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Matthias Bluher *
ABSTRACT
Prevention of obesity and therapeutic weight loss interventions have provided only limited long term success. Therefore there is an urgent need to
develop novel pharmacological treatment strategies, which target mechanisms underlying positive energy balance, excessive fat accumulation and
adverse fat distribution. Adipokines may have potential for future pharmacological treatment strategies of obesity and metabolic diseases, because
they are involved in the regulation of appetite and satiety, energy expenditure, endothelial function, blood pressure, insulin sensitivity, adipogenesis,
fat distribution and insulin secretion and others. There are important road blocks on the way from an adipokine candidate to the clinical use a
therapeutic compound. Such road blocks include an incomplete understanding of the mechanism of action, resistance to a specic adipokine, side
effects of the adipokine and others. This review focuses on the potential of selected adipokines as therapeutic tools or targets and discusses
important road blocks, which currently prevent their clinical use.
& 2014 The Author. Published by Elsevier GmbH. All rights reserved.
Keywords Adipokines; Obesity; Type 2 diabetes; Road blocks; Therapeutic compounds; Leptin; Adiponectin; DPP4; Vaspin; Nampt/visfatin;
Nesfatin-1; Apelin; BMP7
1. INTRODUCTION
Obesity and fat accumulation predominantly in visceral depots are
important risk factors for the development of type 2 diabetes, dyslipidemia, fatty liver disease, chronic subclinical inammation, hypertension, and cardiovascular disease [13]. To develop novel etiology based
strategies for the prevention and treatment of these diseases, a better
understanding of the molecular mechanisms underlying obesity and its
relationship to metabolic and cardiovascular diseases is essential. There
are several open questions about the unresolved, pathogenic mechanisms of obesity and its comorbid disorders. Why is our food intake not
regulated to keep the balance with energy expenditure? Why does
overeating in some, but not all individuals lead to ectopic fat deposition?
To what extent does adipose tissue contribute to the regulation of
energy balance? What are the (missing?) signals from adipose tissue
that may promote overeating and obesity related metabolic and
cardiovascular diseases?
An effective treatment of obesity would require a systematic assessment
of factors potentially affecting energy intake, metabolism and expenditure [4]. Since the factors (and their interaction) causing obesity are only
incompletely understood, weight loss strategies may not address the
root causes of energy imbalance [4,5]. Therefore, current therapeutic
approaches frequently fail. The classical treatment of obesity, based on
decreasing energy intake and increasing physical activity, has not been
This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike License, which permits non-commercial use, distribution, and
reproduction in any medium, provided the original author and source are credited.
230
& 2014 The Author. Published by Elsevier GmbH. All rights reserved.
www.molecularmetabolism.com
Appetite
Satiety
Activity
Incretin
secretion
Resorption
Insulin secretion
Insulin sensitivity
Glucose production
Lipid metabolism
Inflammation
Immune response
Coagulation
Vasoactive factors
Adipokines
Insulin sensitivity
Lipolysis
TG storage
Insulin sensitivity
Figure 1: Adipokines regulate important physiologic processes. Secreted factors from adipose tissue play an important role in the regulation of appetite and satiety, energy expenditure, insulin
sensitivity and insulin secretion, inflammation, blood pressure, hemostasis, endothelial function and others. In addition to an endocrine mode of action, adipokines contribute to the modulation of
adipogenesis, adipose tissue lipolysis, adipocyte metabolism and function in an autocrine and paracrine manner.
& 2014 The Author. Published by Elsevier GmbH. All rights reserved.
www.molecularmetabolism.com
231
Review
Adipokine candidate
Road blocks
Biological
Unknown
Mode of action
Side effects
Structural
Defined mechanisms
(rodents), but lack
of efficacy in humans
Legislation
Infrastructure
High development costs
Lack of funding
type 2 diabetes (e.g. leptin, adiponectin), hypertension (e.g., angiotensinogen), endothelial function (e.g., omentin, apelin), hemostasis (e.
g., brinogen), chronic inammation (e.g., TNF, IL-6, IL-1, MCP-1,
progranulin, chemerin), they have great potential to be clinically
relevant both as biomarkers and as therapeutic compounds [14].
Adipokines have the potential to predict individual treatment success
and disease progression, to monitor clinical responses to therapeutic
and lifestyle interventions, to early identify non-responders to specic
interventions, or to monitor treatment adherence [20]. However, the
validation of the impact of these adipokine markers, ultimately driving
them toward approval by regulators and into clinical practice, is much
more complex [19]. In the past, adipokines have been either systematically developed into a drug following their discovery (e.g. leptin)
[2124] or the importance of a molecule in the treatment of a specic
disease has been appreciated before its identication as an adipose
tissue secreted factor (e.g. DPP4) [25,26]. Noteworthy, the potential
clinical use of adipokines may not be restricted to obesity and
metabolic diseases: some adipokines have been already successfully
introduced for other indications including lipodystrophy, infertility and
bone growth (Table 1).
However, there are important road blocks on the way from an adipokine
(drug) candidate to the clinical use as a therapeutic compound. As one
of the initial road blocks, identication of the most promising adipokine
candidates and characterization of the function, mode of action and
molecular targets for a future therapeutic use remain major tasks
(Table 1).
Additional road blocks include: (1) that a mechanistic concept derived
from rodent studies does not translate into effective treatment in
humans, (2) lack of human data, (3) an incomplete understanding of the
mechanism of action, (4) adverse drug and side effects, (5) a very long
drug development process which may take 15 years from the
discovery of a candidate adipokine to its clinical use or approval by
authorities (Figure 3). After the preclinical identication of potentially
important new therapeutic agents and several steps of mechanistic
232
& 2014 The Author. Published by Elsevier GmbH. All rights reserved.
www.molecularmetabolism.com
Adipokine
Effect or mechanism with (future) therapeutic potential or established use as therapeutic principle (TP)
Leptin
Decreases orexigenic and increases anorexigenic peptide synthesis in the hypothalamus: thereby decreasing appetite
Improves hypertriglyceridemia and insulin sensitivity in patients with lipodystrophy (TP)
Treatment of genetic leptin deficiency (TP)
Adiponectin
TNF
IL-6
Vaspin
RBP4
Apelin
DPP-4
Progranulin
Pro-inflammatory properties
Mutations in the progranulin gene cause familial frontotemporal lobar neurodegeneration
Chemotactic molecule, contributing to macrophage infiltration into adipose tissue
Target for improved glycemia and -cell function (TP)
IL-1
MCP-1
Chemerin
Correlate of systemic inflammation (recruitment of immune cells) and visceral fat accumulation
Resistin
FABP4
FGF21
Omentin
Marker of visceral fat mass; local regulator of visceral adipose tissue biology, promotes endothelial functiona
Improves glucose metabolisma, enzyme in NAD biosynthesis playing a role in -cell function
Nampt/visfatin
Lipocalin-2
Component of the innate immune system, key role in acute-phase response to infections
Adipsin
TGF
VEGF
BMP7
Promotes browning of adipose tissuea, improves fertility (TP), improves osteoblast differentiation and promotes bone injury
healing (TP)
Cathepsins
Nesfatin-1
Table 1: Systemic and tissue specific effects of adipokines establish these molecules as candidates or targets for the treatment of obesity-associated disorders. RBP4, retinol-binding-protein-4;
DPP-4, dipeptidyl peptidase-4; IL, interleukin; FGF21, fibroblast growth factor 21; MCP-1, monocyte-chemotactic-protein-1; FABP4, fatty acid binding protein 4; VEGF, vascular endothelial growth
factor; TGF, transforming growth factor ; BMP7, bone morphogenetic protein 7. aEffects shown in animal models only.
frame for further development was not sufcient to advance them from
candidates to clinical phase I studies.
For several adipokines, there is a rationale to develop specic inhibitors
rather than using the adipokine molecule itself. This approach could be
useful for adipokines which are increasingly secreted in obesity and
metabolic diseases including RBP4, nampt/visfatin, lipocalin-2, chemerin, progranulin, fetuin-A, resistin, MCP-1 and others (Table 1).
Adipokine antagonists are in preclinical development for some of these
molecules and their application may identify previously unrecognized
functions of adipokines. For example the novel chemerin (ChemR23)
antagonist CCX832 has been shown to protect against chemerin-related
arterial contraction, thus linking higher chemerin concentrations in
obesity to impaired vascular function [32]. Many more studies are
required for potential drugs at this stage before they can be tested in
clinical studies.
Adverse reactions and signicant side effects are major road blocks in
drug development in general, but also for adipokines. Ideally, an anti-
obesity pharmacotherapy would produce sustained (if required extensive) weight loss with minimal side effects. Regulation of energy balance
has substantial built-in redundancy, overlap considerably with other
physiological functions, and are inuenced by social, environmental,
hedonic and psychological factors that limit the effectiveness of
pharmacological interventions [27]. Moreover, our current incomplete
understanding of the pathophysiology of obesity does not allow the
design of etiology-based treatment strategies. In my opinion that is one
major road block for the development of novel pharmacotherapies.
Recent anti-obesity drug discovery programs have frequently failed or
approved drugs had to be withdrawn from the market due to adverse
effects that were not fully appreciated at the time of launch [27].
Systematically developed adipokine-based drugs have shown potential
in preclinical studies but only leptin has reached further clinical study
phases. For the DPP-4, approved inhibitors were already widely used in
type 2 diabetes therapy before the notion that DPP-4 is also secreted
from adipose tissue.
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233
Review
Adipokine
candidate
RB
Mechanism of
action studies:
in vitro
KO and TG
animal models
mutations
in humans?
RB
Recombinant
Expression
Crystal structure
RB
Randomized
clinical trials
(Phase III)
RB
RB
RB
Proof of concept
studies in humans
(Phase II)
Approval by
Authorities
(e.g. FDA, EMA)
Administration
to rodents
Safety, tolerabilty
studies (Phase I)
Figure 3: Schematic pathway of drug discovery from an adipokine candidate to its approval for clinical use as pharmacotherapy by the authorities. The path from candidates to an approved
medication may take more than 15 years. At any step in the development there are potential road blocks (RB). Despite advances in technology and understanding of biological systems, drug
discovery is a long, expensive, difficult, and inefficient process still with a low rate of new therapeutic discoveries. KO, knockout; TG, transgenic; FDA, Food and Drug Administration; EMA, European
Medicines Agency.
234
4. LEPTIN
The relationship of leptin with insulin resistance, obesity, and cardiovascular disease has been extensively studied since its discovery [33].
Leptin is secreted from adipocytes and plays an important role in the
regulation of satiety, appetite, food intake, activity and energy expenditure, fertility, atherogenesis and growth [34]. In the hypothalamus,
leptin increases anorexigenic and decreases orexigenic peptide synthesis subsequently resulting in reduced appetite [34]. Leptin was
discovered in 1994 as the protein product of the ob gene [12]. This
discovery marked the identication of the mechanism underlying the
extremely obese phenotype of the ob/ob mouse model, which carry a
mutation in the ob gene subsequently leading to leptin deciency [12].
Recombinant leptin is now available for compassionate use only for
patients with congenital leptin deciency [35]. Noteworthy, recombinant
leptin treatment is only available in a few selected centers (e.g. US
National Institutes of Health, University of Cambridge for the UK,
University of Leipzig for Germany) on a research-protocol basis, i.e.
not for routine clinical use. Metreleptin an analog of the human
hormone leptin has been recently approved for the treatment of
& 2014 The Author. Published by Elsevier GmbH. All rights reserved.
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lipodystrophy in Japan, but has not yet cleared the US and European
regulatory agencies for approval [36]. Recently, the FDA Advisory
Committee voted in favor of metreleptin for the treatment of diabetes
and/or hypertriglyceridemia, in patients with rare forms of lipodystrophy.
Because leptin is an important negative regulator of body weight, it has
been suggested for the treatment of obesity. However, in individuals
with obesity, serum leptin concentrations are increased and do not
reduce food intake or improve hyperglycemia [34]. Moreover, exogenous
administration of leptin does not signicantly inuence appetite and
body weight in obese patients, a phenomenon which has been attributed
to central leptin resistance [37]. Recent ndings suggested that amylin
is able to restore leptin sensitivity and when used in combination with
leptin enhances body weight loss in obese rodents and humans [38].
This therapeutic concept using combined amylin/leptin agonism (with
pramlintide and metreleptin) has been advanced to a clinical proof of
concept study, which demonstrated a signicant weight-lowering effect
in a 24-week study in human obesity [39]. However, the latest
randomized clinical trial on pramlintide/metreleptin as novel strategy
in obesity treatment has been recently stopped because of signicant
problems with antibody generation and skin reactions (http://www.
takeda.com/press/article_42791.html). The potential use of leptin-based
treatment concepts gained further support by recent preclinical data
demonstrating that optimized high activity, long-acting leptin analogs are
additively efcacious when used in combination with exendin-4 and
FGF21 [40]. Importantly, GLP-1 analogs like exendin-4 are approved
drugs for the treatment of type 2 diabetes, but not for weight loss.
Moreover, FGF21 has not been approved for any clinical purpose.
In summary, the drug discovery of leptin has shown that even if the
mechanism of action is well established and the treatment concept has
been successfully proven in rodent models, an efcacious and safe
treatment of human diseases is not guaranteed. Leptin is effective in
inducing weight loss in obese congenitally leptin-decient mice [41] and
humans [42], but in rodent models of diet-induced obesity [43] or in
obese humans [44], leptin has only little weight loss efcacy. Moreover,
treatment with higher doses of native leptin or leptin analogs with
sustained pharmacokinetics failed to enhance weight loss and increased
adverse effects [45]. The example of leptin, which made its way from
the discovery (in 1994) to the approval of a leptin analog for human
metabolic diseases (in 2013) further demonstrates the potential
importance of adipokines as therapeutics, but also reveals important
road blocks. In future translational studies it needs to be tested whether
road blocks related to the clinical use of leptin for additional indications
could be removed by the design of optimized adipokine analogs with
improved efcacy and safety prole. In this context it has been recently
demonstrated that the design and characterization of several sitespecically enhanced leptin analogs have high potency and sustained
action in causing weight loss in diet induced obesity mice [40].
5. TNFa
TNF is recognized as a multifunctional cytokine implicated in inammation, apoptosis and cell survival as well as induction of insulin resistance
[46]. Since TNF is highly expressed in adipose tissue of obese animals
[47] and humans [48], it may be considered as adipokine. Neutralization of
TNF in obese fa/fa rats caused a signicant increase in the peripheral
uptake of glucose in response to insulin [47]. In mice targeted disruption
of the TNF gene results in signicantly improved insulin sensitivity in both
diet-induced and monogenetic obesity models [49]. These data supported
the hypothesis that blocking TNF action may improve insulin sensitivity
6. ADIPONECTIN
Adiponectin may be the most prominent example for the potential use of an
adipokine in the treatment of obesity and obesity-associated metabolic diseases. Adiponectin has been discovered in 1995 and was originally
named Acrp30 [61], adipoQ [62], and apM1 [63], until the consensus name
adiponectin found widespread acceptance [64]. There is consensus that
adiponectin generally exerts insulin sensitizing, anti-inammatory and antiapoptotic actions on a number of different cell types [64]. Consistent with
these properties, adiponectin release from adipocytes is down-regulated
under adverse metabolic conditions, resulting in decreased adiponectin
serum concentrations [64]. Interestingly, various hormones associated with
insulin resistance and obesity including catecholamines, insulin, glucocorticoids, TNF and IL-6 down-regulate adiponectin expression and secretion
in fat cells in vitro [65]. Besides its peripheral effects, adiponectin acts in the
brain to increase energy expenditure and cause weight loss [64]. The role of
adiponectin as an endogenous insulin sensitizer was discovered in
adiponectin knockout mice, which are characterized by impaired insulin
sensitivity [66]. On the contrary, mice with transgenic adiponectin overexpression are protected against obesity, diabetes (ob/ob mice) and
atherosclerosis (ApoE-decient mice) [67,68].
In many (but not all) studies, administration of recombinant adiponectin
results in improved (hepatic) insulin sensitivity, increased insulin
secretion [69] and benecial effects on body weight and hyperglycemia
[reviewed in [19,64]]. In a recent study, no effect of recombinantly
produced adiponectin on glucose levels, HbA1c, plasma lipids or body
weight has been found [70]. However, this failure to lower blood glucose
in animal models of type 2 diabetes could be due to ineffective
recombinant adiponectin preparations [70]. Very recently, Okada-Iwabu
and coworkers reported the production of an orally active, synthetic
& 2014 The Author. Published by Elsevier GmbH. All rights reserved.
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235
Review
small-molecule adiponectin receptor agonist that they have termed
AdipoRon [71]. This molecule binds to adiponectin receptors and
ameliorates insulin resistance and glucose intolerance in mice [71].
Importantly, AdipoRon ameliorates diabetes and prolonged lifespan of
db/db mice on a high-fat diet [71]. Taken together, adiponectin or
adiponectin receptor agonists are promising candidates for further
development as therapeutic for insulin resistant states. The major road
block for the further development of adiponectin-based treatment
strategies is a lack of human data.
7. APELIN
Apelin is an adipokine which may play a role in the regulation of glucose
homeostasis and may contribute to the link between increased adipose
tissue mass and obesity related metabolic diseases [reviewed in [72]].
Higher apelin serum concentrations have been found in patients with
obesity, insulin resistance, liver cirrhosis [72,73] and reduced adipose
tissue apelin expression and serum concentration may contribute to
improved insulin sensitivity independently of signicant weight loss [73].
Apelin receptor antagonist treatment of rats showed diminished hepatic
brosis and loss of ascites suggesting the hepatic apelin system as a
novel therapeutic target in liver disease [74]. In obese and insulinresistant mice, recombinant apelin injection has been shown to have
glucose-lowering effects associated with enhanced glucose utilization in
skeletal muscle and fat thereby restoring glucose tolerance [75]. Apelin
treatment data from different rodent models indicate that apelin
inuences glucose homeostasis and may contribute to the link between
increased adipose tissue mass and obesity related metabolic and
inammatory diseases. However, the exact mechanism how apelin
may have a benecial effect on glucose metabolism needs to be
explored and human data are still not available.
8. VASPIN
Visceral adipose tissue-derived serpin (vaspin) may serve as another
example for a promising adipokine in the therapy of obesity and
diabetes. First identied in adipose tissue of a rat model of obesity and
insulin resistance [76] and related to human obesity and type 2 diabetes
[77], vaspin expression was also found in hypothalamus, stomach and
rodent pancreatic islets [78]. So far, the mechanisms how vaspin
secretion may be linked to deterioration of glucose metabolism and
insulin sensitivity are not entirely understood. Administration of vaspin to
obese mice improves glucose tolerance, insulin sensitivity and altered
gene expression of candidate genes for insulin resistance [79]. Moreover, we could recently show that treatment of different mouse models
with recombinant vaspin leads to sustained glucose lowering and
reduction of food intake [78] which may at least in part be explained by
an inhibition of kallikrein 7 [79]. Although these rodent studies suggest
vaspin as a future pharmacological therapy of obesity and its related
metabolic diseases, further molecular targets of vaspin have to be
identied to fully understand its mechanism of action. Another road
block in the drug development of vaspin is the lack of human data.
9. BMP-7
12. DPP-4
For another promising adipokine drug, BMP7, development to a therapeutic is more advanced. BMP7 has been suggested as a novel therapeutic approach for obesity and metabolic diseases since the discovery,
236
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13. IL-1b
IL-1 is expressed in and secreted from adipose tissue [95]. IL-1 is a
proinammatory cytokine which has been proposed to play a role in
inammatory pancreatic -cell destruction leading to type 1 diabetes [96].
IL-1 inhibits the function and promotes the apoptosis of -cells [96].
The blockade of IL-1 with a recombinant human IL-1-receptor
antagonist (anakinra) has been shown to improve glycemia and
-cell function and reduced markers of systemic inammation in a
double-blind, parallel-group clinical trial involving 70 patients with type
2 diabetes [96]. Therefore IL-1 represents a model that in addition to
the direct use of adipokines as therapeutic strategy, adipokines may
be indirectly used as target molecules for the treatment of obesity
comorbidities.
14. FGF21
FGF21 is a member of the FGF superfamily that is primarily produced by
the liver and adipose tissue and has been recently discovered as an
important metabolic regulator [97]. FGF21 has signicant glucose and
lipid lowering as well as thermogenic effects through interaction with
specic FGF receptors and a cofactor called -Klotho. Administration of
FGF21 produces benecial metabolic effects in animal models [97].
Recently, the promising data from animal studies have been extended by
a randomized, placebo-controlled, double-blind proof-of-concept trial on
the effects of LY2405319, a variant of FGF21, in patients with obesity
and type 2 diabetes [97]. The compound had benecial effects on body
weight reduction, fasting insulin and caused signicant improvements in
dyslipidemia, including decreases in low-density lipoprotein cholesterol
and triglycerides and increases in high-density lipoprotein cholesterol
and a shift to a potentially less atherogenic apolipoprotein concentration
prole [97]. Noteworthy, the compound did not signicantly improve
glucose concentrations [97]. Despite that, the rst clinical trial using
FGF21 as a therapeutic concept suggested that FGF21-based therapies
may be effective for the treatment of distinct obesity related metabolic
disorders.
15. CONCLUSIONS
Anti-obesity interventions have provided only limited long term success
(lifestyle changes, psychological interventions, pharmacotherapies) or
are associated with a relatively high mortality risk (bariatric surgery).
Therefore there is an urgent need to develop novel pharmacological
treatment strategies which target the not entirely understood causative
factors in the pathogenesis of obesity and obesity-related metabolic
diseases. Because adipokines are involved in the regulation of
appetite, satiety, energy expenditure and physical activity, they may
represent tools for weight loss interventions in the future. A lack of
understanding adipokines' actions (and potential side effects) especially for the more recently discovered adipokines are still road blocks
in drug discovery, which need to be removed to generate more specic
therapeutic targets.
However, reduction of body weight might not be the only or best
approach to improve obesity related diseases. Novel treatment
concepts for metabolic diseases may include the attempt to change
a metabolically unhealthy into a metabolically healthy obese
individual. Such a phenotype switch could be achieved by normalization of the pro-inammatory, atherogenic and diabetogenic
cytokine/adipokine prole, a reduction in visceral fat or an improvement of adipose tissue function. For these novel treatment concepts,
adipokines are promising candidates for future pharmacological
treatment strategies. For leptin, an analog (metreleptin) of the
human hormone is already used as a pharmacotherapy in individuals
with congenital leptin deciency and lipodystrophies. Other adipokines such as FGF21 or adipokine-targeting compounds (IL-1
antagonists, adiponectin receptor agonists) may follow this successful example. Novel adipokine-related treatment strategies may offer
exciting new opportunities in a spectrum of diseases with several
unmet clinical needs.
CONFLICT OF INTEREST
None declared.
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237
Review
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