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136 Vet Clin Pathol 38/2 (2009) 136156 c 2009 American Society for Veterinary Clinical Pathology

Veterinary Clinical Pathology ISSN 0275-6382

I N V I T E D R E V I E W

Adipokines: a reviewof biological and analytical principles and an update in

dogs, cats, and horses

M. Judith Radin1, Leslie C. Sharkey2, and Bethany J. Holycross1

1Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, USA; and

2Department of Veterinary Clinical Sciences, University of

Minnesota, St. Paul, MN, USA

Key Words

Adipokines, adiponectin, leptin, obesity,

reninangiotensin system, resistin

Correspondence

M. Judith Radin, Department of Veterinary

Biosciences, The Ohio State University, 1925

Coffey Road, Columbus, OH 43210 E-mail:

[email protected]

DOI:10.1111/j.1939-165X.2009.00133.x

I. IntroductionII. Adipose as an OrganIII. General Biology of AdipokinesIV. Obesity, Adipokines, and DiseaseV. Selected Adipokines

A.Leptin1.Synthesis and regulation2.Leptin receptor and signaling3.Functions of leptin4.Leptin and obesity5.Measurement of leptin6.

Dogs

7.Cats8.Horses

B.Adiponectin1.Synthesis and regulation2.Adiponectin receptors and signaling

3.Functions of adiponectin4.Adiponectin and obesity5.Measurement of adiponectin6.Adiponectin in dogs, cats, and horses

Abstract: In addition to its role as an energy storage depot, adipose tissue is now

recognized as a complex endocrine organ. Adipose tissue releases a variety of

factors, termed adipokines, that regulate energy metabolism, cardiovascular

function, reproductive status, and immune function. Some of the better-studied

adipokines include leptin, adiponectin, and components of the renin-angiotensin

system such as angiotensinogen. The function of more recently discovered

adipokines such as resistin are under intense scrutiny. Abnormal

productionorregulationof adipokinesoccursinobeseindividualsand is implicated in

the development of a variety of associated co-morbidities including metabolic

syndrome, type 2 diabetes, atherosclerosis, heart disease, and cancer in people,

although evaluation in domestic species is just beginning. Adipokines are now

being examined as potential biomarkers for risk assessment for development of

complications related to obesity. This article summarizes the function and

regulation of some better-characterized adipokines. It also reviews the current

information on the characterization of adipokines in some domestic species in

which rates of obesity and obesityrelated disorders are increasing, such as the

dog, cat, and horse.

Introduction

Obesity and associated metabolic diseases are of increasing

prevalence and importance in companion animal

medicine.15

Health risks reported to be associated with

obesity include diabetes mellitus and osteoarthritis in dogs

and cats. There is also evidence for obesityassociated

shortened lifespan in dogs that are fed ad libitum compared

with dogs fed an energy-restricted diet that results in a

more optimal body condition.1,3

In horses, obesity may

predispose to laminitis, hyperlipemia, and strangulating

lipoma.5 Adipokines, which are proteins derived from

adipose tissue that have local and systemic effects, are

important factors in the pathophysiology of obesity and its

related conditions

inpeople.Asratesofobesityincompanionanimalsclimb, the

impact of altered adipokine balance on animal healthC. Angiotensinogen and the renin-angiotensin system

(RAS)

1.Synthesis, receptors, regulation, and function2.The RAS and obesity

D. ResistinE. Inflammatory cytokines VI. Summary


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Radin et al Adipokines in domestic animals

Vet Clin Pathol 38/2 (2009) 136156 c 2009 American Society for Veterinary Clinical Pathology 137

is expected to increase. The biological

characterization of and the measurement tools

available for the more thoroughly investigated

adipokines in dogs, cats, and horses

This review article has been peer-reviewed.

Figure1. Structure of white adipose tissue. Illustration by Tim

Vojt, Biomedical Media, The Ohio State University College of

Veterinary Medicine.

will be the focus of this review. Much of the

information regarding the basic biology of

adipokines is derived from human and rodent

data, while current information describing what

has been established in dogs, cats, and horses is

described in specific sections. A comprehensive

understanding of adipokines is facilitated by a

brief review of current concepts in adiposebiology.

Adipose as an Organ

Adipose tissue makes up a diffuse organ

comprised of adipocytes (50% of the total

cellular content), preadipocytes, multipotent

mesenchymal stem cells, endothelial cells,

pericytes, monocyte/macrophages, and nerve

cells (Figure 1). Previous models of adipocyte

biology suggested that the number of adipocytes

was fixed in childhood, and that expansion andcon-

Figure2. Adipose tissue from a rat showing white adipose tissue (WAT)

on the left and brown adipose tissue (BAT) on the right. Adipocytes

from WAToften contain a single large fat droplet. Adipocytes from

BATcontain multiple small fat droplets. H&E, 40 objective.

traction of adipose mass was due solely to modulation of the

balance of triglyceride storage and fatty acid mobilization.Newer research demonstrates that there is a large pool of stem

cells and preadipocytes in adipose tissue in individuals of all

ages that may be recruited once existing adipocytes reach a

critical level of hypertrophy.6

Adipose tissue hastraditionally been divided into 2 types:

white adipose tissue (WAT) consisting of cells with a single

large droplet of triglycerides, and brown adipose tissue,

consisting of cells containing multilocular lipid droplets

(Figure 2). Classical functions of WAT include insulation and

mechanical support along with storage of surplus energy,7

while brown adipose tissue is associated with thermogenesis

as a result of the expression of distinct genes such as

uncoupling protein-1.8 Adipocytes from different anatomiclocations may vary in their biology due to local influences on

differentiation and gene expression, and may be considered

mini-organs. The distribution of adipose tissue influences

the pathologic sequelae characterizing obesity. Preferential

deposition of fat into visceral deposits instead of

subcutaneous deposits increases the risk of insulin resistance,

atherosclerosis, and diabetes mellitus in people.9

With

impaired deposition of lipid in adipocytes due to aging or

lipodystrophy, lipids may be deposited in nonadipocytes in

the liver, muscle, pancreas, and kidney, resulting in altered fat

and glucose metabolism and impaired organ function due to

lipotoxicity.10

This illustrates the importance of adipose as

a specialized storage organ for excess energy. WAT isbecoming regarded as an important endocrine organ that

secretes a wide variety of substances including steroid

hormones, growth factors and cytokines, eicosanoids,

complement proteins, binding proteins, vasoactive factors,

regulators of lipid metabolism, and others.7Collectively, these

factors are labeled adipokines and they function as part of

a complex set of physiologic control systems that regulate

local tissue and whole organism physiology.


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Adipokines in domestic animals Radin et al


General Biology of Adipokines

Adipokines are defined generally as biologically

active substances produced in adipose tissue that act

in an autocrine/paracrine or endocrine fashion.11

Some

adipokines are produced exclusively or predominantlyby adipose tissue; however, others may be produced

in a variety of different tissues as outlined below for

individual adipokines. Production of adipokines by

adipose tissue may be influenced by sex hormones

and nutritional status.8

While the classic adipokines

such as leptin undoubtedly have an important role in

the regulation of energy balance and metabolism, the

list of adipokines and their potential functions is

expanding rapidly. There is evidence that adipokines

may contribute to the regulation of diverse biological

processes, including inflammation and immune

function,12,13

hemostasis and vascular biology,14,15

hematopoiesis,1618

and cell proliferation and

angiogenesis.19

Obesity, Adipokines, and Disease

At a basic level, obesity is the result of imbalance

between energy intake and energy expenditure. Major

theories regarding the underlying causes for obesity

include recent changes in environmental factors such

as food availability and activity levels, genetic

influences, and developmental programming.

Normally, highly redundant and tightly regulatedphysiologic systems (mostly neural and endocrine)

function to maintain body weight within a narrow

range with499% precision in most individuals over a

period of years.20

This regulation system requires a

sensing mechanism for energy stores (ie, a

lipostat) be coordinated with eating behaviors and

energy metabolism. The thrifty gene hypothesis

predicts that this system will tend to favor

mechanisms promoting weight gain, due to the

survival value of that characteristic in environments

with unpredictableand restrictedaccessto food.21

Thishypothesisis supported by the observation that

overfeeding produces fewer compensatory changes in

energy expenditure than underfeeding.22 Obesity in an

individual likely is

theresultofcomplexinteractionsbetweenenvironmental

factors and genes.

A consequence of increased fat mass is

dysregulation of production and secretion of

adipokines that impact glycemic control,

inflammation, and cardiovascular function. As a result

of these diverse functions of adipose, altered

adipokine production in obesity has been implicated in the

pathophysiology of a diverse group of diseases in people and

in rodent models, including diabetes mellitus, cardiovascular

disease, and cancer. Because of the increasing significance of

adipokines in health and disease, there is a need for awareness

of their biology and measurement in veterinary medicine.

While the list of recognized adipokines continues to grow,this review will focus on those that have been at least partially

characterized in companion animals, including leptin,

adiponectin, the reninangiotensin system (RAS), and resistin.

In particular, we will review these adipokines in dogs, cats,

and horses, species with a documented increased risk for

developing obesity and subsequent health consequences of

excess weight gain.

Selected Adipokines

Leptin

Synthesis and regulation

Leptin is the prototypic adipokine and is the best

characterized adipokine in domestic animal species.

Leptin is a 167 amino acid protein that isencoded by the

ob gene. Both the nucleotide and amino acid sequences

are highly conserved, with homologies of 8395% for

nucleotide and 7996% for amino acid sequence in

vertebrate species examined thus far.2327

Adipocytes are

the main site of leptin synthesis and the main contributor

to serum leptin levels. However, lower levels of

expression of leptin mRNA are detectable in other tissues

such as placenta, mammary gland, gastric mucosa, and

liver.

Leptin is constitutively secreted by adipocytes; its

transcriptional regulation depends upon energy flux

within adipocytes, so circulating levels correlate closely

with body mass index.28

As a result, the serum

concentration of leptin is predominantly defined by body

fat mass but will transiently increase following a meal

and decrease with fasting. Transcription of the ob gene is

controlled by a variety of metabolic and inflammatory

mediators. For example, binding of glucocorticoids or

peroxisome-proliferatoractivated receptor-g (PPARg) to

specific sites in the promoter region of the ob gene willincrease expression of leptin mRNA.23

Transcription also

is increased by insulin endotoxin and proinflammatory

cytokines such as tumor necrosis factor-a (TNFa),

interleukin-1b, and interleukin-6 (IL-6).28

Serum leptin

concentration increases during the luteal phase of the

estrus cycle, and estradiol appears to increase leptin

mRNA expression as well as protein secretion by

WAT.2932

In

contrast,circulatingleptinlevelsareinverselycorrelatedwith


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serum testosterone levels in males.29,33,34

Studies

in rats suggest that testosterone increases leptin

clearance but does not modify leptin synthesis

and secretion.35

Leptin receptor and signaling

Leptin is a cytokine, and its receptor (Ob-R) is

closely related to gp130, a member of the IL-6

family of receptors.36

Multiple variable-length

isoforms of Ob-R are possible due to alternative

splicing of the cytoplasmic domain. While Ob-R

is expressed in highest concentrations in the

satiety centers of the hypothalamus, both long

and shorter splice variants are widely distributed

in many tissues throughout the body, reflecting

the involvement of leptin in the regulation of

diverse physiologic processes.23,37,38

The long

form of the receptor, designated Ob-Rb, mediates

most of leptins physiologic actions; however,

short forms also are capable of signal

transduction.37,3941

With the exception of the soluble Ob-Re

isoform, which acts as a binding protein for

leptin in the circulation, full length and the

shorter receptor isoforms have a cytoplasmic

domain that associates with the janus kinase

family of tyrosine kinases (JAK). Binding of

leptin to full-length Ob-Rb results in activation of

JAK and phosphorylation of signal transducers

and activators of transcription (STAT).37,42

Because STAT activation depends onphosphorylation of tyrosine1138 on Ob-Rb,

shorter isoforms cannot signal via STAT despite

being able to phosphorylate and activate JAK.37,43

ObRb also signals via activation of extracellular-

signalregulated kinases (ERK1/2),41

phosphatidylinositol-3 kinase via activation of

insulin receptor substrate 1/ 2,39,44

and Akt

(protein kinase B).45

Signal transduction through

ERK1/2 and Akt may also be initiated by short

isoforms without concurrent STAT activation,

thus bypassing potentially important negative

feedback mechanisms, as described below.39,40,45

A consequence of activation of STATsignaling is induction of expression of

suppressors of cytokine signaling (SOCS),

especially SOCS-3.46

SOCS proteins are part of

an important negative feedback loop that inhibits

cytokine signaling by binding to phosphorylated

cytokine receptors. SOCS-3 binding to Ob-Rb

has the potential to dampen multiple leptin-

induced signaling pathways.47

In addition, there

is potential for crosstalk to modulate signaling

initiated by other cytokines or insulin, thus modifying

their actions.48

Increased expression and production of

SOCS-3 in brain and adipocytes occurs in rodent models

with obesity and has been proposed as a mechanism

mediating impaired response to leptin and central leptin

resistance.46,49,50

Because shorter leptin receptor isoforms

lack the ability to activate STAT, increased SOCS-3production is not anticipated following leptin binding to

these shorter splice variants. The physiologic

significance of the shorter isoforms and their importance

in the development of leptin resistance and obesity-

associated diseases are still largely unexplored.

Functions of leptin

The primary actions originally described for leptin are

mediated via binding to Ob-R in the brain, resulting in

suppression of appetite and increased energy expenditure

(thermogenesis).23,51

Appetite suppression is mediated via

binding of leptin to its full length receptor (Ob-Rb) in the

hypothalamic satiety centers, with stimulation of

anorexigenic/catabolic neurons (via neurotransmitters

such as cocaine and amphetamine regulated transcript

[CART] and a-melanocyte stimulating hormone [a-

MSH]) and suppression of orexigenic/anabolic neurons

(via neurotransmitters such as neuropeptide Yand agouti-

related peptide).50

Leptin also suppresses the release of

endocannabinoids, which are postsynaptic regulators of

presynaptic activity of orexigenic neurons. As a result,

endocannabinoid antagonists such as rimonabant are

being explored as appetite suppressors for obesity

treatment. Increased thermogenesis is mediated by

central binding of leptin to Ob-Rb, resulting insympathetic nerve stimulation and activation of b3-

adrenergic receptors in brown fat, thus increasing fat

oxidation.23,28

In addition to the primary function of regulationof energy

stores, leptin has been implicated as a growth factor by virtue

of its ability to stimulate angiogenesis, suppress apoptosis,

and act as a mitogen.52

These functions may play a role in the

increased incidence of cancer observed with increasing body

mass index and waist-to-hip ratio in humans. Leptin has been

suggested to have a role in hypothalamic development,

thereby providing a mechanistic link between altered

nutritional states during fetal and neonatal development and

long-term programming of adiposity.53 Other important

physiologic functions of leptin include regulation of

reproductive and immune functions as well as modulation of

insulin sensitivity. Thus, leptin levels regulated by fat stores

may provide a mechanism by which reproductive readiness is

tied to nutritional status as well as an explanation for

suppression of immune function in states of malnutrition.


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Leptin and obesity

Failure to produce leptin (ob/ob mouse) or failure to

produce a functional leptin receptor (db/db mouse and

the Zucker, Koletsky, and SHHF rat models) results

in massive obesity.23,28,54

Such genetic mutations

occur rarely in humans,

23,55

and to our knowledge,have not been documented in dogs, cats, or horses.

Obesity in

speciesotherthangeneticallyengineeredrodentsisusuall

y attributed to other factors, such as high caloric or fat

intake that is disproportionate to the level of physical

activity.15

Obesity unrelated to specific mutations in

leptin or its receptor ischaracterizedby a syndromeof

at least partial leptin resistance and hyperleptinemia.

Hyperleptinemia is also seen with aging and may

occur secondary to weight gain during middle age,

independent of or disproportional to increases in body

fat mass, and as a consequence of aging itself.5659

With leptin resistance, the ability of high levels of

leptin to regulate energy homeostasis is blunted,

abetting further weight gain and predisposing to the

development of metabolic abnormalities and type 2

diabetes mellitus.5966

The blunted response to leptin

may be due in part to saturated transport systems for

leptin across the bloodbrain barrier ortoacquired

defects indownstream signaling in hypothalamic

neurons.11

In adipose tissue, leptin gene expression

increases with age.59

Adipocytes from aged obese rats

have increased levels of SOCS-3, which has a

feedbackinhibitoryeffectonleptinsignalingandfurther

potentiates leptin resistance.67

Leptin resistance with obesity appears to beselective for metabolic functions. This leaves other

functions of leptin intact, contributing to the

development of a variety of co-morbidities associated

with obesity, including cardiac, renal, and vascular

dysfunction. These are at least partially mediated

through a combination of leptin-mediated sympathetic

nervous system hyperactivity,6871

impaired nitric

oxide generation,72,73

and increased endothelin

production.74,75

For example, selective leptin

resistance has been observed in agouti mice in which

the anorexic effect of leptin is blocked by

overexpression of agouti protein (an inhibitor of a-

MSH), but the ability of leptin to stimulate renalsympathetic nerve activity remains intact.68

Leptin has

similar sympathoexcitatory effects in diet-induced

obesity in mice.69

Circulating leptin concentration

correlates with renal sympathetic nerve activity and

urine norepinephrine spillover in men with varying

degrees of obesity.70

In obese humans and rodents,

increases in endothelin contribute to increased

vascular tone, and may play a role in the development

of salt sensitivity.74,76

Generally, leptin appears to be

pro-inflammatory, prothrombotic, and pro-oxidant, therefore

opposing the effects of adiponectin, which will be addressed

in the next section.77

Measurement of leptin

The reported half-life of leptin in the circulation is 25 minutes

for humans,78

1.5 hours for lean mice,79

3 hours for obese

mice,80

and 513 minutes for rats.35,81

Several factors may

account for this wide variability among species, including

methodological differences in the studies, protein binding,

and route or rate of clearance. Leptin binds to the soluble

leptin receptor (Ob-Re), oxidized a2-macroglobulin, and

several other poorly characterized serum binding proteins.82

Leptin does not appear to bind to albumin or lipid but may

aggregate with itself due to its hydrophobicity. All of these

factors may affect distribution and clearance of leptin from

the circulation. Human serum leptin has been shown to be

stable for 2 months at 41C and for 2 years at 201C, and to

tolerate at least 5 freeze thaw cycles.82 Our experience

suggests leptin stability is similar in rodents; however, to our

knowledge, systematic studies have not been published for

dogs, cats, or horses. Multiple variables in reference

populations and methods influence measured leptin levels, as

illustrated in Tables 1 and 2. Owing to the variation in values,

readers are encouraged to consult the original references that

are most relevant to their needs.

To date, the majority of studies have used

radioimmunoassays (RIAs) to measure leptin; however,

ELISAs are becoming more available. The Linco

Multispecies RIA (Linco Research/Millipore, St.

Charles, MO, USA) is the most frequently usedcommercial kit and has been used in cats88

and horses.93

One commercially available enzyme immunoassay (EIA)

also has been evaluated for use in the horse.95

Leptin has

been assessed in relatively few studies in dogs due to

lack of a validated, commercially available test kit,

although one research group has developed an in-house

ELISA.24

While a few studies have used the Linco

Multispecies RIA in dogs with comparable results (Table

1),100

the specificity of the kit for canine leptin is only 3%

as reported by the manufacturer. Millipore has recently

released a new ELISA kit that is specific for canine

leptin, which should aid studies in this species. Serum

and EDTA- or heparin-anticoagulated plasma samples

yield similar results for leptin measured by RIA in

humans82

and this appears to hold true in domestic

animal species (Tables 1 and 2).

When collecting samples for leptin measurement, a

variety of preanalytical factors should be considered.

Circadian rhythm can account for a 30100% difference

between daily peak and trough in human leptin

concentration.101

The fed state may result in serum leptin

concentrations as much as 2-fold higher than those in the


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fasted state. As reviewed above, both sex and

stage of estrus cycle can influence circulating

leptin levels. Fewer studies are available that

address the effects of drug therapy. However,

corticosteroids are well documented to increase

leptin gene expression and secretion and to

potentiate the effect of insulin on leptinproduction in humans and rodent models.23,102

Circulating concentrations of leptin for dogs,

cats, and horses are summarized in Tables 1 and 2 and

are discussed in more detail below.

Dogs

Like humans and rodents, circulating leptin correlates with

body fat mass in the dog. Circulating leptin is


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Table2. Circulating leptin concentrations in horses.

Age Sex Breed Body condition Other factors Lepin (ng/mL) Assay Sample Ref. no.

4 10 yr F (11) TB NR July 4.77 0.45 Multispecies Serum

RIA

Fitzgerald and

McManus93

Mid Sept 8.27 1.02

DecJan 5.92 0.86

JanMar 2.38 0.28

8d24 yr M (14), G (15) QH BCS 38 3.37 0.38 Equine RIAw Serum Buff et al.25

8 d-24 yr F (42) 1.85 0.21

o 2 yr M (5), G (6), F (12) 2.38 0.32

24 yr M (1), G (3), F (10) 2.64 0.55

512 yr M (4), G (3), F (10) 2.93 0.39

412 yr M (4), G (3), M (10) 3.67 0.38

623 yr F (46) LIP 535 10 kg BW Lactating

(1 wk postpartum)

9.5 0.8 Ovine RIAz Plasma Heidler et al.94

519 yr F (11) 522 10 kg BW Nonlactating,nonpregnant

15.0 2.6

79 yr F (5) TB BCS 3 (exercised) Fed 4.23 0.03 EIA Serum Piccione et

al.

95

Fasted (48 hr) 3.96 0.04

F (5) BCS 3.5 (sedentary) Fed 4.24 0.03

Fasted (48 hr) 4.05 0.04

414 yr F (8) Pony BCS 6 Fed 17.20 0.41 Equine RIAw Plasma Buff et al.96

Feed-restricted

(48 hr)

7.29 0.41

34 yrs G (6) STB BCS 4.1 0.1 1.66 0.59 (SD) Multispecies Serum

RIAPratt et al.

97

F (8) BCS 4.8 0.5 2.96 2.05 (SD)

1016 yr F (5), G (2) Various BCS 79 (obese) Median 11.0

(1.030.5)

Equine RIAw Plasma Frank et al.4

716 yr F (5) BSC 46 (nonobese) Median 0.8

(0.511.0)10 3 yr F (23) STB 514 12 kg BW 3.47 0.50 Multispecies Plasma

RIA

Kearns et al.98

4 3 mo F (10), F (2) QH BEL, 227 11 kg BW

QH

1.90 0.34

11 2 yr F (12) STB BCS 6.7 0.2 (unfit;unconditioned)

4.4 2.4 Multispecies Plasma

RIAGordon et al.

99

28 yr M, F, G (34) BCS 4.8 0.1 (fit; exercised) 1.0 0.6

Data are mean SEM unless otherwise indicated.

Linco Multispecies RIA, Linco Research, (now Millipore), St. Charles, MO, USA.

wNoncommercially available RIA as described in reference 25. zNoncommercially

available RIA as described in reference 94.

EIA-2395, DRG Instruments GmbH, Germany.

NR, Not reported; M, male; F, female; G, gelding; STB, Standardbred; QH, Quarter Horse; QH BEL, Quarterhorse Belgium cross; TB, Thoroughbred; LIP,

Lipizzaner; Number of animals shown in parentheses; BW, body weight; BCS, body condition score (scale 19); yr, years; mo, months; hr, hours.

[Correction added after online publication on 6 April 2009: The original Table 2 contained misaligned text. The correct table, above, shows the correctlyaligned text.]

increased in dogs with experimentally induced obesity as well

as in pet dogs with increased body condition scores

(BCS).84,86,103,104

The ob gene is expressed in preadipocytes

and mature adipocytes in WAT from multiple sites in the

dog.105

Unlike species such as human, rodent, and chicken in

which the ob gene may be expressed in other tissues,

expression of the ob gene in dogs appears to be confined to

WAT; whether this finding is dependent on experimental

methodology remains to be determined.23,105

Weight gain

induced by the feeding of a high-fat diet results in increases in

both leptin gene expression in visceral WAT and plasma


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leptin concentrations in dogs.104

Conversely, caloric

restriction and weight loss results in decreased plasma leptin

concentrations.106

The main factor influencing circulating leptin

concentration in dogs appears to be fat mass. However,

like other species, dogs show a transient increase in

circulating leptin following a meal.

107

This postprandialpeak occurs about 58 hours after feeding and leptin

concentration may reach 23 times fasting levels. Thus,

postprandial levels in lean dogs are comparable to levels

observed in fasted dogs with high BCS of 4 to 5/5,86

suggesting that serum or plasma leptin concentrations

must be interpreted with knowledge of the fed/fasted

state. Interestingly, this postprandial peak appears

blunted in thin dogs with BCS of 2/5.108

When dogs are grouped by BCS, there is no

apparent effect of age on plasma leptin, although puppies

(o1 year of age) tended to have lower plasma leptin

concentrations.86

This was speculated to be due to low

body fat mass and a high energy requirement for growthat a young age. In this same study, there was no apparent

effect of sex or neutering in dogs grouped by BCS86

;

however, others have suggested an influence of sex and

estrus cycle.109

Breed may influence leptin levels. In one study,

Shetland Sheepdogs within BCS groups tended to have

higher leptin concentrations than dogs of other breeds

including Miniature Dachshunds, Shih Tzus, and

Labrador Retrievers.86

However the number of animals

per breed was too small to be conclusive and some

common breeds found in the United States were absent

from this study.

Glucocorticoid administration may affect circulating

leptin concentration as well as leptin secretion in

response to a meal. The effect appears to be dependent

on the type and dose of glucocorticoid used. For

example, dexamethasone increases serum leptin levels

and potentiates the leptin peak in response to a

meal,110,111

while oral prednisolone does not appear to

affect leptin levels.111

The effect of methylprednisolone

appears to be dose dependent, with low doses causing an

increase and high doses suppressing leptin

concentration.87

These findings suggest that treatment

with corticosteroids or increased endogenous steroid

production may affect circulating leptin concentrations

and should be considered when evaluating leptin levelsin clinical patients.

Cats

Feline leptin is partially bound to protein in the

circulation.88

Like other species, circulating leptin

primarily reflects body fat mass in cats,88,89,92

and weight

loss is associated with a fall in peripheral blood leptin

levels.112

Leptin levels are mildly increased in the fed

compared with fasted state.88,113

The effect of dietary

composition on leptin levels is not consistent between

studies and appears to be modulated by the relative

insulin resistance and body fat mass of the cats.114,115

Regardless of fat mass, insulin-resistant cats have highercirculating leptin concentrations compared with insulin

sensitive cats.113

Several studies have looked at the effect of neutering on

body weight and circulating leptin in cats. In general,

increases in leptin occur following neutering and are

correlated with the amount of body fat gained

postsurgery,89,90,116

although this finding is not consistent in all

studies.115

There also are conflicting results regarding the

effect of sex. There was no difference in serum leptin

concentration between neutered

maleandfemalecatswithnormal fatmass89

orbetween intact

male and female cats.90

In 1 study, neutered females gained

more weight and had higher leptin levels comparedwithcastratedmales

90whileinanotherstudy castrated males had

greater fat gain and a trend towards higher leptin levels

compared with neutered females.89

In both studies, the group

that had the highest percent bodyfat had the highest average

leptin concentration. If presurgical body weight was

maintained by caloric regulation, males showed small but

significant increases in leptin subsequent to castration,91,114

while females did not show changes in leptin following

ovariohysterectomy.91

This may reflect the leptin lowering

effect of testosterone, as observed in other species. Although

the difference between castrated males and neutered males

was statistically significant, the actual difference was small in

comparison to the effect of weight gain and thus may be ofminor clinical significance (Table 1). No assessment of the

effects of the estrus cycle was done in any of the studies in

cats.

Horses

While fat mass appears to be the primary determinant of

serum leptin concentration in the horse,25,93,98,117

a number of

other factors have been shown to modulate circulating levels.

Fasting results in a decline in serum leptin, which may

decrease by as much as 50% compared with the fed state after

48 hours of feed restriction.95,96,118

Leptin shows a circadian

pattern in horses, with levels peaking at night and a nadir

reached during daylight hours.95,96

However, this finding is

not consistent in all studies,119

and daily fluctuations in leptin

levels result from both the feeding schedule as well as

composition of the feed. Leptin levels will rise 810 hours

subsequent to a high carbohydrate (grain) meal and follow the

rise in insulin levels.120122

In contrast, peaks and troughs in

both insulin and leptin concentrations are blunted in horses

given frequent meals, given ad libitum hay, or on pasture.122


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Thus, husbandry practices have significant impact on

hormonal fluctuationsthat maycontributeto the development

of insulin resistance and hyperleptinemia, an increasingly

common problem in overweight horses. When horses were

matched for BCS, those animals with consistently high serum

leptin levels also were hyperglycemic and hyperinsulinemic

and had exaggerated glucoseandinsulinresponsestodexamethasone.123

These findings are

similar to those in humans with type 2 diabetes mellitus or

metabolic syndrome.124

However, not all overweight mares

are hyperleptinemic and 1 study found that only 35% of

mares with high BCS were hyperleptinemic and insulin

resistant.125

This again is similar to humans in which not all

obese individuals have metabolic derangements.124

To date,

definitive documentation of central or selective leptin

resistance has not been achieved in the horse.

The interaction of sex hormones and leptin is currently

being explored in horses. Geldings and stallions have similar

circulating leptin levels and several studies have noted mild

but significantly higher leptin levels in males compared withfemales.

25,120These data contrast with those in humans in

which leptin levels are higher in women than in men.33,34,126

Neither administration of testosterone to mares127

nor

ovariectomy96

affected peripheral leptin concentration.

Several studies have looked at reproductive status and

leptin in mares. Mares with lower BCS and lower leptin

levels become seasonally anestrus while mares with higher

BCS and higher serum leptin levels continue to cycle

throughout the year.93,117

Blood leptin levels decrease during

the first few days following parturition and remain below

prepartum levels during early lactation.94,128,129

This decrease

in leptin concentration occurs even if BCS remains stable and

may be an adjustment to allow increased caloric intake andavoid negative energy balance during lactation. Interestingly,

this decline in leptin does not seem to impact resumption of

postpartum ovulation.94,130

Leptin also is present in mares

milk, with the concentration in colostrum approximately 2- to

3-fold greater than that found in blood.128,131

It is uncertain if

this high concentration reflects active secretion/concentration

from the blood or local glandular production. The role of

colostral leptin is still uncertain; it has been speculated to aid

in gut development or thermoregulation in the foal. The

concentration of leptin in milk falls within days to below that

found in the mares blood and remains stable thereafter. The

concentration of leptin in the foals blood rises after birth and

stabilizes within a few days to levels similar to those in milk.No work has documented whether maternal leptin contributes

to blood leptin levels in the foal.

Adiponectin

Synthesis and regulation

Adiponectin (also named apM1, Acrp30, GBP28, and

AdipoQ) has very restricted tissue expression and is

thought to be produced almost exclusively by mature

adipocytes. Adiponectin is a 244-amino acid protein and

consists of a signal sequence, a variable domain, a

collagen-like domain, and a globular C-terminal

region.132

The C-terminal globular domain has sequence

homology to complement factor C1q and shows

structural but not sequence similarities to TNFa..

Adiponectin proteins that have undergone extensive post-translational modification are secreted by the adipocyte

as homotrimers.In the circulation,adiponectin may form

trimers, hexamers, or high molecular weight multimers

(HMW, 46 noncovalently bonded trimers). In addition,

the globular domain may circulate independently of the

rest of the molecule. Regulation of multimer formation

and secretion as well as the biological significance of the

various multimeric forms are still under investigation.

Currently, it is thought that the HMW forms have the

most biological activity and are best correlated with

insulin sensitivity.

Adiponectin is one of the most highly expressed

genes in WAT. Secretion of adiponectin by fat cells isstimulated by insulin, and a number of drugs and dietary

constituents modulate blood levels of adiponectin. The

best known pharmaceutical regulators of adiponectin

expression and secretion are the thiazolidinediones

(TZD), which activate PPARg and subsequently

upregulate adiponectin expression.133

Rimonabant, a

selective cannabinoid-1 receptor (CB1) antagonist, also

stimulates adiponectin expression and increases

adiponectinemia, suggesting a role for CB-1 in the

regulation of adiponectin production.134

Various dietary

supplements have been shown to affect circulating

adiponectin levels in rodent models. For example,

supplementation with fish oil,

135

linoleic acid,

136

and soyprotein137

increased circulating adiponectin concentration

in rats in the absence of a change in body weight.

Females have higher total circulating adiponectin

levels compared with males.138,139

This sexual

dimorphism is accounted for by females having a

significantly greater proportion of HMW forms

compared with males, but no difference in the mean

concentration of trimeric or hexameric forms.139141

Testosterone mediates some of this difference by

decreasing the secretion of HMW adiponectin by ad-

ipocytes.142

Studies on the effects of exercise have produced

somewhat conflicting results in humans.143 In general, chronic

exercise training results in small increases in adiponectin

levels. The effect of acute exercise is more variable and

appears to depend on the intensity of exercise as well as the

fitness of the participants. For example, trained athletes

usually show an increase in circulating adiponectin while

unfit or obese individuals may show a decline in adiponectin

levels following a bout of exercise.


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Adiponectin receptors and signaling

The physiologic effects of adiponectin are related to

tissue-specific receptor expression and differences in

binding affinity for the various molecular forms of

adiponectin (reviewed in Kadowaki et al132

). Two

specific adiponectin receptors have been cloned.AdipoR1 is primarily expressed in skeletal muscle, with

affinity for the globular and trimeric forms of

adiponectin, while AdipoR2 is highly expressed in the

liver with affinity for the hexameric and HMW forms of

adiponectin. Both receptors stimulate AMP-activated

protein kinase (AMPK) and PPARa. In the liver, this

results in increased b-oxidation of fats and decreased

gluconeogenesis. In muscle, receptor binding results in

increased b-oxidation of fats as well as increased glucose

uptake. Overall, liver and muscle effects contribute to

increased insulin sensitivity, lowering of blood glucose,

and decreased tissue triglyceride content.

Functions of adiponectin

The best characterized effects of adiponectin include

enhancement of insulin sensitivity, anti-inflammatory

properties, and inhibition of the development of

atherosclerosis.144

Adiponectin appears to play an

important role in increasing insulin sensitivity by

stimulating phosphorylation of AMPK. Activation of

AMPK subsequently increases glucose uptake by

promoting translocation of the glucose transporter,

GLUT4, to the cell surface, increasing glycolysis by

phosphorylation of phosphofructokinase and increasing

fatty acid oxidation by inactivation of acetyl CoAcarboxylase.

A role for adiponectin in cardiovascular function has

been suggested, and treatment with adiponectin may

have a palliative effect on pathologic cardiac remodeling

after myocardial infarction.145

These cardiovascular

effects may stem from adiponectins function as a

vasodilator.146

Adiponectin promotes vasorelaxation

through increased vascular expression of endothelial

nitric oxide synthase and prostacylin synthase.147

It also

is likely that stimulation of AMPK by adiponectin

increases endothelial nitric oxide generation by

endothelial nitric oxide synthase, affecting vascular tone.

Improved insulin sensitivity in endothelial cells may

increase vasorelaxation via Akt-mediated activation of

endothelial nitric oxide synthase. A recent study suggests

that adiponectin relaxes isolated aortic rings and

mesenteric arteries via opening of K1

channels, a

mechanism that is independent of the presence of the

endothelium.146

Adiponectin has anti-inflammatory and anti-atherogenic

properties. These functions appear to be mediated in part by

the ability of adiponectin to suppress TNF-a production by

macrophages and to both suppress myelomonocytic

progenitor cell growth and induce apoptosis.148

Expression of

adhesion molecules by endothelial cells and subsequent

adherence of monocytes is also reduced.149

This curtails

movement of monocytes into subendothelial areas and

inhibits the development of atherosclerotic plaques. Thesesame effects may also provide some protection against

carcinogenesis by inhibiting cancer cell growth and

angiogenesis associated with tumor formation.150

Low

adiponectin levels have been observed in humans with a

variety of cancer types and have been speculated to contribute

to the increased incidence and severity of cancer in

obesity.150,151

Adiponectin and obesity

Unlike leptin, increases in fat mass result in decreased

circulating adiponectin while weight loss results in increased

adiponectin concentrations in humans, primates, and

rodents.152,153

In humans, circulating adiponectin levels are

negatively correlated with body mass index, fasting insulin

concentrations, and plasma triglyceride concentration but are

positively correlated with high density lipoprotein cholesterol

concentrations.154

The decrease in adiponectin in obesity is

more severe with visceral than subcutaneous adiposity in

humans. Changes in adiponectinemia reflect not only total

adiponectin production but changes in the relative proportions

of different molecular weight forms. Overweight and obese

individuals have a relatively lower proportion of the HMW

form of adiponectin compared with other forms, and the

percentage of HMW adiponectin relative to total adiponectin

increases with weight loss.155 The mechanisms underlying

these changes are still being explored. Increased production

of pro-inflammatory cytokines such as TNF-a and IL-6 as

well as reactive oxygen species within the enlarging fat mass

may act as autocrine or paracrine inhibitors of adiponectin

gene expression.156,157

Insulin will downregulate AdipoR1 and

AdipoR2 expression. Therefore, hyperinsulinemia, often

associated with obesity and metabolic syndrome,


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correctly aligned text.]

may contribute to a state of adiponectin resistance through

alterations in receptor availability.132

In humans, decreased circulating adiponectin has been

linked with insulin resistance, type 2 diabetes mellitus,

essential hypertension, and development of progressive

ventricular hypertrophy and diastolic dysfunction.132,158

Spontaneous mutations of the adiponectin gene in humans

and in engineered rodent models corroborate the association

of hypoadiponectinemia with the predilection to develop

metabolic syndrome, type 2 diabetes mellitus, and

cardiovascular disease.132,159,160

While these syndromes are

common co-morbidities associated with obesity, adiponectin

is persistently lower in these conditions even when subjects

are matched for body mass index and adiposity. This suggests

that hypoadiponectinemia may be an independent risk factor

for the development of metabolic and cardiovascular

complications.

Measurement of adiponectin

Adiponectin is present in high concentrations (mg/mL) in

human plasma where it has a half-life of 14 hours.140

Studies

in mice suggest that differences in half-life may depend on

the molecular form, with HMW adiponectin remaining in

circulation longer than smaller forms (9 vs. 4.5 hours,

respectively).141

Studies in dogs and horses have used the

commercially available RIA from Linco as well as an ELISA

(Otsuka, Pharmaceuticals, Tokushima, Japan) to measure

adiponectin (Table 3). Millipore (formerly Linco, St. Charles,

MO, USA) now offers a canine-specific ELISA. These

commercial assays measure total adiponectin. Recent studies

in humans have suggested that measurement of various

molecular weight forms may provide additional risk

assessment for the development of disease such that newer,

less complicated, ELISAs are being developed to assess

individual molecular weight forms.139,155

The clinicalimportance of differentiating the various molecular weight

forms have not been addressed in dogs, cats, or horses.

Adiponectin can be measured in serum or plasma.

Samples anticoagulated with EDTA or heparin have

comparable results. One study in humans suggested that

adiponectin is stable for up to 36 hours in whole blood

before separation of plasma if kept on ice.165

Similar

evaluations have not been done in domestic animal

species.

Adiposity appears to be the primary factor affecting

circulating adiponectin levels. Unlike leptin, adiponectin

does not have a circadian pattern in humans.166

There is

no consensus as to whether adiponectin levels change

between the fed and fasted state or in response to glucose

tolerance testing. The changes are generally mild and

likely influenced by the metabolic state of the test

subjects and the composition of the meal.167,168

Adiponectin in dogs, cats, and horses

Table3. Circulating adiponectin concentrations in dogs and horses.

Species Age Sex Breed Body condition Adiponectin (mg/mL) Assay Sample Ref. no.

Dog 21.6 1.2 mo SF (7) Beagle Lean 94 12 ng/mL RIA Plasma Gayet et al.104

After 25% weight gain 52 6 ng/mL

26 yrs SF, M (5) Beagle BCS 4 to 5 33.6 4.9 Murine/ratELISAw

Plasma Omachi etal.

161Various M (6), F (4) Mixed breed 9.329.5 kg BW 1.22 (range 0.851.5) RIA Serum Brunson et

al.162

13 yrs CM (6) SF (16) Beagle Before weight gain 37.7 2.0 Murine/ratELISAw

Plasma Ishioka et al.163

After 30% weight gain 28.1 2.3

5 mo16 yr M, F (34) Various breeds BCS 3 (optimal) 33.4 2.9

Various (20) Client owned BCS 4 (overweight) 24.0 2.8Various (17) BCS 5 (obese) 16.8 3.0

M 33.8 4.6

F 32.9 3.5

NR M, F (4) Mix 23.1 0.6 kg BW 15.2 2.2 Murine/ratELISAw

Plasma Moore et al.164

Horse 11 2 yr F (12) STB BCS 6.7 0.2 (unfit) 1.3 0.1 RIA Plasma Gordon et al.99

28 yr M, F, G (34) BCS 4.8 0.1 (fit) 1.8 0.05

10 3 yr F (23) STB 514 12 kg BW 2.69 0.17 RIA Plasma Kearns et al.98

4 3 mo F (10), F (2) QH Bel, QH 227 11 kg BW 4.34 0.12

34 yrs G (6) STB BCS 4.1 0.1 4.84 0.66 RIA Plasma Pratt et al.97

F (8) BCS 4.8 0.5 4.49 0.59

Data are mean SEM unless otherwise indicated. Linco

Research (now Millipore), St. Charles, MO, USA. wOtsuka

Pharmaceuticals, Tokushima, Japan.

M, male; F, female; G, gelding; MC, castrated male; SF, spayed female; STB, Standardbred; QH, Quarter Horse; QH BEL, Quarter Horse Belgium cross;

number of animals indicated in parentheses; BW, body weight; BCS, body condition score (dog scale 1 5; horse scale 19); yr, years; mo, months; hr,

hours. [Correction added after online publication on 6 April 2009: The original Table 3 contained misaligned text. The correct table, above, shows the


13/22


14/22



appears to be related to increased expression or activation of

PPARg.185,186

While a few studies have documented activation of the

RAS in diet-induced obesity in dogs,173,174

the impact of

alterations of RAS on obesity-related disorders in dogs, cats,

and horses is incompletely characterized at this time. The

demonstrated significance of RAS in people and laboratoryanimals suggests this system is a good candidate for

evaluation in the pathophysiology of obesity-related disorders

in domestic species, especially because many of the assays

required are functional and should have broad species

applicability.187190

Resistin

Resistin is a relatively recently described adipokine and was

originally demonstrated as a product of murine adipocytes.191

While resistin also is expressed by human adipocytes, it

appears to be primarily produced by macrophages in thisspecies. Resistin expression has been demonstrated in fat and

mammary tissue from cattle,192

and in fat and predominantly

leukocytes from pigs.193

Expression of resistin has not yet

been documented in dogs but this may be due to technical

issues. Resistin is a cysteine-rich protein that is secreted as a

dimer. The amino acid homology between human and murine

resistin is relatively low (60%) but appears to be higher

between human, bovine, and porcine sequences.194

The

receptor for resistin currently is unknown.

Most studies on the effects of resistin have been

performed in rodent models (recently summarized by

Lazar191

). Resistin secretion follows a similar pattern to

that observed with leptin. Circulating levels increase with

increasing fat mass and following a meal.

Hyperresistinemia contributes to the development of

insulin resistance and metabolic derangements

compatible with type 2 diabetes mellitus. Resistin is

proinflammatory and induces upregulation of vascular

adhesion molecules and stimulation of proinflammatory

cytokine secretion by macrophages. Increased circulating

resistin in humans correlates with atherosclerosis.

Resistin is an adipokine that has not been well studied in

domestic species, but is a logical candidate for evaluation

in obesity-related disorders once analytical issues are

worked out.

Inflammatory cytokines

Fat pads are a source for a variety of inflammatory

cytokines, which also may be considered as adipokines.

Recent data suggest that both macrophages and white

adipocytes are the source of inflammatory cytokines such

as TNF-a, interferon-g, interleukins such as IL-1, IL-6,

IL-8, and IL-10, monocyte chemotactic protein-1, and

complement proteins.195

Obesity is considered to be a

cause of chronic inflammation, in which macrophages

infiltrate the enlarging adipose mass and local and

circulating levels of proinflammatory cytokines are

increased.196

Some authors feel that macrophages do not

initiate the inflammatory process, but rather amplify a

response to hypoxia in poorly vascularized areas of the

expanding adipose tissue mass.

197

Inflammation is associated with insulin resistance

via poorly characterized mechanisms, with insulin

resistance contributing to the metabolic derangements

that commonly accompany obesity.198

Excessive

circulating free fatty acids that are present with

overnutrition/obesity appear to activate the innate

immune response via Toll-like receptor 4 and increased

NF-kB signaling,199,200

although the exact mechanism for

the induction of insulin resistance is not clear. Given the

newly documented anti-inflammatory, antithrombotic,

and vasodilatory functions of insulin, impaired insulin

responsiveness has multiple pathways by which it may

modulate comorbidities observed with weight gain.201

There is also evidence that insulin resistance may

contribute to breast cancer development, potentially via

its effect on tissue availability of insulinlike growth

factor-1.202

Interestingly, TNF-a has effects on adipose tissue as

well: it inhibits adipocyte differentiation, thereby leading to

decreased lipid storage capacity; promotes lipid

mobilization; and impairs brown adipose tissue function. In

a nonobese individual, these effects may promote fuel

availability; however. in obesity, they exacerbate

hyperlipidemia and lipotoxicity in other organs.203

Summary

Adipose is an important endocrine organ. It is a

developmentally dynamic tissue with the potential to

produce a broad spectrum of biologically important

modifiers. Adipokines secreted by adipose tissue are key

regulators of energy metabolism, cardiovascular health,

and immune function, and their production and function

may be influenced by nutrition and reproductive status,

with some species-specific considerations. Dysregulation

of adipokines appears to contribute to the development of

a number of complications associated with obesity,including metabolic syndrome, type 2 diabetes,

cardiovascular disease, and cancer via changes in whole

organism physiology or at the local tissue level. These

connections have mostly been explored in humans and

rodent models; similar mechanistic studies are in their

early stages in dogs, cats, and horses. Evaluation of

individual adipokines shows promise as means to assess

pathophysiologic mechanisms and risk for development


15/22



of obesityrelated conditions in veterinary patients. An

understanding of the biology and regulation of

adipokines, and of preanalytical factors that may

influence circulating adipokine levels, will be important

in interpreting measurements of these endocrine factors.

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