The Veterinary Journal 185 (2010) 4–9

Contents lists available at ScienceDirect

The Veterinary Journal

journal homepage: www.elsevier.com/locate/tvjl

Review

Obesity, its associated disorders and the role of inflammatory adipokines

in companion animals
Alexander J. German a,*, Vivien H. Ryan a,b, Allison C. German a, I. Stuart Wood b, Paul Trayhurn b,c
a
School of Veterinary Science, University of Liverpool, Leahurst Campus, Chester High Road, Neston, Wirral CH64 7TE, UK
b
Obesity Biology Research Unit, School of Clinical Sciences, University of Liverpool, Duncan Building, Liverpool L69 3GA, UK
c
Clore Laboratory, University of Buckingham, Hunter Street, Buckingham MK18 1EG, UK

a r t i c l e i n f o a b s t r a c t

Keywords: Obesity is characterised by an expansion of white adipose tissue mass that can lead to adverse health
Biomarkers effects, such as decreased longevity, diabetes mellitus, orthopaedic and respiratory disease and neoplasia.
Overweight Once thought a passive fuel depot, adipose tissue is now recognised as an active endocrine organ that
Obesity communicates with the brain and peripheral tissues by secreting a wide range of hormones and protein
Cat
factors, collectively termed adipokines. Examples include leptin, adiponectin, cytokines (tumour necrosis
Dog
factor-a, interleukin-6), chemokines, acute phase proteins, haemostatic and haemodynamic factors and
Insulin resistance
Metabolic syndrome neurotrophins. Adipokines can influence various body systems, and perturbation of normal endocrine
function is thought central to the development of many associated conditions. This review focuses on
the medical consequences of obesity in companion animals, assesses the endocrine function of adipose
tissue in disease pathogenesis, and highlights the potential role of adipokines as biomarkers of obes-
ity-associated disease.
Ó 2010 Elsevier Ltd. All rights reserved.

Introduction cats (German, 2006), and is now recognised as a major disease in

companion animal medicine. This review highlights the medical
Obesity occurs where the accumulation of excess body fat ad- consequences of obesity in pets and examines the potential endo-
versely affects health (Kopelman, 2000). Recent figures have indi- crine function of adipose tissue in disease pathogenesis.
cated that approximately 25% of men and women in the United
Kingdom are obese (body mass index [BMI] P 30), which repre-
The pathological consequences of obesity
sents a threefold increase in prevalence since 1980 (Rennie and
Jebb, 2005). Obese humans are at higher risk of developing a num-
A recent study of cause-specific mortality in 900,000 humans, re-
ber of diseases including type II diabetes mellitus, hypertension,
vealed BMI to be a strong predictor of overall mortality (Prospective
coronary heart disease, certain cancers (e.g. breast, ovarian, pros-
Studies Collaboration, 2009). Relative to the apparent optimum BMI
tate), osteoarthritis, respiratory disease, and reproductive disor-
of 22.5–25 kg/m2, median lifespan is reduced by 2–4 years and
ders (Kopelman, 2000).
8–10 years, at BMIs of 30–35 kg/m2 and 40–45 kg/m2, respectively.
As with humans, overweight and obesity is a major concern in
Obese humans are more likely to suffer from diseases such as the
the companion animal population. In three of the most recently
metabolic syndrome, type II diabetes mellitus, hypertension, coro-
published canine studies, 29–34% of dogs were classed as over-
nary heart disease, certain cancers, osteoarthritis, respiratory and li-
weight and 5–8% were judged obese (Lund et al., 2006), and in cats
ver disease (Table 1). Obesity is also known to have detrimental
the latest data indicate that 19–29% and 6–8% of animals are over-
effects on both the health and longevity of dogs and cats.
weight and obese, respectively (Lund et al., 2005). The prevalence
A long-term colony-based research study, comparing life-long
of obesity in the pet population also appears to be increasing, given
ad libitum feeding with energy restriction (where animals were
that previous reports suggested prevalences of 24% in dogs (Edney
fed approximately 75% of the ad libitum ration), demonstrated that
and Smith, 1986) and 6–12% in cats (Anderson, 1973). Similar to
ad libitum-fed dogs tended to be overweight, had a shorter life-
humans, obesity also has detrimental health effects in dogs and
span and had increased risk of associated disease (Kealy et al.,
2002). Obesity is also reported to be a major risk factor for ortho-
* Corresponding author. Tel.: +44 151 795 6100; fax: +44 151 795 6101. paedic disease, diabetes mellitus, respiratory and urinary tract dis-
E-mail address: ajgerman@liv.ac.uk (A.J. German). ease (Table 1).

1090-0233/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tvjl.2010.04.004
 A.J. German et al. / The Veterinary Journal 185 (2010) 4–9 5

Table 1
Diseases associated with overweight and obesity in humans, dogs and cats (Kopelman, 2000; German, 2006).

Disease category Species

Human Dog Cat
Endocrine and lipid Type II diabetes, metabolic syndrome, Hypothyroidism, hyperadrenocorticism, Diabetes mellitus, hepatic lipidosis
metabolism dyslipidaemias diabetes mellitus, insulin resistance, metabolic
syndrome (experimental)
Cardio-respiratory Coronary heart disease, atherosclerosis, Tracheal collapse, expiratory airway
hypertension, obstructive sleep apnoea, dysfunction (experimental), hypertension (of
asthma doubtful clinical significance), portal vein
thrombosis, myocardial hypoxia
Orthopaedic (impaired Osteoarthritis, musculoskeletal pain, gout Osteoarthritis, cruciate ligament disease, Lameness
mobility) humeral condylar fractures, intervertebral disc
disease, hip dysplasia
Neoplasia Various cancers including: breast (post- Transitional cell carcinoma, mammary Increased risk
menopausal), renal, endometrial, prostatic, carcinoma (some studies)
oesophageal, colorectal, hepatocellular
Urogenital (Diabetic) nephropathy Urinary tract disease, Calcium oxalate Increased risk of urinary tract disease
urolithiasis, transitional cell carcinoma;
glomerular disease (experimental), dystocia
Alimentary Pancreatitis, hepatic steatosis, cirrhosis Pancreatitis Increased oral cavity and
gastrointestinal disease
Other Depression, post-operative complications, Immune function Increased risk of dermatoses
dermatological disease

Endocrine function of white adipose tissue

Although once considered a passive fuel depot, white adipose

tissue (WAT) is now recognised as an active endocrine organ that
communicates with the brain and peripheral tissues by secreting
a wide range of hormones and protein factors, collectively termed
adipokines (Trayhurn, 2005). This term is restricted to the proteins
secreted by adipocytes themselves and not by WAT as a whole, so
as to exclude proteins secreted by other cells found in WAT such as
macrophages (Trayhurn and Wood, 2004).
Some 100 different adipokines have been characterised in hu-
mans and rodents, and this ‘adipokinome’ together with lipid moi-
eties released by the adipocyte, constitute the ‘secretome’ of the fat
cell (Fig. 1). The effects of these adipokines can influence many bio-
logical systems including glucose homeostasis, inflammation and
immunity, haemostasis, fluid balance, vascular biology, haemato-
poiesis, cell proliferation, angiogenesis and neurotrophic functions
(Radin et al., 2009). Although information is more limited, gene
expression and protein secretion for a variety of adipokines have
been documented from WAT of cats and dogs (Eisele et al., 2005;
German et al., 2009a; Radin et al., 2009; Ryan et al., 2008, 2009).

Obesity as an inflammatory state

Obesity is characterised by chronic, low-grade systemic inflam-

mation (Trayhurn, 2005). Levels of the inflammatory markers C-
reactive protein (CRP), interleukin (IL)-6 and tumour necrosis fac-
tor alpha (TNF-a), are systemically raised in obese humans, whilst
weight loss generally reverses this trend and can improve insulin
sensitivity (Manco et al., 2007). Since both pro-inflammatory cyto-
kines and acute phase proteins (APPs) are produced by WAT, this
tissue is thought to be an important source of the raised concentra-
tions of these compounds in obese individuals and provides a link
between obesity, insulin resistance and the metabolic syndrome
(Trayhurn, 2005).
Tissue hypoxia
It has been proposed that expansion of WAT in obesity leads to
decreased tissue perfusion (Trayhurn and Wood, 2004), leading to
the recruitment of hypoxia inducible factor-1a (HIF-1a) transcrip-
Fig. 1. The evolving view of the biological function of adipose tissue: (a) adipocytes
previously considered inert storage depots releasing fatty acids and glycerol at
times of fasting or starvation; (b) adipocytes now considered endocrinologically
active, secreting important hormones, cytokines, vasoactive substances and other
peptides. IL, interleukin; TNF-a, tumour necrosis factor-a; TGF-b, transforming
growth factor-b; CRP, C-reactive protein; SAA, serum amyloid A; PAI-1, plasmin-
ogen activator inhibitor-1; MCP-1, monocyte chemoattractant protein-1; MIF,
macrophage migration inhibitory factor; NGF, nerve growth factor.
tion factor (Wood et al., 2007), which in turn triggers the produc-
tion and release of inflammatory adipokines. The induction of HIF-
1a can lead to decreased adiponectin production and increased
expression of leptin, macrophage inhibitory factor (MIF), vascular
endothelial growth factor (VEGF) and plasminogen activator inhib-
itor (PAI-1) (Chen et al., 2006).
6 A.J. German et al. / The Veterinary Journal 185 (2010) 4–9
Adipokines and cancer
Studies in rodents and humans have also linked obesity to an
increase in the production of reactive oxygen species within
WAT, leading to oxidative stress and elevated production of pro-
inflammatory markers (Furukawa et al., 2004). Increased endoplas-
mic reticulum stress has also been described, with similar patho-
logical consequences (Hotamisligil, 2005).
Adipose tissue macrophages
Macrophages are an important component of WAT, and accu-
mulate during obesity (Weisberg et al., 2003). Since WAT macro-
phages are derived from bone marrow, expansion during obesity
is related to recruitment of circulating monocytes, likely due to in-
creased expression of macrophage chemotactic factor (MCP-1) and
MIF by WAT (Weisberg et al., 2003). Increased macrophage num-
bers can then result in a significant amplification of inflammatory
pathways within adipose tissue, involving extensive cross-talk be-
tween macrophages and adipocytes (Trayhurn, 2005). Macro-
phage-conditioned media can up-regulate various genes
associated with inflammation in adipocytes including many matrix
metalloproteinase genes, suggesting that macrophages can stimu-
late tissue remodelling during adipose tissue expansion in obesity
(O’Hara et al., 2009). Obesity is also thought to induce a phenotypic
switch in macrophages within adipose tissue from an M2, or ‘alter-
natively activated’, state in lean individuals to an M1, or ‘classically
activated’, state in the obese. Such M1 macrophages are capable of
increasing gene expression of pro-inflammatory cytokines such as
TNF-a (Lumeng et al., 2007).
Adipokines and the development of obesity-associated
disorders
There are two main mechanisms by which excessive WAT can
predispose to disease. Firstly, the deposition of excess fat can have
mechanical/physical effects that exacerbate orthopaedic disease,
constrict upper airways, restrict grooming and reduce heat dissipa-
tion. Secondly, and most importantly, the perturbation of the nor-
mal endocrine function of WAT can trigger or exacerbate a number
of associated conditions.
Obesity-related changes in adipokine profiles
In humans, the tissue expression and circulating concentration
of many adipokines increase with increasing adiposity, as is the
case for leptin (Considine et al., 1996), TNF-a (Hotamisligil et al.,
1995), IL-6 and IL-18 (Esposito et al., 2003), serum amyloid A
(SAA) (O’Brien et al., 2004), CRP (Esposito et al., 2003; O’Brien
et al., 2004), haptoglobin (Cheillini et al., 2004), angiotensinogen
(Engeli et al., 2005), PAI-1 (Folsom et al., 1993), MIF (Church
et al., 2005), and MCP-1 (Christiansen et al., 2005). An exception
is adiponectin, the concentration of which is inversely related to
bodyweight, and reduced WAT expression of this compound occurs
in both obesity and type II diabetes mellitus (Abbasi et al., 2004).
Similar findings have been noted in companion animals, where-
by increasing adiposity is related to increased plasma leptin con-
centration (Appleton et al., 2000; Sagawa et al., 2002) and
decreased plasma adiponectin concentration (Ishioka et al., 2006;
Hoenig et al., 2007). Furthermore, weight loss results in decreased
leptin concentrations (Hoenig et al., 2007; Jeusette et al., 2007),
whilst the adiponectin concentration is increased (Ishioka et al.,
2006). Detectable circulating TNF-a concentrations are found in al-
most 50% of dogs with naturally occurring obesity, with concentra-
tions declining significantly after weight loss (German et al.,
2009b). The concentrations of CRP and haptoglobin were also
found to be in the high-normal to mildly elevated range in obese
dogs, with both parameters decreasing modestly after weight loss
(German et al., 2009b).
Adipokines, the metabolic syndrome and insulin resistance
Insulin resistance is associated with obesity in various species
including humans, dogs and cats (Kopelman, 2000; Hoenig et al.,
2007; German et al., 2009b). Furthermore, circulating levels of sev-
eral adipokines are raised in both human type II diabetes and obes-
ity. The most studied is TNF-a, which can promote insulin
resistance at various levels, both centrally in the hypothalamus
and within the adipocyte (Hotamisligil et al., 1994, 1995). Both de-
creased insulin sensitivity and elevated circulating TNF-a concen-
trations are found in obese dogs, suggesting a relationship also
exists between these events in this species (German et al.,
2009b). The management of obesity improves insulin sensitivity
in humans (Hotamisligil et al., 1995), cats (Hoenig et al., 2007)
and dogs (German et al., 2009b). Plasma IL-6 concentrations are
elevated in obese humans (Mohamed-Ali et al., 2001), and this
cytokine is thought to play a direct role in insulin resistance by
altering insulin signalling in hepatocytes (Senn et al., 2002). Ele-
vated levels of PAI-1 have been linked to insulin resistance (Ju-
han-Vague et al., 1991), whilst circulating nerve growth factor
(NGF) concentrations are increased in obesity and the metabolic
syndrome in women (Bullo et al., 2005).
Leptin enhances the action of insulin on both the inhibition of
hepatic glucose production and in stimulating glucose uptake
(Barzilai et al., 1997), perhaps explaining why leptin may have a
role in the regulation of insulin sensitivity (Ebihara et al., 2001).
Plasma leptin concentrations are independently associated with
insulin sensitivity in both lean and overweight cats (Appleton
et al., 2002). In addition, adiponectin acts as an insulin sensitiser
by increasing fatty-acid oxidation, which in turn reduces the tri-
glyceride content of these tissues in obese and type II diabetic mice
(Yamauchi et al., 2001). There are also inverse correlations be-
tween plasma adiponectin concentration and risk factors associ-
ated with cardiovascular disease, such as impaired vasoreactivity
and levels of CRP (Ouchi et al., 2003).
Adipokines and inflammation
Obesity is characterised by chronic, low-grade systemic inflam-
mation, with increased concentrations of inflammatory markers
such as CRP, IL-6 and TNF-a (Trayhurn and Wood, 2004). The con-
centration of IL-1b is increased in obese humans (Um et al., 2004),
with the combination of elevated IL-1b and IL-6 increasing the risk
of both type II diabetes and the metabolic syndrome (Spranger
et al., 2003). Plasma IL-18 concentration is also elevated in obesity
and the level of this cytokine declines in response to weight loss
(Esposito et al., 2002). Increased serum IL-18 concentration has
been associated with hypoadiponectinaemia in obesity indepen-
dent of insulin resistance (Straczkowski et al., 2007). The expres-
sion of IL-10 is raised in obesity (Juge-Aubry et al., 2005) and, in
contrast to most other cytokines secreted by WAT, IL-10 is thought
to play an anti-inflammatory role countering pro-inflammatory
agents such as lipopolysaccharide (LPS) and TNF-a.
In addition to the effects of APPs and pro-inflammatory cyto-
kines, leptin is a significant modulator of both immune and inflam-
matory responses, including the activation of neutrophils,
macrophages and natural killer cells and in influencing lymphocyte
proliferation (Otero et al., 2003). Adiponectin has also a strong
anti-inflammatory function (Tilg and Wolf, 2005), and the hypoa-
diponectinaemia seen in obesity has been associated with the
raised levels of several pro-inflammatory cytokines such as IL-6,
 A.J. German et al. / The Veterinary Journal 185 (2010) 4–9
IL-8 and TNF-a (Engeli et al., 2003). It has been suggested that the
raised levels of these endogenous cytokines may be directly
responsible for the inhibition of adiponectin secretion (Bruun
et al., 2001).
Adipokines, hypertension and thrombosis
Elevated angiotensinogen in obese humans is associated with
the development of hypertension (Engeli et al., 2003). The expres-
sion of WAT angiotensinogen decreases in response to weight loss
in humans, and is thought to contribute to the fall in blood pres-
sure observed (Engeli et al., 2005). Although hypertension occurs
in obese dogs, it is mild and of doubtful clinical significance (Bodey
and Mitchell, 1996). It remains unclear if this species difference is
the result of differences in the pattern of adipokine expression.
Plasminogen activator inhibitor (PAI)-1 production is increased in
human obesity, is linked to several pro-inflammatory cytokines,
including TNF-a (Wang et al., 2005) and IL-6, and has also been
associated with increased risk of the atherosclerotic complications
associated with obesity (Ziccardi et al., 2002). This provides evi-
dence of a strong link between visceral adiposity, PAI-1 levels
and the increased incidence of atherothrombosis frequently associ-
ated with human obesity.
Adipokines and respiratory disease
Human obesity is associated with both obstructive sleep apnoea
and asthma, and the association can be partly explained by the
physical impairment caused by fat on both chest wall and dia-
phragmatic function (Kopelman, 2000). However, a large waist (a
marker of visceral adiposity) is also associated with an increased
prevalence of asthma in women of normal bodyweight. Since vis-
ceral adipose tissue is more metabolically active than subcutane-
ous fat, it is tempting to speculate that endocrine factors may
also play a role. Indeed, many of the pro-inflammatory factors in-
creased in the plasma of obese subjects are also central to the path-
ogenesis of asthma (Chung and Barnes, 1999). For instance, IL-6
can modulate T-helper 2 (Th2) cell immunity (Heijink et al.,
2002), TNF-a can augment airway inflammation (Thomas, 2001)
and increases airway contractility (Sukkar et al., 2001), whilst lep-
tin may facilitate airway hyper-responsiveness (Shore, 2007).
However, in a recent study, although markers of systemic inflam-
mation increased with obesity and Th2 cytokines were increased
in asthma, a direct interaction between the two could not be dem-
onstrated (Sutherland et al., 2008).
Adipokines and orthopaedic disease
Most of the increased risk for orthopaedic diseases, such as
osteoarthritis (OA), can be explained by the ‘mechanical overload’
effect of obesity. However, the development of OA in non-weight-
bearing joints, such as the hand, is also associated with increasing
BMI in humans (Cicuttini et al., 1996), and symptomatic improve-
ment of OA is more closely related to loss of body fat than overall
weight loss (Toda et al., 1998). Therefore, other pathogenetic, likely
metabolic, mechanisms may contribute to the link between OA and
obesity. In this context, leptin and adiponectin have been detected
in synovial fluid and leptin expression is up-regulated in both
osteophytes and cartilage from patients with OA (Dumond et al.,
2003). Leptin can also increase the effects of pro-inflammatory
cytokines on chrondrocytes (Otero et al., 2003). Furthermore, a re-
cent study has demonstrated that synovium, infra-patellar fat pad
and osteophytes are the major sources of adipokines present in
synovial fluid, suggesting that local adipokine production within
joints may contribute to the development of OA (Presle et al.,
2006).
7
Adipokines and cancer
Increased leptin levels have been implicated in some human
cancers including oesophageal and hepatocellular carcinomas
(Redinger, 2007). Leptin may stimulate insulin-like growth factor
(IGF)-1 and other growth hormone secretagogues, thereby enhanc-
ing cellular proliferation and/or de-differentiation (Kim and Pop-
kin, 2006) and stimulating angiogenesis, all of which may
promote neoplasia (Renehan et al., 2006). Leptin may also be a pro-
moting factor for hepatocellular carcinoma (Wang et al., 2006), as
well as contributing to cellular proliferation and de-differentiation,
and to inhibiting apoptosis in oesophageal cancer (Ogunwobi et al.,
2006). In contrast, adiponectin can reduce adhesion molecule
expression, providing some protection against carcinogenesis by
inhibiting cancer cell growth and tumour-associated angiogenesis
(Barb et al., 2007). Low adiponectin levels are observed in humans
with various types of cancer, and might contribute to their inci-
dence and severity (Barb et al., 2007).
Another potential link between obesity and cancer is hyperinsu-
linaemia, which can arise from the deranged adipokine expression
associated with obesity, and has been directly associated with co-
lon cancer in obese humans (Schoen et al., 1999). The inflamma-
tory adipokines associated with obesity may also contribute to
the development of pancreatic cancer by causing chronic inflam-
mation, which may progress ultimately to pancreatic adenocarci-
noma (Calle and Kaaks, 2004). Barrett’s oesophagus is a chronic
oesophagitis, predominantly the result of chronic acid reflux com-
monly found in obese humans. This inflammation may be accentu-
ated by chronic adipokine injury from peri-oesophageal adiposity,
thereby enhancing the progression to high-grade dysplasia and
ultimately to malignant neoplasia.
Adipokines as potential biomarkers in companion animal
obesity
Given the plethora of endocrine factors associated with obesity,
there is huge potential for these compounds to be used as biomark-
ers. However, given that the diagnosis of companion animal obes-
ity is usually straightforward, there is little need to develop
biomarkers as a diagnostic test. Of greater importance however
would be the development of biomarkers to identify co-morbidi-
ties. Furthermore, alterations in such biomarkers may be helpful
in monitoring the patient response to obesity management, not
only directed at weight loss, but also at decreasing the risk of met-
abolic disease.
To date, the most promising biomarkers include plasma insulin
(as a means of indirectly assessing insulin sensitivity) and circulat-
ing adipokines, particularly those of the inflammatory group. With
respect to the latter, validated canine and feline commercial assays
are already available for a number of these adipokines and their
potential has been demonstrated in a recent canine study. The con-
currence of insulin resistance and alterations in TNF-a, CRP and
haptoglobin in obese dogs, found in this study, was similar to the
sub-clinical state found in obese humans (German et al., 2009b).
Moreover, significant decreases were noted after weight loss high-
lighting that these factors could be useful independent markers of
response to therapy. Other potential adipokine biomarkers include
leptin and adiponectin although validated, commercially available
assays for these adipokines in companion animals have yet to be
developed.
Conclusions
Adipose tissue has the capacity to secrete a wide range of
endocrinologically active adipokines and perturbation of this func-
8 A.J. German et al. / The Veterinary Journal 185 (2010) 4–9
tion is thought central to the development of many conditions
associated with obesity. Further work is required to establish if
these compounds can be used as biomarkers to predict obesity-
associated disease in companion animals.
Conflict of interest statement
Allison C. German’s post at the University of Liverpool is sup-
ported by Royal Canin and Cats Protection.
Acknowledgements
Alexander J. German’s Senior Lectureship at The University of
Liverpool is funded by Royal Canin. The work of the authors is sup-
ported by grants from the Biological Sciences Research Council
(UK), Waltham and Royal Canin.
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