TIPS-1235; No.
of Pages 10
Review
Adipokines in health and disease
Mathias Fasshauer and Matthias Blüher
Department of Medicine, University of Leipzig, Liebigstrasse 20, D-04103 Leipzig, Germany
Obesity increases the risk for metabolic, cardiovascular,
chronic inflammatory, and several malignant diseases
and, therefore, may contribute to shortened lifespan.
Adipokines are peptides that signal the functional status
of adipose tissue to targets in the brain, liver, pancreas,
immune system, vasculature, muscle, and other tissues.
Secretion of adipokines, including leptin, adiponectin,
fibroblast growth factor 21 (FGF21), retinol-binding pro-
tein 4 (RBP4), dipeptidyl peptidase 4 (DPP-4), bone mor-
phogenetic protein (BMP)-4, BMP-7, vaspin, apelin, and
progranulin, is altered in adipose tissue dysfunction and
may contribute to a spectrum of obesity-associated dis-
eases. Adipokines are promising candidates both for
novel pharmacological treatment strategies and as di-
agnostic tools, provided that we can develop a better
understanding of the function and molecular targets of
the more recently discovered adipokines.
Adipokines
Obesity significantly increases the risk for metabolic dis-
eases [type 2 diabetes mellitus (T2DM), fatty liver disease,
and dyslipidemia], cardiovascular disorders (hypertension,
coronary heart disease, and stroke), diseases of the central
nervous system (dementia), obstructive sleep apnea, and
different types of cancer [1–3]. The main functions of
adipose tissue include the storage of triglycerides under
conditions of excess calories and their release during per-
iods of fasting, thermoregulation, and mechanical organ
protection [4,5]. Adipose tissue has also been recognized as
an endocrine organ [4–6]. Adipocytes, precursor, endothe-
lial and immune cells, fibroblasts, and others contribute to
the release of metabolites, lipids, and bioactive peptides;
so-called ‘adipokines’ (Figure 1). To identify the complete
adipose tissue secretome, several proteomic profiling
approaches have been performed recently [7–9]. Although
the full set of human adipokines is still not entirely char-
acterized, it has become clear that adipose tissue is a
source of more than 600 potentially secretory proteins
[7]. Adipokines contribute to the regulation of appetite
and satiety, fat distribution, insulin secretion and sensi-
tivity, energy expenditure, endothelial function, inflamma-
tion, blood pressure, and hemostasis [3,10] (Table 1).
Within adipose tissue, adipokines have been shown to
modulate adipogenesis, immune cell migration into adi-
pose tissue, and adipocyte metabolism and function
[3,11,12] (Figure 2). At the systemic level, adipokines
Corresponding author: Blüher, M. (bluma@medizin.uni-leipzig.de).
Keywords: adipokines; obesity; adipose tissue; type 2 diabetes mellitus.
0165-6147/
ß 2015 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tips.2015.04.014
regulate or modulate different biological processes in tar-
get organs, including the brain, liver, muscle, vasculature,
heart and pancreas, immune system, and others (Figure 2)
[10,11]. Adipokines may exert specific effects on a variety of
biological processes, including: immune response [e.g.,
adipsin, acylating simulation protein (ASP), and serum
amyloid A3 (SAA3)]; inflammation [e.g., interleukin (IL)-
1b, -6, -8, and -10, tumor necrosis factor a (TNFa), C-
reactive protein (CrP), monocyte chemotactic protein-1
(MCP-1), resistin, progranulin, and chemerin]; glucose
metabolism [e.g., leptin, adiponectin, DPP-4, FGF21, resis-
tin, vaspin, and angiopoietin-like protein 8 (Angptl8)];
insulin sensitivity (e.g., leptin, adiponectin, chemerin,
RBP4, and omentin); insulin secretion (e.g., apelin and
nesfatin-1); blood pressure (e.g., apelin and angiotensino-
gen); myocardial contractility [e.g., fatty acid binding pro-
tein-4 (FABP-4)]; cell adhesion [e.g., plasminogen activator
inhibitor-1 (PAI-1)]; vascular growth and function [e.g.,
vascular endothelial growth factor (VEGF)]; adipogenesis
and bone morphogenesis (e.g., BMP-4 and -7); growth [e.g.,
insulin-like growth factor-1 (IGF-1), transforming growth
factor b (TGFb), and fibronectin]; lipid metabolism (e.g.,
soluble CD36 and apelin); lipid accumulation in the liver
(e.g., fetuin-A); regulation of appetite and satiety (e.g.,
leptin and vaspin); and other biological processes
[11]. Therefore, alterations in adipokine secretion may link
obesity to its inflammatory, metabolic, and cardiovascular
comorbidities [3,10]. Importantly, the function, molecular
targets, and potential clinical relevance of many adipo-
kines are still not known. Functional characterization, in
particular of the more recently identified adipokines, is a
major task in future adipokine research.
Our understanding of the mechanisms linking obesity
and adipose tissue dysfunction to metabolic and cardiovas-
cular disorders is still incomplete. Alterations in adipokine
secretion may contribute to obesity-related diseases. Within
the past few years, the number of newly discovered adipo-
kines has increased significantly and unraveling adipokine
effects has become a hot topic in obesity research. Here, we
discuss the role of selected adipokines as promising candi-
dates for future treatment of obesity and obesity-related
diseases. We present research data on how adipose tissue
dysfunction changes the adipokine secretion pattern, and
focus on the potential of leptin, adiponectin, FGF21, BMP-4,
BMP-7, vaspin, apelin, DPP-4, TNFa, and IL-1b as candi-
dates for novel pharmacological treatment strategies.
Adipose tissue function determines the adipokine
secretion profile
In overweight and obese individuals, genetic and environ-
mental factors result in a chronic positive energy balance
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Review Trends in Pharmacological Sciences xxx xxxx, Vol. xxx, No. x

Secretory cells of
adipose ssue
Cytokine and cytokine-
like proteins Adipokines
Lepn
TNFα
Adiponecn
IL-6
Visfan/Nampt/PBEF
MCP-1
Vaspin
Resisn • Adipocytes RBP4
Progranulin • Precursor cells FGF21
• Endothelial cells BMPs
• Macrophages Nesfan-1
Proteins of the
• Foam cells Cathepsins
fibrinolyc system
• Neutrophils Apelin
PAI-1
• Lymphocytes Omenn
Tissue factor
• Fibroblasts Lipocalin
• Others and hundreds more
Complement and
complement-related proteins
Adipsin Proteins of RAS
Complement factor B Angiotensinogen
ASP
CTRPs Endocannabinoids and
Lipid transport other lipids
Enzymes Apolipoprotein E Anandamide
DPP-4 Cholesterol ester transfer protein 2-AG
Lipoprotein lipase Free fay acids
TRENDS in Pharmacological Sciences

Figure 1. Factors released or secreted by adipose tissue. Adipocytes, immune cells, fibroblasts, endothelial cells, and others contribute to the release of metabolites, lipids,
and adipokines. Examples of adipose tissue-derived molecules are provided here. Abbreviations: 2-AG, 2-Arachidonoylglycerol; ASP, acylating simulation protein; BMPs,
bone morphogenetic proteins; CTRPs, C1q/TNF-related proteins; FGF21, fibroblast growth factor 21; MCP-1, monocyte chemotactic protein-1; PAI-1, plasminogen activator
inhibitor-1; RAS, renin angiotensin system; RBP4, retinol binding protein 4. Modified from [3,5,6].

Genec and environmental factors that leads to weight gain. With increasing body weight,
energy imbalance adipose tissue changes its size, distribution, cellular com-
position, and function (Figure 3). The expansion of adipose
Adipose ssue size, cellular composion, and funcon
tissue significantly influences adipocyte biology and may
lead to either the physiologic response of adipose tissue or
to impaired adipose tissue function (Figure 3). In the latter
Impaired
i
(adipocyte hypertrophy, ectopic
case, individuals develop adipocyte hypertrophy (rather
Physiologic
fat accumulaon, and adipose than hyperplasia), ectopic fat deposition, hypoxia, and
ssue inflammaon) chronic stress in adipose tissue, which subsequently causes
an adverse adipokine secretion profile [4] (Figure 3). Hy-
pertrophy of adipocytes is considered a key event associat-
Normal Adverse ed with a loss of insulin sensitivity in both lean and obese
adipokine adipokine
conditions [4,13,14]. Individuals with larger adipocytes
secreon secreon
typically have elevated proinflammatory factors, including
leptin, IL-6, IL-8, and monocyte chemotactic protein 1
Metabolic, inflammatory,
Health (MCP-1) [15], reduced levels of the insulin sensitivity-
and cardiovascular
diseases, cancer related adipokine adiponectin and anti-inflammatory IL-
10 [4,15,16], as well as increased basal and catecholamine-
TRENDS in Pharmacological Sciences
stimulated lipolysis [17]. Adipocyte hypertrophy most like-
Figure 2. Local and systemic effects of adipokines. Within adipose tissue ly initiates alterations in adipose tissue, which predisposes
(representative histologic slide of human omental adipose tissue), adipokines adipose tissue to immune cell infiltration and an adverse
contribute to the regulation of adipogenesis, immune cell migration, adipocyte
metabolism, triglyceride storage, and others. At the whole-body level, adipokines
(proinflammatory, diabetogenic, and atherogenic) adipo-
are important regulators of appetite and satiety, energy expenditure, kine secretion pattern [4]. In addition, adipokine secretion
inflammation, blood pressure, hemostasis, endothelial function influence, insulin may be influenced by fat distribution or may contribute to
sensitivity, and energy metabolism in insulin-sensitive tissues, such as liver,
muscle, and fat, as well as insulin secretion in pancreatic b cells. Modified from
distinct fat distribution subtypes [18]. Several adipokines,
[10,11]. including leptin, IL-6 [19], RBP4 [20], chemerin [21],
2
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Table 1. The role of selected adipokines in health and diseasea

Adipokine Main actions
Adiponectin Improves insulin sensitivity; antidiabetic, antiatherogenic, and anti-inflammatory
Adipsin Activates the alternative complement pathway
Angiopoietin-like protein 8 Promotes pancreatic b cell proliferation; improves glucose tolerance
Apelin Inhibits insulin secretion
BMP-4 Regulates adipogenic precursor cell commitment and differentiation
BMP-7 Stimulates brown adipogenesis; reduces food intake; increases energy expenditure
Cathepsins S, L, K Regulate glucose metabolism and adipose tissue mass
Chemerin Chemoattractant protein; regulates adipogenesis
Clusterin Promotes tumor progression and angiogenesis
DPP-4 Degrades GIP and GLP-1; inhibitors in clinical use for T2DM
FABP-4 Associated with increased T2DM risk and impaired myocardial contractility
Fetuin-A Reflects liver fat content; associated with lipid-induced inflammation and insulin resistance;
promotes cancer progression
FGF21 Stimulates glucose uptake into adipocytes; increases thermogenesis, energy expenditure, and fat utilization;
improves glucose and lipid metabolism
Gremlin-1 Inhibits BMP-4 and BMP-7
IL-1b Proinflammatory
IL-6 Proinflammatory
Leptin Satiety signal; regulates appetite, food intake, locomotor activity, energy expenditure, fertility, and other
processes
Lipocalin 2 Related to insulin resistance and inflammation
MCP-1 Chemoattractant protein; adipose tissue inflammation
Nesfatin-1 Direct glucose-dependent insulinotropic effect on b cells
Omentin Anti-inflammatory; insulin sensitizing
Progranulin Chemoattractant protein; neurodegenerative diseases; adipose tissue inflammation
RBP4 Related to insulin resistance, visceral fat distribution, and dyslipidemia
Resistin Related to obesity, insulin resistance, and inflammation
TGFb Regulates cell proliferation, differentiation, and apoptosis
Tissue inhibitor of matrix Decreases adipogenesis; impairs glucose tolerance
metalloproteinase-1
TNFa Proinflammatory
Vaspin Serine protease inhibitor; decreases food intake; improves hyperglycemia
VEGF Stimulates angiogenesis in adipose tissue
Visfatin/PBEF/Nampt Nampt-mediated systemic NAD biosynthesis is critical for b cell function
Wnt1 inducible signaling Regulates adipogenesis and adipose tissue inflammation
pathway protein 1
a
Modified from [3,5,10].

progranulin [22], and others, are differentially expressed
in various fat compartments and correlate with obesity-
related traits, further supporting their role as potential
mediators of metabolic alterations associated with a dis-
tinct fat distribution [18,23]. The chronically altered adi-
pokine secretion may not only reflect adipose tissue
dysfunction, but also contribute to the development of
metabolic, cardiovascular, inflammatory, and malignant
diseases (Figure 3). Moreover, using an unbiased hierar-
chical clustering approach, two major adipokine clusters
were recently identified that are related to either body fat
mass and inflammation or a combined trait of insulin
sensitivity, glucose, and lipid metabolism [23]. In these
analyses, it was found that even including 20 different
adipokine serum concentrations in a T2DM prediction
model did not reach the sensitivity and specificity of clas-
sical parameters [e.g., hemoglobin (Hb) A1c, homeostatic
model assessment-insulin resistance (HOMA-IR)] for the
diagnosis of the disease [23], suggesting that measurement
of circulating adipokines alone is currently not clinically
useful for the diagnosis of metabolic diseases. By contrast,
individuals who remain insulin sensitive despite obesity
[body mass index (BMI) >40 kg/m2] could be clearly dis-
tinguished from age-, gender-, and BMI-matched insulin-
resistant metabolically healthy obese patients by a normal
adipokine pattern [16]. In the future, adipokines may offer
new opportunities for the pharmacotherapy of obesity and
obesity-related diseases and as diagnostic tools [10].
An in-depth discussion of most adipokines is beyond the
scope of this overview. Therefore, we focus here on selected
adipokines that are currently used for pharmacotherapy
(leptin) or have the potential to be used as therapeutic tools
(adiponectin, FGF21, BMP-7, vaspin, and apelin) or tar-
gets (DPP-4, IL-1b, TNFa, and BMP-4).
Leptin
Although the endocrine function of adipose tissue has been
established by observations that adipsin/complement fac-
tor D [24–26] and sex steroids [27] are secreted from
adipose tissue, the discovery of leptin in 1994 [28] could
be considered the initial milestone for adipokine research
[10]. Since then, leptin has represented the prototype for
all subsequently identified adipocyte-secreted hormones
[10]. The cloning of leptin also marked the identification
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Appete
Saety
Energy expenditure
Acvity
Immune system
Immune cell aracon Blood pressure
Differenaon Endothelial funcon
Systemic inflammaon Heart muscle contraclity
Wound healing Smooth muscle cells

Insulin sensivity
Lipid accumulaon
Hepatokine secreon
Lipid metabolism
Growth factors

Insulin secreon
Glucagon secreon
Insulin sensivity

Insulin sensivity
Myokine secreon
Lipid storage
Triglyceride storage
Insulin sensivity
Glucose and lipid transport
Adipokine secreon
Differenaon
Cell growth Resorpon
Fat distribuon Incren secreon
Browning

TRENDS in Pharmacological Sciences

Figure 3. Model of the development of either normal or adverse adipokine secretion. As a result of the interaction between genetic and environmental factors, a positive
energy balance affects the size, distribution, cellular composition, and function of adipose tissue. As long as these characteristics of adipose tissue are regulated in a
physiologic manner, adipokine secretion is normal and may contribute to whole-body homeostasis and ‘health’. However, typically a chronic positive energy balance leads
to impaired adipose tissue function, characterized by adipocyte hypertrophy, adipose tissue inflammation, and ectopic fat deposition, which lead to an adverse adipokine
secretion pattern and subsequently contribute to metabolic, cardiovascular, and inflammatory diseases, and cancer.

of the mechanism underlying the extremely obese pheno-
type of the ob/ob mouse model, which carries a mutation in
the ob gene subsequently leading to leptin deficiency
[28]. For the rare cases of monogenetically inherited leptin
deficiency in humans, recombinant leptin is now available
for compassionate use and leads to significant weight loss
[29,30]. Leptin is a 16-kDa protein of 167 amino acids,
which circulates both in its free form and bound to proteins.
Circulating leptin is directly proportional to body fat mass
[31]. Leptin signals via the leptin receptor on target cells, is
secreted from adipocytes, and has an important role in the
regulation of satiety, appetite, food intake, reproductive
function, fertility, puberty, activity, energy expenditure,
atherogenesis (reviewed in [10,31]), and fetal growth
[32]. In the hypothalamus, leptin increases anorexigenic
and decreases orexigenic peptide synthesis, subsequently
resulting in reduced appetite [31].
In addition, leptin may exert insulin-sensitizing effects
and is considered an important regulator of b cell mass and
survival (reviewed in [3]). Given its appetite-reducing
function in normal or low circulating leptin states, recom-
binant leptin has been developed as a weight loss phar-
macotherapy for obesity [10,11,29]. Against expectations,
4
leptin treatment of obese patients had only a little effect on
weight loss; both high leptin doses or treatment with
pegylated leptin once weekly did not cause significant
weight loss, but did increase the risk for adverse effects
of recombinant leptin therapy [33,34]. The most likely
reason for the lack of leptin effects on body weight reduc-
tion is the development of central leptin resistance or
tolerance in obese patients with already very high circu-
lating leptin levels [10,11]. This hypothesis is further
supported by clinical studies demonstrating that leptin
given in combination with amylin (pramlintide), which is
co-secreted with insulin from pancreatic b cells and may
improve glycemic control as well as leptin sensitivity, is
effective to induce weight loss [35,36]. Recently, a random-
ized clinical trial using a combination of pramlintide with
metreleptin, a synthetic analog of leptin, in obese patients
was terminated, because of adverse events, such as anti-
body generation and skin reactions [11,37]. However, for
the treatment of lipodystrophy, metreleptin is already an
approved pharmacotherapy in the USA and Japan, and
further indications, such as hypothalamic amenorrhea or
Rabson–Mendenhall syndrome, are currently under con-
sideration [10,11,38].
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To date, leptin is the best example of a successful path
from its discovery to the clinical application of an adipo-
kine.
Adiponectin
Adiponectin was discovered in 1995, shortly after leptin,
and has been characterized in mice as the mRNA tran-
script most highly expressed in adipocytes [39–42]. Adipo-
nectin is a 30-kDa protein of 244 amino acids and signals
via at least two adiponectin receptors, AdipoR1 and Adi-
poR2, on target cells [39]. It has become a biochemical
paradigm of proteins that are secreted without using the
canonical secretory pathway. Adiponectin is almost exclu-
sively produced by adipocytes and has gained a lot of
interest due to its insulin sensitizing, anti-inflammatory,
and antiapoptotic properties [3,32,39]. Moreover, adipo-
nectin enhances insulin secretion by stimulating both the
expression of the insulin gene and exocytosis of insulin
granules. Adiponectin also acts in the brain to increase
energy expenditure and thereby may promote weight loss
[43]. In clinical studies, circulating adiponectin is indepen-
dently and negatively related to facets of the metabolic
syndrome, including insulin resistance, body weight, blood
pressure, and serum lipids [3,32].
Post-translational adiponectin modifications result in
secreted oligomers of 90-kDa trimers, which are found in
the circulation as 180-kDa hexamers [low molecular
weight (LMW)] and 18- to 36-mers [high molecular weight
(HMW)] [39,43]. HMW adiponectin correlated better with
systemic insulin sensitivity compared with LMW adipo-
nectin in both mouse and human studies [39,43].
The molecular actions of adiponectin suggest that the
molecule itself or agonists of its receptors have potential for
the treatment of obesity and its comorbidities [39]. Indeed,
in rodent models, adiponectin administration improved
insulin sensitivity and glucose metabolism, increased in-
sulin secretion, and reduced body weight [39,44]. Very
recently, it was demonstrated that so-called ‘AdipoRon’,
an orally active, synthetic small-molecule adiponectin re-
ceptor agonist, significantly improved insulin sensitivity
and glucose tolerance in mice [45]. In high fat-fed db/db
mice, treatment with AdipoRon extended longevity [45]
supporting previous suggestions that high adiponectin
serum concentrations are associated with prolonged life
span in obesity [46]. Of note, adiponectin levels have been
shown to inversely correlate with obesity, visceral fat
distribution, T2DM, and other obesity-related diseases
[32,39,43]. Therefore, in addition to its potential future
clinical importance as a therapeutic tool, adiponectin
represents a promising and easily detectable stable mark-
er for a variety of diseases [10]. However, in large longi-
tudinal studies, higher adiponectin concentrations have
been suggested as either a positive marker for all-cause
mortality, heart failure, and coronary artery disease
[47,48] or a negative predictor of cardiovascular events
[49], whereas other studies did not find any association
between circulating adiponectin and cardiovascular dis-
eases [50]. By contrast, higher adiponectin levels were
associated with a substantially reduced risk of developing
T2DM in 27 548 apparently healthy participants of the
population-based European Prospective Investigation into
Trends in Pharmacological Sciences xxx xxxx, Vol. xxx, No. x
Cancer and Nutrition (EPIC) Potsdam cohort [51]. Low
circulating adiponectin has been shown to predict T2DM
even beyond the associations with age, gender, fat distri-
bution, BMI, smoking, exercise, alcohol consumption, edu-
cation, and HbA1c [51]. In accordance with these
epidemiologic data, it was recently shown that, together
with immune cell infiltration into visceral adipose tissue,
adiponectin is the strongest predictor of insulin sensitivity
in metabolically healthy obese individuals [16].
Taken together, adiponectin and adiponectin-pathways
are promising candidates for future development in both
the pharmacotherapy and prediction of cardiometabolic
diseases.
FGF21
FGF21 (23 kDa, 209 amino acids) is a member of the FGF
superfamily that is produced by the liver, adipose tissue,
and skeletal muscle [52]. Through direct effects on specific
FGF receptors, FGF21 together with the cofactor b-Klotho
has been shown to exert glucose- and lipid-lowering as well
as thermogenic effects [52–55]. In animal studies, recom-
binant FGF21 reduced hyperglycemia along with addition-
al beneficial metabolic effects [52]. These FGF21 effects
could be due, at least in part, to its role in promoting
browning of white adipose tissue and in adaptive thermo-
genesis [55]. In humans, similar effects were shown in a
randomized, placebo-controlled, double-blind, proof-of-con-
cept trial on the effects of LY2405319 (an FGF21 variant)
in obese patients with T2DM [53]. Over a treatment period
of 28 days, LY2405319 significantly improved body weight,
fasting insulin, adiponectin, dyslipidemia [including
decreases in low-density lipoprotein (LDL) cholesterol
and triglycerides, and increases in high-density lipoprotein
(HDL) cholesterol], and a shift to a potentially less athero-
genic apolipoprotein concentration profile [53]. In contrast
to FGF21 overexpression studies in transgenic mice or of
recombinant FGF21 treatment in humans, there was only
a trend for a glucose-lowering effect of LY2405319 in the
clinical study [53].
Counterintuitively to data from FGF21 treatment or
overexpression studies, FGF21 serum concentrations were
elevated in states of insulin resistance and obesity in
clinical studies [56]. This may suggest either the develop-
ment of FGF21 resistance in insulin-resistant states or an
adaptive response to endogenously elevated circulating
FGF21 concentrations.
Although treatment with this FGF21 variant shows
promising results for potential future clinical use, safety
concerns associated with targeting the FGF21 pathway
have emerged [57].
Mice with a transgenic overexpression of FGF21 have
reduced body length, most likely due to a decrease in bone
mass [57,58]. However, FGF21 transgenic mice have in-
creased longevity and remain apparently healthy through-
out their lifespan [59]. Data from several FGF21
transgenic and knockout mouse models led to the hypoth-
esis that FGF21 is a critical regulator of bone turnover
[57]. In the context of potentially harmful adverse effects
on the skeletal system, it remains an open question wheth-
er this might have negative consequences for the potential
clinical use of FGF21-based treatment strategies.
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Regardless of its future clinical use, the FGF21 drug
discovery path from identification in a functional in vitro
screen, to the evaluation of its utility in patients [57], may
serve as an example of successful translational adipokine
research.
BMP-4 and -7
BMPs are members of the TGFb superfamily and regulate
several processes of organogenesis, patterning during em-
bryonic development, brown and white adipogenesis, and
energy expenditure [60–63]. BMP-4 is a 46-kDa protein
and BMP-7 a 49-kDa protein circulating bound to albumin
and other proteins. Both BMPs are expressed in different
tissues (e.g., placenta, thyroid, skin, adipose tissue, and
digestive tract) and signal via two specific BMP receptors,
BMPR1 and BMPR2, on target cells. Adipose tissue ex-
pression and/or serum concentrations of different BMPs
are associated with obesity and fat distribution [18]. More-
over, it has been recently demonstrated that BMP-7 has a
role in appetite regulation [63]. Systemic treatment of diet-
induced obese mice with BMP-7 led to a significant reduc-
tion in body weight and improvement of metabolic param-
eters, most likely due to increased energy expenditure and
decreased food intake [63]. The reduction in appetite was
also observed in leptin-deficient ob/ob mice, suggesting
that the action of BMP-7 on food intake is independent of
leptin [63]. Of note, human recombinant BMP-7 is already
available under the brand name ‘OP1’, which is used in the
context of surgical procedures to aid bone fusion after
fractures [64]. So far, no local or systemic adverse events
have been reported from this clinical application
[64]. Therefore, it is not unlikely that recombinant BMP-
7 may also enter the development path as a treatment of
obesity or metabolic diseases.
BMP-7 may not be the only BMP with a potential future
clinical application. It has been recently shown that dif-
ferentiated human adipocytes can promote adipogenesis
via endogenous BMP-4 activation, a process that may be
counterbalanced by the expression of the BMP-4 (and -7)
inhibitor Gremlin-1 [65]. BMP-4 is secreted by differenti-
ated preadipocytes and adipocytes, with higher expression
in larger adipocytes [65]. BMP-4 alone, and/or suppression
of Gremlin-1, causes increased peroxisome proliferator-
activated receptor g (PPARg) expression and drives pre-
adipocytes towards a beige/brown adipocyte phenotype
[66]. Recently, brown adipose tissue gained a lot of scien-
tific interest with the notion that its occurrence in adult
humans is associated with lower BMI, younger age, and
normal glucose metabolism [67–69]. Therefore, there is
growing scientific interest in transforming white into
brown adipose tissue as a novel strategy to treat obesity
and its related metabolic diseases. BMP-4-related mecha-
nisms could represent a future tool for this therapeutic
strategy. In hypertrophic obesity, adipose precursor cells
are resistant to BMP-4, which may contribute to the limit-
ed expandability of adipose tissue and, subsequently, to
obesity-related metabolic diseases [16,65]. Taken together,
these data underscore the importance of BMPs in regulat-
ing food intake, energy expenditure, and adipogenesis, and
suggest BMPs as a new therapeutic approach to treat
obesity and its comorbidities.
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Vaspin
Visceral adipose tissue-derived serpin (vaspin) was identi-
fied as a member of the serine protease inhibitor family.
Vaspin (47 kDa, 415 amino acids) was found to be highly
expressed in visceral adipose tissue of Otsuka Long-Evans
Tokushima Fatty (OLETF) rats at the age when obesity
and insulin plasma concentrations peaked [70]. It is not yet
known whether vaspin circulates in its free form or bound
to proteins. Elevated vaspin serum concentrations are
associated with obesity, as well as impaired insulin sensi-
tivity, fitness level, and leptin serum concentrations
[71]. In subsequent studies, it became clear that vaspin
expression is not restricted to adipose tissue and can be
detected in the skin, stomach, and rodent hypothalamus
and pancreatic islets [72,73]. Recombinant vaspin admin-
istration to obese mice improved insulin sensitivity and
glucose tolerance [71,73]. In addition, it was shown that
both peripheral and intracerebroventricular vaspin treat-
ment of different mouse models caused a sustained glucose
lowering and reduction of food intake [73]. These beneficial
vaspin effects could be mediated by its ability to inhibit
kallikrein 7 as one target protease [74]. Importantly, at
least in vitro, kallikrein 7 is able to cleave and degrade
insulin in the A and B chain. Vaspin inhibits kallikrein 7 by
a classical serpin mechanism with high specificity in vitro
and thereby may contribute to reduced insulin degradation
in the circulation [74]. Moreover, vaspin-kallikrein 7 com-
plexes have been detected in human plasma and both
proteins are co-expressed in murine pancreatic b cells.
Therefore, improved glucose metabolism upon vaspin
treatment could be mediated by increased insulin plasma
concentrations [74]. Further studies are required to trans-
late the promising data from vaspin treatment studies in
animal models into a potential human application.
Apelin
Apelin, a 36 amino-acid peptide (approximately 1.5 kDa)
and the endogenous ligand of the G protein-coupled recep-
tor APLNR, exists in several active forms [32,75,76]. In
addition to its role as an adipokine, apelin is expressed in
the central nervous system (with particularly high expres-
sion in the hypothalamus), heart, skeletal muscle, and
stomach [3,76]. It has been suggested to contribute to
the regulation of glucose metabolism, lipolysis, blood pres-
sure, cardiovascular and fluid homoeostasis, food intake,
cell proliferation, and angiogenesis [75–80]. In particular,
the ability of apelin to decrease lipolysis and induce vaso-
dilation with subsequent reduction in blood pressure may
open new therapeutic avenues [78–80]. Mice with a dis-
ruption of the apelin gene did not exhibit metabolic altera-
tions, but developed a dysfunction of cardiac contractility
with aging [81]. Most clinical studies found an association
of higher circulating apelin with obesity and insulin resis-
tance [79,82]. One potential mechanistic link between
elevated circulating apelin and deterioration of glucose
metabolism could be provided by experimental evidence
that apelin inhibited insulin secretion in mice [83]. In
insulin-resistant and obese mouse models, administration
of recombinant apelin had significant beneficial effects on
glucose tolerance and glucose utilization [83]. These data
suggest that, in obesity and diabetes, increased circulating
TIPS-1235; No. of Pages 10
Review
apelin is a symptom of apelin resistance or represents an
adaptation of the body to elevated endogenous apelin
levels. However, there is a need to investigate the meta-
bolic effects of apelin administration in both physiological
and pathological situations in humans.
DPP-4
Intake of nutrients may stimulate the release of the incre-
tin hormones, including glucose-dependent insulinotropic
polypeptide (GIP) and glucagon-like peptide-1 (GLP-1)
[84,85]. Incretins have been shown to enhance glucose-
dependent insulin secretion and inhibit glucagon secre-
tion, which together may reduce hepatic gluconeogenesis
[85]. The effect of incretins is significantly reduced in
patients with T2DM and contributes to impaired insulin
secretion and chronic hyperglycemia [85]. Under normal
physiological conditions, DPP-4 rapidly degrades GIP and
GLP-1 [86]. Inhibition of DPP-4 is a therapeutic option to
lower hyperglycemia in patients with T2DM. DPP-4 inhi-
bitors are a relatively new class of oral glucose-lowering
drugs, and exert their hypoglycemic effect indirectly by
increasing plasma concentration, and the duration and
action of incretins [85,87]. Currently, the DPP4-inhibitors
alogliptin, sitagliptin, linagliptin, saxagliptin, and vilda-
gliptin are in clinical use as antidiabetes drugs to improve
glycemic control by stimulating glucose-induced pancreatic
insulin secretion and suppressing glucagon production
[85–87].
DPP-4 is an 88-kDa protein that is expressed in glan-
dular cells in salivary gland, prostate, seminal vesicles,
endometrium, renal tubules, and small intestine and de-
cidual cells. Recently, adipose tissue was shown to be an
additional source of circulating DPP-4 [88]. Compared with
healthy lean individuals, patients with obesity and insulin
resistance have higher DPP-4 expression in (visceral) adi-
pose tissue, which may contribute to increased fat-derived
DPP-4 secretion and higher circulating DPP-4, particular-
ly in individuals with high visceral fat mass [18,89]. Given
that DPP-4 is an important drug target for the treatment of
T2DM, it could be hypothesized that enhanced secretion of
DPP-4 in patients with adverse fat distribution [18] may
contribute to the development of impaired insulin sensi-
tivity in obesity. However, so far there is no evidence that
increased DPP-4 levels from adipose tissue affect endoge-
nous GLP-1 levels or that DPP-4 inhibitors might be more
efficacious in patients with higher DPP-4 expression in
adipose tissue. Importantly, recent data suggest that the
role of DPP-4 in diabetes is not restricted to its incretin-
degrading properties. Under physiologic concentrations,
DPP-4 directly induced insulin resistance in adipocytes
and skeletal muscle [88]. In mice, production of DPP-4 in
adipocytes was shown to be negatively regulated by high
glucose concentration under physiological conditions, an
effect that was abolished in mouse models of diabetes
[90]. In humans, DPP-4 is more highly expressed in adi-
pose tissue dysfunction [89], but recent data suggest that,
in addition to increased expression, hypoxia-mediated
upregulation of DPP-4 shedding in adipocytes and smooth
muscle cells by metalloproteases also contributes to higher
DPP-4 activity in obesity [91]. Therefore, DPP-4 may
not only reflect, but also contribute to adipose tissue
Trends in Pharmacological Sciences xxx xxxx, Vol. xxx, No. x
dysfunction. In future studies, it should be investigated
whether treatment with DPP-4 inhibitors may improve
adipose tissue function and whether such treatment leads
to a better response in those patients with T2DM and
higher DPP-4 activity and serum concentration.
TNFa
TNFa (25 kDa, 233 amino acids) is a proinflammatory adi-
pokine that is expressed in monocytes and macrophages
and has a central role in inflammation and autoimmune
diseases (reviewed in [32]). TNFa can bind two receptors,
TNFR1 and TNFR2. Although adipose tissue TNFa expres-
sion in humans is relatively low, it correlates with obesity
and decreases with weight loss [92–94]. TNFa has been
shown to directly impair both insulin signaling in insulin-
sensitive tissues and insulin secretion [92,93]. Therefore,
inhibiting TNFa action may exert beneficial metabolic
effects. Indeed, neutralization of TNFa by antibodies as well
as genetic ablation of the TNFa gene had insulin-sensitizing
effects in various rodent models obesity and diabetes
[94–96]. Moreover, in several independent animal models,
treatment with TNFa antibodies was shown to reduce in-
flammation, improve fatty liver disease [93], and protect
against diet-induced obesity and insulin resistance [97].
However, these promising data could not be translated
into a clinically relevant treatment option in humans. Of
note, in patients with spondyloarthritis, anti-TNFa thera-
py contributed to an early significant increase in both
visceral and subcutaneous abdominal adipose tissue after
1–2 years of treatment [98]. Moreover, in a prospective,
randomized, double-blind, placebo-controlled pilot study of
insulin-resistant obese men, chronic TNFa neutralization
by infliximab did not improve insulin resistance and ques-
tioned the suggested causative link between adiposity and
insulin resistance, at least in human disease [99].
IL-1b
IL-1b (17 kDa, 153 amino acids) is a proinflammatory
cytokine that is not only produced by immune cells, but
also secreted from adipose tissue. It circulates mainly
bound to albumin and signals via two IL-1 receptors (IL-
1R1 and IL-1R2) on target cells. Importantly, IL-1b may
have a role in inflammatory pancreatic b cell destruction
and apoptosis, thus contributing to the development of
type 1 diabetes mellitus [100]. It has been suggested that
blocking IL-1b could be beneficial for preventing obesity-
associated insulin resistance and inflammation in human
adipose tissue [101,102]. Indeed, in the context of a con-
trolled clinical trial including 70 patients with T2DM,
treatment with a recombinant human IL-1R antagonist
(anakinra) was shown to improve glycemia and b cell
function [100]. In humans with obesity and diabetes, IL-
1b release increased with glycemic deterioration and de-
creased after gastric bypass surgery in a recent study
[103]. Moreover, in these human intervention studies,
IL-1b and the T cell cytokine IL-22 were identified as
key players in a paracrine inflammatory pathway in adi-
pose tissue [103]. However, the predominant beneficial
effects of targeting IL-1b may be due to protection of
pancreatic b cells rather than improvement of peripheral
insulin sensitivity.
7
TIPS-1235; No. of Pages 10
Review
Concluding remarks
Adipose tissue secretes hundreds of bioactive molecules,
the majority of which are peptide hormones called adipo-
kines. In obesity, metabolic and inflammatory diseases
adipokine secretion may change and thereby mechanisti-
cally link adipocyte hypertrophy and adipose tissue dys-
function in obesity to related metabolic, cardiovascular and
even malignant comorbidities. Adipokines are important
modulators of appetite and satiety, energy expenditure
and activity, fat distribution, adipocyte function, glucose
and lipid metabolism, insulin sensitivity, chronic inflam-
mation, and other processes. Over recent years, many
novel adipokines have been discovered. The main chal-
lenge in adipokine research remains to elucidate their
function and main targets. Understanding the mode of
action for novel adipokines may facilitate their future
clinical use as pharmacotherapies, drug targets, or pre-
dictors of a variety of diseases.
In summary, adipokines are promising candidates for
the future treatment of obesity and obesity-related dis-
eases. Over the past few years, drug discovery paths have
been advanced to clinical studies for the use of leptin,
FGF21 and BMP-7 as therapeutics, as well as DPP-4,
TNFa, and IL-1b as targets for pharmacotherapy. For
adiponectin and the majority of more recently discovered
adipokines, we may expect efforts to translate promising
data from animal studies into human clinical trials within
the next 2–4 years. However, the drug development pro-
cess may take approximately 15 years from the discovery of
a candidate adipokine to its clinical use or approval by
authorities.
For most adipokines, the major outstanding question is
how altered secretion leads to metabolic, cardiovascular,
inflammatory, and malignant diseases. The field could be
driven forward by the characterization of the mode of
action of adipokines and identification of molecular adipo-
kine targets. In the drug discovery path, there are always
Box 1. Outstanding questions
Questions
 What are the unrecognized signals from adipose tissue that may
promote overeating?
 Are there potential synergistic effects and concerted actions of
adipokines (which will not be recognized by single gene deletion
and/or overexpression studies in animals)?
 Do adipokines have a role in food preferences?
 Do adipokines predict and/or promote weight regain following
intended weight loss?
 Why are some individuals protected against the development of
adverse adipokine secretion?
 What are the molecular mechanisms linking altered adipokine
secretion to metabolic, cardiovascular, inflammatory, and malig-
nant diseases?
Unmet needs
 Definition of function, molecular action, and targets for the
majority of recently identified adipokines
 Development of adipokine-based pharmacological treatment
strategies
 Establish specific adipokines as tools for the early diagnosis of
diseases
8
Trends in Pharmacological Sciences xxx xxxx, Vol. xxx, No. x
risks that a mechanistic concept derived from animal
experiments does not translate into effective treatment
in humans or that it causes inacceptable adverse effects.
These important barriers have to be overcome in the next
years to develop (more) adipokine-based pharmacothera-
pies (Box 1).
Acknowledgments
This work was supported by a grant from Deutsche Forschungsge-
meinschaft (Sonderforschungsbereich 1052 ‘Obesity Mechanisms’; pro-
jects B01 and C06), and by the Helmholtz Alliance ICEMED – Imaging
and Curing Environmental Metabolic Diseases, through the Initiative
and Networking Fund of the Helmholtz Association.
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