Clinical Science (2005) 109, 243–256 (Printed in Great Britain) doi:10.

1042/CS20050078 243

R E V I E W

Role of resistin in obesity, insulin

resistance and Type II diabetes

Christine M. KUSMINSKI, Philip G. MCTERNAN and Sudhesh KUMAR

Diabetes and Metabolism Research Laboratory, Clinical Sciences Research Institute, UHCW Trust, Clifford Bridge Road,
Walsgrave, Coventry CV2 2DX, U.K.

A B S T R A C T

Resistin is a member of a class of cysteine-rich proteins collectively termed resistin-like mol-

ecules. Resistin has been implicated in the pathogenesis of obesity-mediated insulin resistance and
T2DM (Type II diabetes mellitus), at least in rodent models. In addition, resistin also appears to
be a pro-inflammatory cytokine. Taken together, resistin, like many other adipocytokines, may
possess a dual role in contributing to disease risk. However, to date there has been considerable
controversy surrounding this 12.5 kDa polypeptide in understanding its physiological relevance in
both human and rodent systems. Furthermore, this has led some to question whether resistin
represents an important pathogenic factor in the aetiology of T2DM and cardiovascular disease.
Although researchers still remain divided as to the role of resistin, this review will place available
data on resistin in the context of our current knowledge of the pathogenesis of obesity-mediated
diabetes, and discuss key controversies and developments.

INTRODUCTION factors leading to diabetes, as such, the expression and

Adipose tissue is known to produce a vast array of adipo-
cyte-derived factors, known as adipocytokines. Under
‘normal’ physiological conditions adipocytokines may
play an influential role in energy homoeostasis, tri-
acylglycerol (triglyceride) storage and mobilization of fat,
with increased adiposity, specifically central adiposity.
These processes can be substantially dysregulated [1].
Furthermore, it seems apparent that the pathogenesis of
T2DM (Type II diabetes mellitus) is mediated through
the concurrent progression of insulin resistance and sub-
clinical inflammation, although the molecular mechan-
isms for this are less understood. It is, however, apparent
that obesity represents one of the foremost contributory
functional properties of adipocytokines and their effects
on metabolism have been the subject of intense research.
Indeed, studies on adipocytokines and their potential
effects in human obesity and T2DM have implicated them
in the pathogenesis of the metabolic syndrome. Such
factors include TNF-α (tumour necrosis factor-α), IL
(interleukin)-6, angiotensinogen, leptin, PAI-1 (plas-
minogen activator inhibitor-1) and resistin (Table 1).
This review will address our current understanding of
the pathophysiological role of resistin, and evaluate re-
sistin as a pathogenic factor implicated in metabolic and
inflammatory mechanisms leading to diabetes. In ad-
dition, we will highlight the continuing complexity of the
biology of resistin and its role in the progression of

Key words: adipocytokine, inflammation, insulin resistance, obesity, resistin, Type II diabetes.
Abbreviations: BMI, body mass index; CAC, coronary artery calcification; CRP, C-reactive protein; CVD, cardiovascular
disease; ET-1, endothelin-1; HMM, high-molecular-mass; ICAM-1, intercellular cell-adhesion molecule-1; IL, interleukin; LMM,
low-molecular-mass; LPS, lipopolysaccharide; NF-κB, nuclear factor κB; PAI-1, plasminogen activator inhibitor-1; PBMC,
peripheral blood mononuclear cell; PPAR-γ , peroxisome-proliferator-activated receptor-γ ; PPRE, PPAR-γ -response element;
PTX3, pentraxin 3; RELM, resistin-like molecule; RSG, rosiglitazone; SNP, single nucleotide polymorphism; SOCS, suppressor of
cytokine signalling; sTNF-R2, soluble TNF-receptor 2; T2DM, Type II diabetes mellitus; TNF-α, tumour necrosis factor-α; TZD,
thiozolidinedione; VCAM-1, vascular cell adhesion molecule-1; WAT, white adipose tissue.
Correspondence: Professor Sudhesh Kumar (email sudhesh.kumar@warwick.ac.uk).

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244 C. M. Kusminski, P. G. McTernan and S. Kumar

Table 1 Summary of factors implicated in the pathogenesis of obesity-related T2DM

AGT, angiotensinogen; AT, adipose tissue; BAT, brown AT; Om, omental; Sc, subcutaneous; TGF-β, transforming growth factor-β.

Molecule Function/effect Normal distribution Effect of obesity References

Leptin Satiety and appetite; signals to
the brain to regulate energy
homoeostasis and body weight.
TNF-α Reduces insulin secretion and
insulin signalling in AT, pancreatic
cells, liver and muscle.
IL-6 Affects glucose and lipid
metabolism; improves insulin
sensitivity and glucose tolerance;
has anti-inflammatory properties.
PAI-1 Potent inhibitor of the fibrinolytic
pathway.
AGT Precursor of angiotensin II;
regulator of blood supply and
induces differentiation of
pre-adipocytes.
Adiponectin Regulator of energy
homoeostasis: enhances
insulin sensitivity and glucose
uptake; has anti-inflammatory
properties.
TGF-β Varied role in proliferation,
differentiation, apoptosis and
development.
PPAR-γ Regulates adipose cell
differentiation.
Ghrelin Implicated in the coordination
of energy balance and weight
regulation.
Adiponutrin Possible contribution to energy
homoeostasis, vesicular targeting
and protein transport.
Secreted by WAT, BAT, skeletal
muscle, stomach and placenta;
2.5 times more leptin in Sc AT than
Om AT; more leptin in adipocytes
than pre-adipocytes.
Predominant in adipocytes in
WAT; 1.67 times more TNF-α
in Sc AT compared with Om AT
35 % of the basal supply is derived
from WAT; produced by macrophages,
fibroblasts, endothelial cells and
skeletal muscle cells.
Correlation with abdominal adiposity;
pattern of adipose tissue distribution:
mRNA greater in Om AT than Sc AT
Exclusively secreted by adipocytes.
mRNA and protein greater in Sc AT
than Om AT.
Multifunctional, produced by
variety of cells; inhibitor of
differentiation.
Sc adipocytes = Om adipocytes
(BMI < 28 kg/m2 )
Secreted by endocrine cells in the
gastrointestinal tract.
Non-secreted adipocyte protein.
Expressed exclusively in inguinal and
epididymal WAT and in interscapular
BAT.
↑In human obesity and correlates [38,112–114]
with BMI, and ↓after fasting or
weight loss.
Correlates with BMI, ↑ in human [112,115–120]
obesity; 2-fold increase in obese
compared with lean subjects; ↑
in a rodent model of obesity; ↓
adipose differentiation.
↑ In morbidly obese patients, [38,121–125]
↓ after weight loss.
↑ In humans leads to ↑ thromboembolic [126]
complications.
↑ In humans. [127,128]
↓ In mouse models of obesity and [76,78,103,129–131]
insulin resistance (ob/ob and db/db );
↓ in human obesity and T2DM;
↑ after weight loss.
↑ob/ob obese and db/db mice; ↑ in [132]
pre-adipocyte cell proliferation,
as with ↑ in TNF-α.
↑ In Sc WAT 2 times greater than in [133,134]
Om WAT (BMI < 30 kg/m2 )
↑ In human obesity and T2DM. [38,135–140]
↑ Circulating levels after chronic
weight loss in humans.
↑ mRNA (50-fold) in obese fa/fa rats; [141–143]
↓ fasting mRNA levels; human gene
expression may be regulated by
changes in energy balance.

disease and the potential interplay between several mech-
anisms associated in the pathogenesis of T2DM. Since
the discovery of resistin in 2001, there have been over 260
publications that have informed our present understand-
ing of its function. This has paradoxically created a mael-
strom of controversy and ambiguity surrounding the
functional significance of resistin. Indeed, researchers
outside the field of resistin over the last few years have
been unclear as to whether this molecule may deserve
much attention as an important pathogenic factor in the
progression of obesity-mediated diabetes. Nevertheless,
although several questions remain unanswered to date
regarding resistin, one question remains pertinent to all
others, what is the precise physiological function of res-
istin? Although this is not necessarily an easy question to
answer and this review may only highlight some aspects
of resistin in disease, it is clear that the physiological role
of resistin is more complex than originally envisioned.
Despite an incomplete current understanding of the
role of resistin, this review will assemble and discuss
the existing literature on resistin to evaluate the cur-
rent metabolic, inflammatory and cardiovascular effects
of this protein, with the intent of providing an insight as
to where the role of resistin may lie.

C 2005 The Biochemical Society

Figure 1 Ribbon diagram representations of resistin
(A) Monomeric structure of resistin, whereas (B) shows its hexameric form com-
prising of two disulphide-linked trimers. (C) Highly exposed interchain disulphide
linkages present in the hexameric form of resistin. Reprinted (abstracted/excerpted)
with permission from Patel, S. D., Rajala, M. W., Rossetti, L., Scherer, P. E. and
Shapiro, L., Disulfide-dependent multimeric assembly of resistin family hormones,
Science 304, 1154–1158.
c (2004) AAAS (www.sciencemag.org).
THE DISCOVERY OF RESISTIN
Resistin, a putative adipocyte-derived signalling poly-
peptide, was originally identified by three independent
groups using a variety of techniques [2–4]. Initial studies
showed that resistin was up-regulated in rodent models
of obesity and insulin resistance and down-regulated
by an insulin-sensitizer, RSG (rosiglitazone) [3]; however,
immunoneutralization of resistin reduced hypergly-
caemia and improved insulin sensitivity [3]. These
observations not only brought resistin to much scientific
attention, but characterized it as a potential aetiological
link between obesity and diabetes, with a clear functional
role as a pathogenic factor contributing to insulin
resistance. Additionally, this revealed possibilities of the
mechanistic action for TZDs (thiozolidinediones) and
their subsequent therapeutic applications.
THE STRUCTURE OF RESISTIN
Studies determined the resistin gene, referred to as Retn,
encoded a 114-amino acid polypeptide [3], secreted as a
disulphide-linked homodimer [5]. Recent X-ray crystal-
lographic studies of resistin [6] have determined its com-
plex hexameric structure (Figure 1). Resistin was shown
to circulate in two distinct assembly states; the more pre-
dominant HMM (high-molecular-mass) hexamer and
the substantially more bioactive LMM (low-molecular-
Role of resistin in obesity, insulin resistance and Type II diabetes 245
mass) complex, which is unable to form intertrimer
disulphide bonds [6]. This implied that regulated pro-
cessing through disulphide cleavage is required to initiate
bioactivity of the LMM form, and suggested further a
potential target site for receptor interaction [6].
TISSUE DISTRIBUTION OF RESISTIN AND
OTHER RELM (RESISTIN-LIKE MOLECULE)
FAMILY MEMBERS
Resistin belongs to a family of cysteine-rich proteins,
termed RELMs, which include RELM-α/FIZZ 1,
RELM-β/FIZZ 2 and the recently discovered RELM-γ ,
with each member having an unique differential tissue
distribution [2,7,8]. Resistin expression was first de-
scribed in adipose tissue [3], with circulating levels
detected in rodents and humans [9–12]. Our present
knowledge of the expression of resistin and RELM-α, -β
and -γ in human and rodent tissues is shown in Table 2.
Although the expression of resistin in mice was
originally restricted to adipocytes [3], the principle origin
of human resistin has remained somewhat contentious.
Unlike the mouse gene, the human homologue of re-
sistin was sparsely detectable in human adipocytes [13];
this was confounded further by confusion over the pro-
posed sites of resistin production [13–15]. These studies
led to many of the current perceptions that resistin was
an inconsequential factor in the progression of obesity-
related T2DM, thereby contrasting rodent data. Con-
versely, McTernan et al. [16] detected resistin in adipose
tissue, thus describing resistin as a potential pathogenic
factor increased in central adiposity. The discrepancy
between studies may have partially related to method-
ology of detection or quantification of resistin. How-
ever, to date, although a difference in resistin mRNA
levels between adipocytes and macrophages is apparent
[14,17,18], studies have not yet identified whether this
difference is observed at the protein level. Determining
the relative contribution of the adipocyte in obesity with
regards to circulating resistin levels would also prove
beneficial.
HOMOLOGY OF HUMAN AND RODENT
RESISTIN
Although four genes for the family of RELMs have been
identified in mice, only two homologues have been id-
entified in the complete human genome [7,8]. Re-
cently, an alternatively spliced variant of the Retn gene
was identified in humans (resistin 2) [19], and
another was identified in rats, termed ‘S-Resistin’ (short
resistin) [20].
The human Retn gene is located on chromosome 19
in a region syntenic to the mouse Retn gene on chromo-
some 8. In relation to this, one group posed the view that


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246 C. M. Kusminski, P. G. McTernan and S. Kumar

Table 2 Distribution of mRNA and protein expression of resistin and RELM-β in rodents and humans, and RELM-α and
RELM-γ in rodents
R, mRNA expression; P, protein expression.

Resistin RELM-β RELM-α RELM-γ

Rodent Human Rodent Human Rodent Rodent

Tissue R P R P R P R P R P R P References

WAT × × × × × × [3,7,8,16,18,19,23,25,86,144,145]
Pre-adipocytes × × × [14,25]
Adipocytes × × × × [3,15,25,29]
Mononuclear blood cells × × [8,13,15,17,68,86,88]
Hypothalamus × × [19,145,146]
Pituitary gland × [145,146]
Adrenal gland × × [19,72]
Spleen × × × [8,19,147]
Skeletal muscle × × × [19,72,148]
Pancreas × × × [19,149]
Placenta × × [7,19,150]
Gastrointestinal tract × × × × × × × [7,8,19,29,72]
Lung × × × × × [2,7,8,19,29]

explain such diverse expression and regulatory patterns

of this protein, or simply suggest resistin may not be
evolutionary well conserved across species.

THE METABOLIC ROLE FOR RESISTIN:

Figure 2 Amino acid sequence identities of rodent, porcine
and bovine resistin, other RELM family members and the
recently identified human alternatively spliced variant of
resistin, resistin 2
Percentage sequence identities were obtained from the EMBL-EBI (European Bioin-
formatics Institute) server (http://www.ebi.ac.uk). The different colours represent
the different RELM family members. b, bovine; h, human, p, porcine; r, rodent.
orthology existed between human and mouse genes [21],
whereas another questioned the relevance of resistin, due
to the absence of a true homologue for the murine Retn
gene in humans [22]. Contrasting opinions regarding the
orthology may relate to how genomic, transcribed and
translated sequence identities are viewed. However, it
is evident that human and mouse resistin have diverse
genomic organizations [22]. Moreover, at the protein
level, human resistin is only 55 % identical with its
murine counterpart (Figure 2), and this could, in part,
AN ONGOING DEBATE
Resistin and obesity
Initial observations
Since the initial investigation of resistin in numerous
rodent models of obesity and insulin resistance [3,23,24],
ongoing experimental data has generated further in-
consistency. Human studies have highlighted increased
resistin expression in adipose tissue [15], particularly
abdominal depots [16,25]; furthermore, positive correl-
ations between serum resistin and body fat content have
also been reported [26]. On the contrary, several studies
have failed to demonstrate such correlations in rodents,
with groups also reporting either reduced [27–30]
or no alteration [31,32] of resistin levels in various
models of obesity. Although it is difficult to address such
diverse findings using similar, and in some instances the
same, rodent models, inconsistencies may depend upon
methodological differences [18]. The following sections
will review cases for and against the role for resistin as an
important pathogenic factor in obesity, insulin resistance
and T2DM in light of recent studies.
Recent observations supporting a role for resistin in obesity
Studies by Lee et al. [33] showed that various murine
models of obesity had higher circulating resistin levels

C 2005 The Biochemical Society

compared with their lean counterparts. These obser-
vations coincided with rodent studies by Rajala and co-
workers [34], showing circulating resistin levels were
significantly elevated and concordant with increasing
levels of insulin, glucose and lipids; thus substantiating
the initial evidence that addressed the aetiology of resistin
with increasing adiposity [3]. Recently, Asensio et al.
[35] determined that high-fat-fed mice had induced
adipocyte differentiation, denoted by fatty acid binding
protein (AP-2) gene expression, a surrogate marker of
differentiation, which positively correlated with resistin
gene expression. Subsequently, in view of this and previ-
ous studies [4,36], it was suggested that elevated resistin
expression was a result of adipocyte differentiation [35].
Moreover, the increase in adipocyte number may have
caused a rise in local resistin production, inhibiting insulin
action on glucose uptake in adipose tissue and, thus, pre-
venting further adipocyte differentiation [35]. Therefore,
at least in rodents, a regulatory feedback mechanism
for resistin in adipogenesis may occur, acting as an adi-
pose sensor for nutritional status. In accordance with
these observations, Kim et al. [37] generated transgenic
mice overexpressing a dominant inhibitory form of re-
sistin which functioned to block the inhibition of resistin-
mediated adipocyte differentiation. These transgenic mice
developed obesity, possibly owing to enhanced adipocyte
differentiation and adipocyte hypertrophy, as indicated
by increased circulating levels of adiponectin and leptin
[37].
Recent investigations of human resistin in relation to
obesity have shown higher serum resistin levels in obese
subjects compared with lean subjects [38–40], which
positively correlated with the changes in BMI (body mass
index) and visceral fat area [11,40–42]. The implication
that resistin is important in human adipose tissue has
been corroborated by studies showing increased protein
expression with obesity [40], as well as protein secretion
from isolated adipocytes [43]. These recent observations
are concomitant with initial studies that showed increased
serum resistin levels [26] and gene expression levels in
abdominal depots [16,25] in states of increased adiposity.
A further study has shown a significant reduction in
circulating resistin levels following moderate weight loss
[12] and post-gastric bypass [38]. Collectively, these ob-
servations suggest resistin could indirectly be subjected
to nutritional regulation in humans.
Observations that argue against a major role for resistin
in obesity
Contrary with the studies suggesting a role for resistin in
obesity, Maebuchi et al. [44] have reported resistin was
undetectable in serum of obese mice, with the same study
indicating reductions of resistin mRNA and protein
expression in obesity. Others have reported no associ-
ation of resistin expression with increased adiposity, de-
spite observing elevated circulating levels [33–35]. How-
Role of resistin in obesity, insulin resistance and Type II diabetes 247
ever, it has been suggested recently that resistin mRNA
expression does not necessarily correlate with protein ex-
pression [34]. Possible explanations for such diverse
observations include differences in post-transcrip-
tional and post-translational modifications, consequently
affecting secretory rates of resistin. Increased serum levels
may enhance transcript degradation rates via negative
feedback mechanisms, or the initiation and recruitment
of inhibitors of translation. The secreted form of resistin
is considered to have paracrine properties, and this
may imply the majority of regulation occurs at the
protein level. Similarly, Rajala and co-workers [34]
have suggested that binding of serum cofactors to the
resistin protein may prolong its half-life, thereby reduc-
ing clearance; this hypothesis is supported by studies
showing protein interactions and tertiary alterations can
influence adipocytokines, such as leptin and TNF-α
[45–47]. Indeed, these studies demonstrate the limit-
ations of attempting to derive all necessary inform-
ation regarding resistin and obesity from gene expression
studies.
Further recent human studies have shown no cor-
relation of serum [48] or plasma levels of resistin with
any markers of adiposity [49]. Heilbronn et al. [50] re-
ported no relationship between resistin serum levels and
percentage body fat, visceral adiposity and BMI. How-
ever, the authors [50] suggested that the lack of correlation
of serum resistin and increased adiposity was partly due
to the confounding variable of age, as non-obese sub-
jects were significantly younger than obese subjects [50].
Another study showed similar levels of resistin expressed
in gluteal femoral and subcutaneous abdominal depots in
non-diabetic subjects [51]. However, no indication of the
number of ‘gluteal’ subjects compared with ‘abdominal’
subjects was given. Moreover, the study used a high pro-
portion of male subjects and, as previous studies had
shown resistin to exhibit sexual dimorphism, with women
having approx. 20 % higher levels than men [42,48,49],
this may explain these findings.
Although a high degree of discrepancy has emerged
from publications regarding the association of resistin
with obesity in the context of mRNA and serum levels,
it is worth highlighting the importance of developing
highly accurate methods of determining serum resistin
concentrations. Methodological limitations may result in
variations among serum concentrations, mRNA and pro-
tein levels, or may simply indicate that resistin does not
play a significant role in the pathophysiology of obesity-
mediated insulin resistance. However, with reference to
the use of commercially available ELISAs, both rodent
and human ELISAs have potential to cross-react with
circulating RELMs. To date, not all studies using resistin
ELISAs have assessed RELM cross-reactivity prior to
analysis; therefore it may be that different ELISAs
used may provide varying serum concentrations [52–55].
Similarly, assessment of serum resistin in rodents has


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248 C. M. Kusminski, P. G. McTernan and S. Kumar
proved contentious [33,34]. Furthermore, due to recent
advances in the understanding of the tertiary and quatern-
ary structure of resistin [6], further studies are required
to establish whether the complex distribution of the
individual structural forms of resistin affect the validity
of the currently available human and rodent assays.
Resistin, insulin resistance and T2DM
It is currently established that central obesity is a
contributing factor to the pathogenesis of insulin resist-
ance and consequently to T2DM. Although it is apparent
that inconsistencies remain in the data for a role of resistin
in obesity, there is a growing body of evidence suggesting
a role for resistin in the aetiology of insulin resistance and
T2DM.
Regulation of resistin in models of insulin resistance and
glucose intolerance
Early rodent studies determined that reduced serum res-
istin levels in mice were associated with decreased adipos-
ity and improved insulin sensitivity [56]. Rajala et al.
[34] recently demonstrated that circulating resistin levels
were significantly elevated and positively concordant
with rising levels of insulin, glucose and lipids in Lepob/ob
mice. This study also highlighted the potential interplay
between resistin and leptin, with leptin suppressing
resistin mRNA and protein levels, concomitant with the
reduction in glucose and insulin [34]. Furthermore,
Asensio et al. [35] highlighted that leptin administration
in ob/ob mice improved insulin sensitivity, which was
affiliated with a decrease in resistin gene expression. Col-
lectively, these studies suggest leptin may exert insulin-
resistance-ameliorating effects via counter-regulatory
interactions and potentially suppressive mechanisms
towards resistin. In contrast, Lee and co-workers [33] re-
ported that neither transcriptional regulation of resistin
nor circulating resistin levels correlated with serum
insulin or glucose levels. Subsequent studies have
denoted resistin expression was either suppressed [57] or
unchanged [31] in rodent models of insulin resistance.
Furthermore, although resistin mRNA levels were
increased in insulin-resistant rats, no apparent change in
insulin sensitivity was observed [24].
In evaluating resistin and its association with insulin
sensitivity in humans, several studies have identified posi-
tive correlations between resistin levels and insulin re-
sistance in vivo [49] and in vitro [51]. Additionally,
serum resistin levels were increased by approx. 20 % in
T2DM subjects [43], such findings have been re-affirmed
by Fujinami et al. [52]. In contrast, other studies have
reported no associations between serum resistin levels and
markers of insulin resistance in T2DM patients [48,53,58]
or insulin-resistant patients [59]. Moreover, serum and
plasma resistin levels were either reduced or increased
in T2DM patients with no significant correlation with


C 2005 The Biochemical Society
HOMA-IR (homoeostasis model assessment for insulin
resistance), waist circumference, BMI or total cholesterol
[54,55]. Consequently, these studies suggest resistin is
unlikely to play a critical endocrine role in insulin re-
sistance or energy homoeostasis in humans. Nevertheless,
a paracrine or autocrine manner of resistin to moderately
affect metabolism cannot be ruled out.
Effect of resistin on glucose homoeostasis
Recently, it has been reported that transgenic mice over-
expressing resistin exhibited impaired insulin-mediated
glucose transport [60]. This altered glucose metabolism
appeared to occur without affecting insulin receptor sig-
nalling, therefore acting by reducing the intrinsic activity
of cell-surface glucose transporters [60]. Lazar and co-
workers [61] have recently shown resistin induced the
expression of SOCS (suppressor of cytokine signalling)-
3, a known inhibitor of insulin signalling. Moreover,
the loss of SOCS function was shown to impair resistin
from antagonizing insulin action in adipocytes [61]. This
suggested that the insulin-independent action of resistin
on adipocytes could partly be mediated by SOCS-3,
which could have an impact on normal glucose homo-
eostasis [61].
Rajala et al. [9] have shown that infusion of either
resistin or RELM-β into rats decreased insulin sensitivity,
primarily at the site of the liver. This worsening of glucose
homoeostasis was shown to be entirely attributable to the
severely impaired insulin-mediated suppression of hep-
atic gluconeogenesis, rather than peripheral insulin re-
sistance [9]. The study consequently suggested that fat-
and gut-derived resistin and RELM-β may have clear and
rapid effects on stimulating the rate of hepatic glucose
production, as opposed to increasing glucose uptake or
influencing peripheral insulin sensitivity [9]. In this
regard, the secretion of RELM-β into the portal venous
circulation appears to link the intestinal epithelium to the
liver, enhancing changes in hepatic intermediate meta-
bolism as a result [9]. Furthermore, this supported the
notion of the existence of a feedback mechanism between
adipose tissue and insulin-target organs, such as the liver.
These findings have been reinforced by studies show-
ing that the ablation of the resistin gene in mice lowering
fasting glucose levels through reducing hepatic glucose
production without significantly altering whole-body
glucose disposal [62]. This study showed that improve-
ment in glucose homoeostasis was partly mediated via
increased activation of hepatic AMPK (AMP-activated
protein kinase) with reduced gene expression of the glu-
coneogenic enzymes G6Pase (glucose 6-phosphatase) and
PEPCK (phosphoenolypyruvate carboxykinase) [62].
Conversely, the authors [62] also showed that resistin
treatment in these knockout mice enhanced hepatic
production by increasing glucose levels by approx. 25 %.
Furthermore, Rangwala et al. [63] documented that mice
with chronic hyper-resistinaemia exhibited higher blood

glucose levels and impaired glucose tolerance; this was
associated with increased hepatic glucose production,
partially due to increased hepatic expression of glu-
coneogenic enzymes. Nonetheless, impairment of normal
glucose homoeostasis caused by chronic hyper-resistin-
aemia may require more severe measures to counter-
regulate these effects.
In the human context, early studies showed contradict-
ory findings for correlations between resistin and glucose
disposal, with recent studies still providing inconsistent
results. Studies in Pima Indians have reported serum re-
sistin levels were not associated with fasting glucose and
insulin levels, although they were proportional to the de-
gree of adiposity [41]. Additionally, one study indicated
serum resistin levels were inversely correlated with glu-
cose disposal rates [50], whereas others indicate a modest
effect of resistin on glucose uptake in vitro [43]. Col-
lectively, resistin transgenic and gene-deletion studies in
rodents have provided evidence that resistin may have
a predominant physiological role in the liver by contri-
buting to the regulation of fasting blood glucose levels.
Consequently this may have important implications in
humans, but further studies regarding this are clearly
required.
Regulation of resistin by insulin sensitizers
Several studies have reported the down-regulation of
resistin expression following RSG treatment in WAT
(white adipose tissue) of db/db mice, diabetic fatty rats
[3,64] and 3T3-L1 adipocytes [36]. Furthermore, resistin
expression is down-regulated not only by RSG, but
also by darglitazone [36] and troglitazone [65]. Con-
versely, subsequent rodent studies report that PPAR-γ
(peroxisome-proliferator-activated receptor-γ ) agonists
[27], pioglitazone and troglitazone [28], and metformin
[66] increase resistin gene and protein expression. How-
ever, human studies have shown that treatment of mono-
cytes with PPAR-γ agonists failed to have any effect
on resistin levels [15]. These initial observations suggest
that down-regulation of resistin is not crucial for the
antidiabetic effect of TZDs in all model systems. How-
ever, recent human studies have shed favourable light on
the modulation of resistin by TZDs. Pioglitazone treat-
ment suppressed plasma resistin concentrations in T2DM
patients, which positively correlated with decreased
hepatic fat content and improved insulin sensitivity [67].
Furthermore, RSG reduced resistin secretion from
human adipocytes [43] and resistin expression in human
macrophages [17,68]. To understand whether the down-
regulation of resistin expression by RSG occurred
through a direct PPAR-γ -mediated transcriptional mech-
anism, Patel et al. [17] identified five putative PPREs
(PPAR-γ -response elements) in the resistin gene. One
such response element, PPRE2, was shown to bind
PPAR-γ [17]. However, how PPAR-γ exerts its sup-
pressive actions on resistin expression remains to be eluci-
Role of resistin in obesity, insulin resistance and Type II diabetes 249
dated, although it has been suggested that recruitment of
co-repressors of transcription may play a role [69]. RSG
has also been shown to have anti-inflammatory effects
in human macrophages [70] by reducing inflammatory
cytokine production, which may consequently affect re-
sistin production [71]. Collectively, these human studies
indicate that suppression of resistin expression may
contribute to the insulin-sensitizing and glucose-lower-
ing actions of the TZDs. Furthermore, the potential anti-
inflammatory effects of TZDs on adipocytokine me-
diation may be of equal importance in the prevention
of T2DM.
Hormone and cytokine modulators of resistin expression
Studies investigating metabolic hormones and cytokines
that are associated with insulin resistance have looked for
their relationship with resistin. Such studies have pro-
duced data suggesting an interplay between hormones,
cytokines and resistin, as shown in Table 3. Although the
reported regulation of resistin by these factors appears
intriguing, no underlying mechanistic principles are cur-
rently apparent. Therefore the physiological relevance of
most of these factors with respect to resistin remain to be
determined.
Gender effects on resistin regulation
In WAT, it has been shown that resistin mRNA ex-
pression is higher in male than female rats [72,73], in
contrast with a similar study also undertaken in mice [74].
In human subjects, Yannakoulia and co-workers [42]
reported that resistin concentrations were significantly
higher in females compared with males, which was also
confirmed by two other studies suggesting a significant
gender difference [48,49]. However, a subsequent study
examining both age and gender in relation to serum
resistin indicated a lack of association in healthy subjects,
as well as patients with Type I diabetes and T2DM [39]. As
a result, the significance of gender on the degree of resistin
expression in rodents and humans remains unclear, per-
haps complicated by the issue of specificity of resistin
ELISAs.
Adiponectin, insulin resistance and T2DM
Although resistin has been implicated in the pathogenesis
of insulin resistance and T2DM, it is noteworthy to
mention another novel adipocytokine proposed to have
a role in the aetiology of human T2DM. Adiponectin
expression and plasma levels, in contrast with resistin and
other adipocytokines whose levels are increased in states
of obesity, are reduced in insulin resistance and obesity
[75,76]. Additionally, it has been reported that gastric
bypass in morbidly obese patients has resulted in elevated
levels of plasma adiponectin [77]. Interestingly, low
serum levels of adiponectin have been shown to indepen-
dently predict future risk of developing T2DM [78]. With
regards to insulin sensitizers, adiponectin synthesis and
secretion are up-regulated by TZDs in vitro and in vivo


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250 C. M. Kusminski, P. G. McTernan and S. Kumar

Table 3 Effects of hormones and cytokines on the level of resistin expression and secretion

Hormone/cytokine Effect on resistin References

Pituitary hormones Growth hormone (somatotrophin; 1 mg · kg−1 · day−1 ) ↑ resistin gene expression (720–950 %) in WAT [65,151,152]
of spontaneous dwarf rats and has moderate inhibitory effects on resistin transcript and protein
(30–50 %) levels in 3T3-L1 adipocytes; ↑ gene expression levels in response to hyperprolactinaemia
in mice;↓ mRNA and protein expression (30–50 %) in 3T3-L1 adipocytes.
Steroid hormones Dexamethasone ↑ mRNA and protein levels (2.5- to 3.5–fold) in 3T3-L1 adipocytes and approx. [36,65]
70 % in mouse WAT.
Sex hormones ↑ In mice with elevated androgen levels; ↑ by hyperprolactinaemia and testosterone; administration [73,152–154]
of dehydroepiandrosterone ↑ gene expression in WAT of male Wistar rats; oestrogen ↓ adipose
gene expression in ovariectomized rats and in isolated rat adipocytes in vitro ; testosterone ↑ adipose
tissue mRNA levels in male rats.
Thyroid hormone Severely ↓ expression in hyperthyroid rats; ↓ serum levels in subjects with hyperthyroidism. [73,155]
Adrenaline ↓ Transcript and protein levels (30–50 %) in 3T3-L1 adipocytes. [65]
Neuropeptide Y Intracerebroventricular administration of neuropeptide Y ↑ gene expression in mice WAT. [156]
β 3 -Adrenoreceptors The β 3 -agonist isoproterenol ↓ gene expression levels in vitro by 20 % in 3T3-L1 adipocytes, which [157]
is reversible with the β 3 -antagonist propranolol.
ET-1 ET-1 (100 nM) ↓ basal secretion by 59 % in 3T3-L1 adipocytes. [158]
Insulin ↓ Gene expression (approx. 50 %) in 3T3-L1 adipocytes; ↑ secretion from 3T3-L1 adipocytes; [4,27,34,36,43,65,158]
↑ mRNA synthesis (23-fold) in streptozotocin-diabetic mice or Zucker diabetic fatty rats; gene
expression and protein concentration ↑ in fasted mice; ↑resistin protein secretion in a
concentration-dependent manner in human subcutaneous adipocytes.

[79–81] and suppressed by insulin-resistance-inducing
hormones [82,83]. The precise function of adiponectin
as a therapeutic target, improving glucose metabolism by
increasing insulin sensitivity in humans, is currently of
great interest.
Potential role of resistin in inflammation
Recent studies have highlighted the importance of
inflammation in linking obesity and the occurrence of the
metabolic syndrome, suggesting that the metabolic syn-
drome is a low-grade systemic inflammatory condition
[84]. Although this emerging concept of inflammation has
been recognized in the context of increasing adiposity, its
molecular basis and physiological significance in terms of
the pathogenesis of T2DM is yet to be fully elucidated.
Thus adipose tissue may act as a site for mediation of
this chronic inflammation through the action of known
pro-inflammatory adipocytokines such as leptin, TNF-α,
IL-6 and, most recently proposed, resistin [85]. Resistin,
although postulated to contribute to insulin resistance,
may also contribute to inflammatory responses.
Early investigations into the role of resistin as an in-
flammatory factor demonstrated that LPS (lipopolysac-
charide) up-regulated resistin expression in rat WAT,
3T3-L1 adipocytes and human monocytes [86]. However,
contradicting these findings, a down-regulation of resistin
expression in response to LPS in adipose tissue of FVB
mice has been identified, with no effect transcriptionally
or translationally in 3T3-L1 adipocytes reported [29].
Such a discrepancy between studies may have arisen from
different doses and time points of LPS treatment or the
animal models used. Assessing the effect of pro-inflam-
matory cytokines on resistin expression showed that
treatment with TNF-α down-regulates resistin, suggest-
ing TNF-α as a negative regulator of resistin [29]. How-
ever, in one case, no apparent effect was observed with
treatment of IL-6 [87].
Although initial rodent studies have produced dis-
crepancies as to whether pro-inflammatory cytokines
may regulate resistin, several recent human studies have
supported the concept of inflammatory cytokine me-
diation of resistin. One study has shown resistin to be
significantly correlated with IL-6 and ICAM-1 (inter-
cellular cell-adhesion molecule-1) in obese patients
with obstructive sleep apnoea syndrome [88], whereas
another reported LPS, IL-1, TNF-α and IL-6 strongly
stimulated resistin expression in human [PBMCs (peri-
pheral blood mononuclear cells)] [38,43,58]. Correlations
between resistin expression and secretion and other in-
flammatory markers, including IL-6, leptin, sTNF-R2
(soluble TNF-receptor 2) and CRP (C-reactive pro-
tein), have also been reported in patients with severe
inflammatory disease, obesity and T2DM [68]. Recently,
Lehrke et al. [68] demonstrated that endotoxaemia caused
a dramatic increase in resistin in primary human macro-
phages, and this was attenuated by aspirin and RSG. In
this situation, RSG was suggested to possess dual insulin-
sensitizing and anti-inflammatory properties. Addition-
ally, LPS induced TNF-α, which preceded the increase
in resistin, and therefore, in this study, the authors

C 2005 The Biochemical Society

hypothesized that TNF-α was responsible for the later
induction of resistin [89]. Thus cytokine induction of
resistin may contribute to insulin resistance in endo-
toxaemia, obesity and inflammation.
Obesity is associated with adipose tissue infiltration
by macrophages, thus contributing to resistin expression,
and this may propagate further recruitment of more
macrophages potentially interacting with adipocytes.
Adipose tissue may therefore represent a site of an innate
immune response in humans [90]. Alternatively, it is
hypothesized that macrophage recruitment may instead
arise from the trans-differentiation of pre-adipocytes into
macrophage-like cells [68,88], highlighting the close inter-
relationship between adipocyte and macrophage lineages.
This would be consistent with the emerging concept
that adipocytes and macrophages share the property of
secreting pro-inflammatory cytokines that regulate meta-
bolic function. To date, resistin gene expression levels
have been reported to be higher in human PBMCs
[25]. However, comparative studies have not shown the
relative resistin protein expression in macrophages
compared with adipocytes; this could alter our perception
of the contribution to resistin made by the adipocyte.
Furthermore, studies have highlighted increased resistin
protein expression in human abdominal fat, irrespective
of the presence of mononuclear blood cells [91]. At the
very least, it seems apparent that the findings on the pat-
tern of resistin mRNA expression suggest that adipocytes
contribute modestly to hyper-resistinaemia. Although,
combined with the significant biomass that adipose tissue
can contribute to whole-body weight, particularly in
obese individuals, there is little doubt that the systemic
contribution of adipose tissue is significant [92]. It has
been suggested that obesity and T2DM are associated
with chronic inflammation and activation of innate
immune pathways [93,94]. In obesity, where pro-inflam-
matory cytokine levels are known to be elevated, it may
be plausible that resistin could function as a signalling
component of the innate immune response to circuitously
induce the production of pro-inflammatory cytokines,
such as TNF-α and IL-6, within macrophages and adipo-
cytes. In turn, such immune dysregulation could con-
tribute to the development of a pro-inflammatory milieu
associated with insulin resistance. Overall, it is apparent
that the relationships between obesity, inflammation
and resistin expression are complex. Further studies are
clearly required to explain the role of the adipocyte as a
site of an immune response, potentially contributing to
coupling of immunity and metabolic dysregulation.
In addition to resistin, adiponectin may possess anti-
inflammatory properties. Recent studies have shown that
adiponectin suppressed cytokine production in macro-
phages [95] and disrupted the activation of NF-κB
(nuclear factor κB) in an aortic endothelial cell model
[96]. Ajuwon and Spurlock [96] reported that adiponectin
attenuated LPS-induced NF-κB activation and IL-6
Role of resistin in obesity, insulin resistance and Type II diabetes 251
production in 3T3-L1 adipocytes, and antagonized an
endotoxin-induced increase of TNF-α expression [97].
These studies suggest a regulatory role for adiponectin
in inflammation within adipose tissue, possibly acting via
the regulation of NF-κB. Hypoadiponectinaemia may
contribute to the pathogenesis of obesity-related insulin
resistance, inflammation and T2DM, and therefore fur-
ther studies should elucidate mechanisms of action.
Relationship of resistin with CVD
(cardiovascular disease)
Adipocyte-derived hormones not only function promin-
ently in the pathogenesis of T2DM, but may also serve
as important vasoactive factors directly affecting endo-
thelial function and vascular homoeostasis [98]. Therefore
these factors may represent an important point of con-
vergence in linking insulin resistance to an increased
risk of atherosclerotic vascular disease. Although the
precise molecular mechanisms responsible for this con-
vergence remain nebulous, resistin may have a role in its
pathogenesis. A recent study by Reilly and co-workers
[98] suggested resistin as a metabolic link between in-
flammation and atherosclerosis. This group reported that,
in non-diabetic and diabetic subjects, plasma resistin
levels were associated with metabolic and inflammatory
markers, including sTNF-R2, IL-6 and LpPLA2 (lipo-
protein-associated phospholipase A2 ) [98]. Furthermore,
resistin levels correlated with CAC (coronary artery cal-
cification), a quantitative measure of coronary athero-
sclerosis [98]. Notably, in metabolic syndrome subjects,
resistin levels further predicted CAC, whereas CRP levels
did not [99]. Such results imply resistin may be an
independent marker of atherosclerosis in humans.
Several studies have examined resistin as a cardiovas-
cular risk factor and a potential contributor to endothelial
dysregulation and atherosclerotic lesion formation [99].
Such studies have shown resistin stimulated factors,
including ET-1 (endothelin-1), VCAM-1 (vascular cell
adhesion molecule-1) and MCP-1 (monocyte chemoat-
tractant protein-1), thus contributing to CVD [100]. Ad-
ditional confirmation of the potential effects of resistin on
the vasculature have arisen through studies examining hu-
man aortic endothelial cells. One study reported that re-
sistin up-regulated the expression of adhesion molecules,
including VCAM-1 and ICAM-1, as well as long PTX3
(pentraxin 3), a marker of inflammation [100–102].
Therefore, as adhesion molecules may represent the initial
stages of atherosclerotic lesions and PTX3 expression is
increased in atherosclerotic lesions, resistin may exert a
pro-inflammatory effect on vascular endothelial cells,
promoting the onset of atherosclerosis [100]. In contrast
with resistin, adiponectin, known to enhance insulin sen-
sitivity and reduce atherosclerotic plaques, suppressed a
resistin-mediated rise in VCAM-1 and ICAM-1 [103].
These observations coincide well with a study showing


C 2005 The Biochemical Society
252 C. M. Kusminski, P. G. McTernan and S. Kumar
that adiponectin suppressed the TNF-α-stimulated ex-
pression of E-selectin, VCAM-1 and ICAM-1 in human
endothelial cells [104–106]. This suggests further that
adiponectin may be vasoprotective and negatively modu-
late the atherogenic processes. These findings raise the
possibility that resistin, in conjunction with other adipo-
cytokines, may influence the degree of inflammation
in the vasculature via direct modulation of endothelial
function. However, further studies are required to fully
elucidate the relationship of resistin and adiponectin with
inflammatory-related CVD.
HUMAN GENETIC STUDIES OF RESISTIN
Several SNPs (single nucleotide polymorphisms) have
been identified in the Retn gene, but only few have minor
allele frequencies over 5 % and are associated with dis-
ease risk [104–106]. Therefore further confusion ensues
when reviewing genetic studies examining associations
between resistin and disease. In a study of non-
diabetic French Canadians in Quebec [104], two Retn
5 -flanking SNPs (− 537 and − 420) were associated
with increased BMI. Furthermore, a resistin genotype
at nucleotide + 299 (IVS2 + 181G → A) and obesity was
a significant determinant of T2DM risk among Type II
diabetic Caucasians in Boston (MA, U.S.A.) [107].
Additionally, the − 420C → G SNP (− 180 relative to
putative transcription start site) was associated with
higher resistin mRNA levels in abdominal fat of obese
subjects [51]. Conversely, Mattevi et al. [105] showed
an association between the − 420C → G polymorphism
with lower BMI in non-diabetic individuals from a
Brazilian population of European descent, although,
among non-diabetic Caucasians in Sicily and Gargano
(Italy), an ATG triplet repeat in the 3 -untranslated region
of the resistin gene was associated with a decreased
risk of insulin resistance [108].
Genetic analysis of resistin using a Japanese population
demonstrated that a − 420G/G genotype was associated
with T2DM and could accelerate the onset of disease
by 4.9 years [106]; moreover, the genotype itself was a
primary variant determining T2DM susceptibility [106].
Consistent with these findings, elevated levels of serum
resistin were reported in T2DM subjects carrying the
− 420G/G genotype [109]. In contrast, studies in a
Japanese obese population reported the − 638G → A,
− 420C → G, and − 358G → A SNPs, which although
associated with serum resistin, did not confer any associ-
ation with obesity or insulin resistance [110,111]. These
genetic studies highlight the discrepancies in resistin
SNP analysis examining the association with obesity-
related insulin resistance; these may partly be explained
by different genetic backgrounds or environmental
conditions of the populations studied. Further studies
on the physiology of resistin and genetic implications for
the development of this disease are therefore crucial.


C 2005 The Biochemical Society
CONCLUSIONS
It is apparent that the pathogenesis of T2DM and CVD
is complex and multifactorial in which several adipo-
cytokines have been implicated. Over the last 4 years our
understanding of the role of resistin in this process has led
some to question its relative importance in man. Recent
studies have shed more light on differences between
rodents and humans, indicating the diversity of resistin
action in these species. Further studies are required to
establish the relevance of resistin to human diabetes, in
particular its effects on the central nervous system and
β-cell function that have not been characterized. It is
also clear that further work is required to understand the
basis for formation of different higher and lower mol-
ecular-mass forms of resistin in the circulation and their
effects on function. Clearly, identifying a receptor for
resistin would represent a major advance and could lead
to a clearer understanding of its function. However, our
growing knowledge of the role of pro-inflammatory mol-
ecules generated within adipose tissue and their link to
diabetes means that interventions that reduce the pro-
duction of pro-inflammatory cytokines, including re-
sistin, may prove to have therapeutic potential.
ACKNOWLEDGMENTS
We thank Diabetes UK and the Dunhill Medical Trust for
providing funding of a PhD Studentship and a Research
Fellowship respectively.
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