 347–355
Adipokines: inflammation and the pleiotropic role of white adipose tissue
Neuroendocrine and Obesity Biology Unit, Liverpool Centre for Nutritional Genomics, School of Clinical Sciences,University of Liverpool, Daulby Street, Liverpool L69 3GA, UK
White adipose tissue is now recognised to be a multifunctional organ; in addition to the central role of lipid storage, it has a major endo-crine function secreting several hormones, notably leptin and adiponectin, and a diverse range of other protein factors. These various pro-tein signals have been given the collective name ‘adipocytokines’ or ‘adipokines’. However, since most are neither ‘cytokines’ nor‘cytokine-like’, it is recommended that the term ‘adipokine’ be universally adopted to describe a protein that is secreted from (and syn-thesised by) adipocytes. It is suggested that the term is restricted to proteins secreted from adipocytes, excluding signals released only bythe other cell types (such as macrophages) in adipose tissue. The adipokinome (which together with lipid moieties released, such as fattyacids and prostaglandins, constitute the secretome of fat cells) includes proteins involved in lipid metabolism, insulin sensitivity, thealternative complement system, vascular haemostasis, blood pressure regulation and angiogenesis, as well as the regulation of energy bal-ance. In addition, there is a growing list of adipokines involved in inflammation (TNFa, IL-1b, IL-6, IL-8, IL-10, transforming growthfactor-b, nerve growth factor) and the acute-phase response (plasminogen activator inhibitor-1, haptoglobin, serum amyloid A). Productionof these proteins by adipose tissue is increased in obesity, and raised circulating levels of several acute-phase proteins and inflammatorycytokines has led to the view that the obese are characterised by a state of chronic low-grade inflammation, and that this links causally toinsulin resistance and the metabolic syndrome. It is, however, unclear as to the extent to which adipose tissue contributes quantitatively tothe elevated circulating levels of these factors in obesity and whether there is a generalised or local state of inflammation. The parsimo-nious view is that the increased production of inflammatory cytokines and acute-phase proteins by adipose tissue in obesity relates pri-marily to localised events within the expanding fat depots. It is suggested that these events reflect hypoxia in parts of the growingadipose tissue mass in advance of angiogenesis, and involve the key controller of the cellular response to hypoxia, the transcriptionfactor hypoxia inducible factor-1.
White adipose tissue: Adipokines: Inflammation: Obesity: Hypoxia: Cytokines: Acute phase proteins
White adipose tissue (WAT) is the main site of energy sto-
(Mohamed-Ali et al. 1998; Fru¨hbeck et al. 2001; Trayhurn
rage in mammals and birds, substrate being deposited as
triacylglycerols at a high energy density. Until the last
In the present article we consider one of the key recent
decade energy storage was seen as essentially the only
developments in the function of white fat, i.e. inflammation
role of white fat, apart from providing thermal and mech-
and the role of the tissue as a source of proteins character-
anical insulation. A revolution has occurred recently, how-
istic of the inflammatory response. Specific aspects of this
ever, in our understanding of the biological function of
area have also been addressed in other recent reviews
WAT; the tissue is now seen as a highly dynamic organ,
(Coppack, 2001; Fru¨hbeck et al. 2001; Rajala & Scherer,
being involved in a wide range of physiological and meta-
2003; Klaus, 2004). We consider first some important
bolic processes far beyond the paradigm of fuel storage.
issues of definition and nomenclature which we believe
This changed perspective has occurred through the recog-
require clarification and agreement.
nition that WAT is an endocrine organ; white adipocytessecrete several major hormones, most notably leptin and
Definitions: ‘adipokines’ not ‘adipocytokines’?
adiponectin, together with a diverse range of other proteinsignals and factors. This is in addition to the adipocytes’
As the number of protein signals recognised to be secreted
central role in the deposition and release of fatty acids
from adipose tissue rapidly increased it became helpful to
Abbreviations: CRP, C-reactive protein; HIF-1, hypoxia-inducible factor-1; , NGF, nerve growth factor; PAI-1, plasminogen activator inhibitor-1; SAA,
serum amyloid A; VEGF, vascular endothelial growth factor; WAT, white adipose tissue.
* Corresponding author: Professor Paul Trayhurn, fax þ 44 151 706 5802, email [email protected]
accord them a collective name. The term initially intro-
pre-adipocytes – whether primary culture or from clonal
duced was ‘adipocytokines’ (Funahashi et al. 1999), and
cell lines. Alternative approaches, which are more challen-
this has been used extensively. Although the name has
ging, include detection of the protein in the venous drai-
merit, it is potentially misleading since there is an infer-
nage from WAT at a concentration higher than in arterial
ence that the adipocyte-secreted proteins are cytokines, or
cytokine-like. While this is the case for some, such as
The initial stage in the identification of a candidate adi-
TNFa and IL-6, it is clearly not so with the majority.
pokine is frequently detection of the expression of a gene
The alternative name coined is ‘adipokines’, and this is
in adipose tissue, or in adipocytes differentiated in culture.
rather more satisfactory since it does not imply that the
Such a gene may encode either: (i) a product recognised to
proteins belong to a particular functional group. We there-
be secreted from other tissues (for example, IL-6), or (ii)
fore recommend that the term ‘adipokine’ be universally
reflect a protein found in the circulation, or (iii) if a
adopted to describe a protein that is secreted from (and
novel gene, the derived protein should contain a signal
sequence. When expression is first identified in adipose
Secretion is the critical characteristic of an adipokine,
tissue itself, it is essential to determine whether that
and we emphasise this since the term has also been used
expression occurs within mature adipocytes or in the
in connection with other adipocyte proteins such as adipo-
other cells that constitute the tissue, either histologically
nutrin (Wiesner et al. 2004), which is a transmembrane
(in situ hybridisation) or by separation of the adipocytes
protein rather than a secretory product. ‘Adipokine’ has
from the stromal vascular fraction by collagenase diges-
also been employed to describe a protein that is secreted
tion. Equally, expression in an adipocyte clonal line
by adipose tissue, rather than by adipocytes. However, it
needs to be verified for the native tissue. Gene expression
is preferable to restrict the term to those proteins that are
must, of course, be followed by detection of the encoded
released by adipocytes themselves. The principal reason
for this is that cells such as macrophages which also secrete
When a protein which is present in the circulation, or
protein signals are found in a number of organs, as well as
recognised to be secreted from other tissues, is synthesised
being present in adipose tissue (Weisberg et al. 2003; Xu
in adipocytes there is an a priori case for it being con-
et al. 2003). There is, therefore, a lack of specificity in
sidered an adipokine. Nevertheless, secretion from the adi-
giving the secreted proteins a special designation when
pocyte needs to be directly demonstrated before such a
such cells happen to be within fat depots, even though
protein should be accepted as a genuine adipokine.
their presence may well be of considerable functionalimportance.
There is also a question of whether the term adipokine
should be restricted to proteins released from white adipo-
The total number of adipokines, both documented and puta-
cytes, or include those secreted from brown adipocytes.
tive, is now well over fifty; the main functional categories
White and brown adipocytes are functionally different, of
are summarised in The earliest to be identified was
course, with the latter being specialised for the production
in practice the enzyme lipoprotein lipase, responsible for
of heat through the presence of the mitochondrial uncou-
the hydrolysis of circulating triacylglycerols to NEFA;
pling protein, UCP-1. In practice, no proteins appear to
this was followed in the mid 1980s by adipsin, a serine pro-
be secreted from brown adipocytes which are not also
tease and part of the alternative complement pathway
released by white fat cells, so in effect this may not be
(Cook et al. 1985, 1987). The key development which led
to the current focus on adipose tissue as a major site of
Given the current focus on ‘omic’ approaches in biology
the secretion of protein signals was, however, the discovery
(genome, transcriptome, proteome, metabolome/metabo-
in 1994 of leptin (Zhang et al. 1994). Leptin, which is a
nome), the totality of secreted proteins may be described
16 000 molecular-weight cytokine-like hormone with a
as constituting the adipokinome. Proteins are, however,
wide range of biological functions, established adipocytes
clearly not the only class of molecule secreted from adipo-
cytes. In addition to fatty acids, which quantitatively aremuch the largest secretory product, there are other lipidsubstances, including cholesterol, steroid hormones, prosta-glandins and prostanoids, and retinol (neither retinol norcholesterol are actually synthesised within adipocytes, butare stored and released). The lipid substances and adipoki-nome together can be said to constitute the ‘secretome’ ofthe adipocyte.
The identification of a protein as an adipokine requires thatsecretion from adipocytes be demonstrated. In practice, thiswill generally reflect selective release from adipocytes invitro. This may be either from freshly isolated adipocytes,or adipocytes derived by differentiation from fibroblastic
Fig. 1. Adipokines classified by functional role.
Role of white adipose tissue in inflammation
The diversity of the adipokines both in terms of
than adipose tissue, primarily the liver (and immune
protein structure and of putative function, is considerable
cells). The second explanation is that WAT is secreting
(Fru¨hbeck et al. 2001; Trayhurn & Beattie, 2001). The
factors that stimulate the production of inflammatory mar-
group includes: classical cytokines (e.g., TNFa, IL-6, IL-
kers from the liver and other organs; this may well be the
8), growth factors (e.g., transforming growth factor-b;
case with CRP, where it is argued that hepatic production
TGF-b) and proteins of the alternative complement
is stimulated by increased IL-6 from the expanded fat mass
system (e.g., adipsin, acylation-stimulating protein). The
of the obese (Yudkin et al. 2000; Yudkin, 2003). The third
group also includes: proteins involved in vascular haemo-
possibility is that adipocytes themselves are the immediate
stasis (e.g., plasminogen activator inhibitor-1 (PAI-1),
source of some, or most, of these inflammatory markers,
tissue factor), the regulation of blood pressure (angiotensi-
raised circulating levels in obesity reflecting production
nogen), lipid metabolism (e.g., retinol-binding protein,
from the increased WAT mass. There is also, of course,
cholesteryl ester transfer protein), glucose homeostasis
the possibility of there being a combination of production
(e.g., adiponectin, possibly resistin) and angiogenesis
(e.g., vascular endothelial growth factor; VEGF), as well
From the perspective of adipose tissue biology, a key
as acute-phase and stress responses (e.g., haptoglobin,
question is whether adipocytes (or adipose tissue) directly
contribute to the raised circulating levels of specific inflam-
From the wide range of protein signals and factors
matory markers and, if so, to what extent? Although
already identified, it is evident that WAT is a secretory
obtaining quantitative information on the contribution
and endocrine organ of considerable complexity which is
from particular cells within adipose tissue is difficult, the
highly integrated into the overall physiological and meta-
issue that can be readily addressed is whether adipocytes
bolic control systems of mammals. It is not easy to put for-
express certain inflammatory genes and their encoded pro-
ward a coherent framework for why such a diversity of
teins secreted. Recent reports demonstrating that WAT is
factors is secreted by white adipocytes. However, one
infiltrated by macrophages in obesity clearly suggest that
hypothesis would be that the various factors may relate
the non-adipocyte fraction may be a significant component
ultimately to the central lipid storage and release function
of the inflammatory state within adipose tissue (Weisberg
of the tissue (Trayhurn & Beattie, 2001). A corollary to
the secretion of such a wide range of adipokines is thatWAT has an extensive system for communication with
other tissues and organs. Co-culture studies have indicated,
Tumour necrosis factor-a and interleukin-6
for example, that adipocytes directly signal to other tissuessuch as skeletal muscle and the adrenal cortex (Dietze et al.
Several inflammatory cytokines are now recognised to be
2002; Ehrhart-Bornstein et al. 2003). There is also, in par-
expressed in, and secreted by, white adipocytes, the first
ticular, a distinct cross-talk between white adipocytes and
to be identified being TNFa (Hotamisligil et al. 1993).
the brain through leptin and the sympathetic nervous
TNFa expression in WAT was initially demonstrated in
system (Rayner & Trayhurn, 2001).
rodents, and found to be markedly increased in obesemodels (Hotamisligil et al. 1993). From this it was pro-posed that TNFa is linked to the development of insulin
resistance. The cytokine has been extensively examined
An important recent development in our understanding of
in relation to insulin action, and multiple effects have
obesity is the emergence of the concept that it (and dia-
been described, including the inhibition of the insulin
betes) is characterised by a state of chronic low-grade
receptor signalling pathway (Coppack, 2001; Hotamisligil,
inflammation (Yudkin et al. 1999; Das, 2001; Festa et al.
2003). In man, the secretion of TNFa is reported to be
2001; Engstro¨m et al. 2003). The basis for this view is
mainly due to the cells of the stromal vascular and
that increased circulating levels of several markers of
matrix fractions, including the macrophages, despite the
fact that previously most of the mRNA for TNFa was
acute-phase proteins, are elevated in the obese; these mar-
thought to be found within the adipocytes themselves
kers include IL-6, the TNFa system, C-reactive protein
(Weisberg et al. 2003; Fain et al. 2004a). An apparent
(CRP) and haptoglobin (Das, 2001; Bullo´ et al. 2003).
The implications in terms of the site of inflammation
human WAT is evident for several adipokines in recent
itself, whether systemic or local, are unclear. Nevertheless,
reports by Fain et al. (2004a,b) and requires further
it is increasingly evident that the inflammatory state may
be causal in the development of insulin resistance and
TNFa is a powerful local regulator within adipose
the other disorders associated with obesity, such as hyper-
tissue, acting in both an autocrine and a paracrine
lipidaemia and the metabolic syndrome (Hotamisligil,
manner to influence a range of processes, including apop-
2003; Yudkin, 2003). While the general assumption is
tosis (Prins et al. 1997; Coppack, 2001). There appears
that inflammation is consequent to obesity, it has been
to be a hierarchy of cytokines within WAT, with TNFa
suggested that obesity is in fact a result of inflammatory
playing a pivotal role in relation to the production of sev-
eral cytokines and other adipokines (Coppack, 2001). Thus,
A central question is the origin of the inflammatory mar-
for example, TNFa is a key regulator of the synthesis of
kers in obesity, and there are three possibilities. The first is
IL-6, of the acute-phase protein, haptoglobin (Chiellini
that it reflects production and release from organs other
et al. 2002; Oller do Nascimento et al. 2004), and of the
Fig. 2. Inflammatory and acute-phase response proteins secreted from adipocytes. The proteins in red have been clearly identified as adipo-kines (i.e. shown to be released by adipocytes) while those in blue are putative adipokines. CRP, C-reactive protein; IL, interleukin; NGF,nerve growth factor; PAI-1, plasminogen activator inhibitor-1; TGF-b, transforming growth factor-b; TNF-a, tumour necrosis factor-a; MCP-1,monocyte chemoattractant protein 1.
neurotrophin, nerve growth factor (NGF; Peeraully et al.
This cytokine stimulates the production of IL-6 and IL-8
2004). The extent to which TNFa produced in WAT is
from endothelial cells (Starnes et al. 2002). However, its
released into the circulation has been a matter of debate,
release from adipocytes has not been documented, so at pre-
but a relationship between the plasma TNFa system
sent it can only be considered as a putative adipokine.
(including the soluble receptors) and indices of obesityhas been reported (Bullo´ et al. 2003).
The other cytokine that has been the subject of major
interest in WAT is IL-6. It is expressed in, and secreted
There are a number of acute-phase proteins whose plasma
by, adipocytes and although it has local actions within
concentration increases substantially during the early
the tissue, it is released into the circulation (Mohamed-
stages of the inflammatory response, and a small number
Ali et al. 1997). Both plasma levels of IL-6 and expression
where the level falls (Gabay & Kushner, 1999). Several
in WAT are elevated in obesity and insulin resistance
of these proteins are now recognised as adipokines, with
(Mohamed-Ali et al. 1997; Bastard et al. 2000; Vozarova
adipose tissue being a potential contributor (either major
et al. 2001). It has been proposed that IL-6 has direct cen-
or minor) to the raised circulating levels in obesity;
tral actions, as IL-6 receptors are found in the hypothala-
mus in mice (Mohamed-Ali et al. 1997; Wallenius et al.
Expression of the genes encoding some acute-phase reac-
2002). As such, it is a candidate molecule for conveying
tants, such as a1-acid glycoprotein and 24p3, has been
information from adipocytes to the hypothalamus in the
observed in either adipocyte cell culture or in murine tis-
regulation of energy balance, additional to leptin.
sues (Soukas et al. 2000; Lin et al. 2001), but secretionas such has not yet been reported.
Although there has been considerable focus on TNFa and
IL-6, several other cytokines and related factors are syn-
PAI-1 is an important factor in the maintenance of vascular
thesised within adipose tissue, including IL-1b, TGF-b
haemostasis, inhibiting the activation of plasminogen, the
and, of course, leptin. Recent reports have included IL-8,
precursor of plasmin, which is involved in the breakdown
IL-10 and IL-17D. The IL-8 gene is expressed in human
of fibrin (Mutch et al. 2001). The expression and secretion
adipocytes and the protein released from both fat cells
of PAI-1 by adipocytes, both rodent and human, is well
and adipose tissue fragments (Bruun et al. 2000, 2001).
documented (Lundgren et al. 1996; Eriksson et al. 1998;
IL-1b and TNFa stimulate IL-8 release, while dexametha-
Cigolini et al. 1999; Mutch et al. 2001). The circulating
sone is inhibitory (Bruun et al. 2001). As with IL-6, the
level of PAI-1 is increased in obesity and synthesis in
plasma level of IL-8 is increased in obesity (Straczkowski
WAT is also raised (Alessi et al. 2000). This has led to
the view that adipose tissue is the major source of the ele-
Circulating levels of IL-18 are also increased in obesity
vated PAI-1 levels in the obese (Lundgren et al. 1996;
and fall with weight reduction (Esposito et al. 2002). As a
Samad et al. 1996; Alessi et al. 2000). As the risk of
consequence, it is speculated that WAT is a probable site
atherothrombotic disease is increased in obesity, this is a
of production of IL-18. Although there are no published
potent example of how the co-morbidities, such as diabetes
reports on this, we have recently observed IL-18 gene
and cardiovascular risk, associated with a high body fat can
expression in human WAT (IS Wood and P Trayhurn, unpub-
be directly linked to alterations in the production of
lished results). Similarly, the levels of IL-10, an anti-inflam-
specific adipokines. In addition to its role in haemostasis,
matory cytokine, are also raised in the obese (Esposito et al.
PAI-1 is also an acute-phase response protein, the levels
2003); the secretion of IL-10 from human adipocytes, as well
rising in inflammation (Gabay & Kushner, 1999).
as from the stromal vascular fraction and tissue matrix ofhuman fat depots, has been reported (Fain et al. 2004b).
The expression of IL-17D, believed to be the last member
of the IL-17 family to be identified, has recently been
Several studies have now reported that the haptoglobin
described in (human?) adipocytes (Starnes et al. 2002).
gene is expressed in murine adipose tissue (Friedrichs
Role of white adipose tissue in inflammation
et al. 1995; Chiellini et al. 2002; Oller do Nascimento et al.
(IS Wood and P Trayhurn, unpublished results). It should
2004). Similarly, gene expression has also been shown in
be noted that murine CRP is not regarded as an acute-
human WAT (Oller do Nascimento et al. 2004). A very
phase protein due to its very low expression (Volanakis,
recent study has demonstrated direct release of haptoglobin
from human adipose tissue explants (Fain et al. 2004a) and
Very low levels of expression would suggest that adipo-
release of haptoglobin into the medium has been observed
cytes are unlikely to be a significant direct contributor to
in 3T3-L1 adipocytes by a proteomic approach (Kratch-
circulating CRP levels. However, IL-6 is secreted by adi-
marova et al. 2002). Both transgenic studies and studies
pose tissue in increased amounts in obesity, as noted ear-
on 3T3-L1 adipocytes indicate that TNFa is a key factor
lier, and this is the major cytokine regulating the hepatic
in the stimulation of haptoglobin expression (Chiellini
production of CRP (Heinrich et al. 1990; Yudkin et al.
et al. 2002; Chinetti et al. 2003; Oller do Nascimento
2000). Thus WAT may be a major player in the raised cir-
et al. 2004), with IL-6 also being stimulatory.
culating levels of CRP in obesity, but through the indirect
Stimulation of the PPARg nuclear receptor through the
administration of the thiazolidienedione, rosiglitazone,strongly inhibits haptoglobin gene expression (Oller do
Nascimento et al. 2004). This is consistent with the emer-ging view that PPARs have substantial anti-inflammatory
There are several other adipokines involved in the inflam-
actions (Moller & Berger, 2003). Indeed, several other
matory response that are neither cytokines nor acute-phase
inflammation-related adipokines are down regulated by
proteins. Interestingly, adiponectin (also known as Acrp30,
PPARg ligands, including TNFa, leptin and NGF, while
AdipoQ, ApM1 or GBP28), which is synthesised only in
there is evidence that adiponectin is up regulated (Moller
adipose tissue, appears to have an anti-inflammatory
effect, inhibiting phagocytic activity and TNFa productionin macrophages (Ouchi et al. 1999; Yokota et al. 2000).
This adipokine is now very much centre stage; this is
partly because, in contrast to many other adipokines, its
Serum amyloid A (SAA), the precursor to amyloid A pro-
expression and release fall in obesity (Arita et al. 1999;
tein found in secondary amyloid plaques, consists of a
Hotta et al. 2000). However, the principal reason for the
family of apolipoproteins which bind to, and substitute
recent focus on adiponectin is the evidence that it is
for, apo A-I in HDL. These apolipoproteins are expressed
involved in modulating insulin sensitivity (Berg et al.
as either major acute-phase reactants SAA, or constitutive
2001; Yamauchi et al. 2001), as well as having anti-athero-
SAA, the functions of which are largely unknown. How-
geneic properties (Engeli et al. 2003).
ever, a few clinically important functions have been
We have recently observed that the target-derived neuro-
suggested that include pro-inflammatory and anti-inflam-
trophin, NGF, is synthesised by the main adipose tissue
matory roles. A number of genes have now been identified
depots in both rodents and man, and is secreted from
in man and mice which share very similar sequence iden-
white adipocytes (Peeraully et al. 2004). This protein,
tities and genomic organisation (Uhlar & Whitehead,
which was the first of the family of neurotrophins to be dis-
1999). These genes are up regulated by pro-inflammatory
covered, was originally linked to the growth and survival
cytokines such as TNFa and IL-6, as well as by glucocor-
of sympathetic neurones; however, although not a cyto-
ticoids. The expression of SAA, as with other acute-phase
kine, it is now recognised as also being involved in
reactants, is predominantly in the liver. However, extrahe-
immune and inflammatory responses (Levi-Montalcini
patic expression of SAA, including adipocytes, has been
et al. 1996; Vega et al. 2003). Indeed, NGF is expressed
reported; expression and release of SAA3 occurs in
in adipocytes specifically associated with wound healing
murine adipocytes, and this is up regulated under hypergly-
and with atherosclerotic lesions (Hasan et al. 2000; Chal-
caemic conditions (Lin et al. 2001).
dakov et al. 2001). Importantly, TNFa has a strong stimu-latory effect on NGF gene expression and NGF releasefrom 3T3-L1 adipocytes, suggesting that the neurotrophin
is an inflammatory response protein in adipose tissue (Peer-
The circulating level of CRP rises with BMI (Visser et al.
1999; Pannacciulli et al. 2001; Bullo´ et al. 2003), and elev-ated levels of this inflammatory marker have been associ-
Why inflammation in obesity: a response to hypoxia?
ated with both obesity and diabetes, falling with weightloss (Tchernof et al. 2002). There is evidence from a
Much attention has been directed towards unravelling the
study using real-time PCR that the gene encoding CRP is
pathological and clinical implications of inflammation in
expressed in adipose tissue, an inverse correlation between
obesity, and establishing the links with insulin resistance
the levels of the mRNA for CRP and adiponectin being
and other metabolic disorders – the metabolic syndrome.
apparent (Ouchi et al. 2003). This raises the possibility
However, a central issue is why does WAT release pro-
that adipose tissue contributes directly to the circulating
inflammatory cytokines and acute-phase proteins, and why
pool of CRP. Unfortunately, it is not clear whether CRP
do these rise sharply as fat mass increases? Linked to this
expression in adipocytes is in practice significant; our
is the question of why obesity should be associated
own studies using conventional RT-PCR have found that
with chronic low-grade inflammation. Adipose tissue may,
there is little expression in human WAT, or adipocytes
of course, be contributing inflammation-related factors
to a specific site of inflammation in an organ (or organs)
occurs in both the adipocytes and in the stromal vascular
elsewhere, or as part of a systemic state of inflammation.
cells, and in the WAT of obese (ob/ob) mice the level of
However, an alternative view is that the inflammatory
the mRNA is markedly increased compared with lean sib-
state is mainly within WAT itself. If the inflammatory
lings (L Hunter, IS Wood and P Trayhurn, unpublished
response is primarily local to adipose tissue, at least in
results). Thus a link between the increased WAT mass in
terms of its initiation, then the elevated circulating levels
obesity, adipocyte hypoxia, inflammation and the stimu-
of inflammation-related products may in effect reflect spil-
lation of angiogenesis is plausible.
lover from the tissue, and the link with insulin resistancewould be an incidental consequence.
In the absence of any specific indication to the contrary,
the parsimonious view is that the secretion of inflammatory
We have focused in the present paper on the role of WAT
cytokines and acute-phase proteins by adipocytes in obesity
in inflammatory responses. There have, however, been a
relates to events within WAT itself. If this is correct, what
number of other important recent developments in the adi-
could be the rationale for a local effect? A possible expla-
pokine field. For example, a recent report has indicated that
nation is that it is a response to hypoxia in areas of the fat
human white adipocytes secrete mineralocorticoid-releas-
depots as the tissue mass increases during the progressive
ing factors, aldosterone secretion by adrenocortical cells
development of obesity. The sequence of events might be
being stimulated (Ehrhart-Bornstein et al. 2003). These
that as the tissue expands, the vasculature (which is less
results indicate a direct link between obesity and hyperten-
extensive in WAT than in brown fat) is insufficient to main-
sion through adipose tissue regulating mineralocorticoid
tain normoxia throughout the organ. Clusters of adipocytes
then become relatively hypoxic, and an inflammatory
There is continuing interest in whether adipocytes
response ensues which serves to increase blood flow and
secrete centrally acting signals in the regulation of appetite
to stimulate angiogenesis. This has some parallels with
and energy balance additional to leptin, as noted earlier. An
tumour growth in cancer. That vascular development is an
initial candidate for such a role was fasting-induced adi-
important issue in WAT function is indicated by the fact
pose factor (also known as PPARg angiopoietin-related
that adipose tissue mass is sensitive to angiogenesis inhibi-
gene) (Kersten et al. 2000; Yoon et al. 2000). Fasting-
tors and can be regulated by its vasculature (Rupnick et al.
induced adipose factor is an angiopoietin-related protein,
2002), and that several angiogenic factors are secreted by
the expression of which is strongly stimulated by fasting
adipocytes (Claffey et al. 1992; Rupnick et al. 2002; Lol-
in a manner which may be reciprocal to leptin. Fasting-
mede et al. 2003). These factors include recognised angio-
induced adipose factor is potentially of considerable inter-
genic signals (VEGF, PAI-1 and leptin), as well as
est, not only as a putative signal in energy balance, but as
putative signals such as metallothionein and haptoglobin.
part of the adaptive response to nutritional deprivation. In
A pivotal signal in the cellular response to hypoxia is
this regard, since it is induced by fasting, it is a positive
signal of the fasted state, in contrast to leptin which signals
factor is a heterodimeric protein consisting of a and b sub-
food deprivation through a reduction in its expression
units. The b subunit is constitutively expressed, but the a
subunit is highly induced by hypoxia leading to the formation
An intriguing report using DNA microarrays for gene
of functional HIF-1 (Semenza, 2001; Wenger, 2002; Ho¨pfl
expression profiling of human visceral adipose tissue has
et al. 2004). Hypoxia is characteristic of tumours, where
suggested that a constellation of neuroendocrine factors
HIF-1 expression is increased, as well as in other disorders
may be produced by white adipocytes (Yang et al. 2003).
such as ischaemic heart disease (Binley et al. 2003; Ho¨pfl
These factors included cholecystokinin, neurotensin and
et al. 2004). A number of genes are regulated by HIF-1,
neuropeptide Y. If correct, it suggests that the adipocyte
which acts as a central controller of oxygen-regulated gene
is even more remarkable as a secretory cell than currently
expression. The transcription factor is stabilised and its
envisaged; indeed, it would be a veritable powerhouse in
expression stimulated by cytokines such as TNFa and IL-
the secretion of neuroendocrine signals. However, our
1b (Hellwig-Bu¨rgel et al. 1999). The target genes for HIF-
attempts to identify transcripts of some of these genes
1 include VEGF and PAI-1 (Ho¨pfl et al. 2004). In addition,
using conventional RT – PCR have proved unsuccessful
there is now evidence for the transcriptional activation of
(L Hunter, IS Wood and P Trayhurn, unpublished results),
leptin through HIF-1a in response to hypoxia (Ambrosini
and the reported expression may in practice reflect the pro-
blems inherent in setting a suitable (arbitrary) threshold in
Immunoreactive HIF-1a has been reported in 3T3-
microarray studies when comparisons between groups are
F442A adipocytes and hypoxia results in an increase in
not part of the experimental paradigm.
the amount of the protein in the cultured cells (Lolmedeet al. 2003). Furthermore, hypoxia leads to an induction
of leptin and VEGF expression in these adipocytes, raisingthe likelihood that a low oxygen tension leads to the stimu-
The biology of WAT seems ever more rich and complex.
lation of angiogenesis in adipose tissue through the HIF-1
The family of adipokines is increasing rapidly, these
proteins being highly diverse in structure and in function.
HIF-1a expression is not just a feature of cultured adipo-
A critical issue is the physiological role that many of
cytes, since we have recently observed that the HIF-1a
them play. The role may be local (through an autocrine
gene is expressed in mouse WAT depots. Expression
or paracrine function) or endocrine, or involve multiple
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LEA DETENIDAMENTE ESTE DOCUMENTO Y TENGA EN CUENTA LAS ORIENTACIONES ANTES DE ACUDIR A LA CONSULTA PRE-OPERATORIA DEL HOSPITAL DE OJOS DEBE MOSTRARLE A SU MÉDICO TRATANTE ESTE DOCUMENTO Y SI TIENE ALGUNA DUDA SE PUEDE COMUNICAR CON LA COORDINACIÓN QUE LE CORRESPONDA. ASPECTOS GENERALES: Es importante que sepa que usted no acude a operarse, sino a una evaluación pre-opera
GENEESMIDDELEN EN RIJVAARDIGHEID R.A. Bredewoud Hoofd medische zaken CBR Postbus 3014, 2280 GA Rijswijk Inleiding Het Centraal Bureau Rijvaardigheidsbewijzen (CBR) is als organisatie vooral bekend vanwege het toetsen van de rijvaardigheid: het rijexamen. Daarnaast toetst de afdeling Medische Zaken sinds 1951 echter ook de rijgeschiktheid: de lichamelijke en geestelijke geschiktheid