REVIEWS

The endocrine function of adipose

tissues in health and cardiometabolic
disease
Ludger Scheja and Joerg Heeren *
Abstract | In addition to their role in glucose and lipid metabolism, adipocytes respond
differentially to physiological cues or metabolic stress by releasing endocrine factors that
regulate diverse processes, such as energy expenditure, appetite control, glucose homeostasis,
insulin sensitivity, inflammation and tissue repair. Both energy-storing white adipocytes and
thermogenic brown and beige adipocytes secrete hormones, which can be peptides (adipokines),
lipids (lipokines) and exosomal microRNAs. Some of these factors have defined targets;
for example, adiponectin and leptin signal through their respective receptors that are expressed
in multiple organs. For other adipocyte hormones, receptors are more promiscuous or remain to
be identified. Furthermore, many of these hormones are also produced by other organs and
tissues, which makes defining the endocrine contribution of adipose tissues a challenge. In this
Review, we discuss the functional role of adipose tissue-derived endocrine hormones for
metabolic adaptations to the environment and we highlight how these factors contribute to the
development of cardiometabolic diseases. We also cover how this knowledge can be translated
into human therapies. In addition, we discuss recent findings that emphasize the endocrine role
of white versus thermogenic adipocytes in conditions of health and disease.

Department of Biochemistry
and Molecular Cell Biology,
University Medical Center
Hamburg-Eppendorf,
Hamburg, Germany.
*e-mail: heeren@uke.de
https://doi.org/10.1038/
s41574-019-0230-6
Leptin, which is a peptide hormone expressed by adi-
pocytes that is essential for body weight control and
many other functions, was discovered in 1994. Its dis-
covery established adipose tissue as an essential endo-
crine organ1. Since then, research has revealed many
adipose tissue-derived peptide hormones (adipokines)
and non-peptide endocrine factors, which are the topic
of this Review (Box 1; Fig. 1). Important highlighted
aspects include regulation of the expression and secre-
tion of adipose tissue endocrine factors as well as their
modes of action. We focus on the impact of the acti-
vation state of adipose tissue depots for the secretion
of endocrine factors. Moreover, we discuss the role of
brown adipose tissue (BAT) compared with that of the
various white adipose tissue (WAT) depots. In addition,
we present the current views of how adipose tissue hor-
mones contribute to the development and progression of
cardiometabolic diseases in animal models and humans,
including therapeutic implications.
Notably, only a few of the factors released by adi-
pose tissue are established endocrine hormones, and
many of them, especially those molecules secreted by
non-adipocytes, exert predominantly paracrine func-
tions2. Only leptin and adiponectin are currently gene­
rally accepted as true adipose tissue-derived endocrine
hormones, which are released from adipose tissues and
exert defined responses in target organs. Nevertheless,
many studies indicate endocrine roles for various other
factors. Overall, unbiased approaches have found a very
large number of molecules with proven or potential sig-
nalling activity that are secreted by adipocytes, which are
lipid-storing connective tissue cells found throughout
the body, and other adipose tissue cells3. For example, a
2018 proteomic study compared the secretome of mouse
white and brown adipocytes and identified more than
1000 unique secreted proteins, of which more than 100
were differentially released between white and brown
adipocytes4. Another comprehensive bioinformatics
study, based on RNA sequencing data from more than
100 different mouse strains, addressed endocrine inter-
actions between adipose tissue and various organs.
Using this elegant approach, researchers identified sev-
eral novel adipose tissue-derived endocrine candidates,
such as lipocalin 5 (ref.5).
Owing to the sheer number of potential adipose
tissue-derived endocrine factors, we can cover only a
small number in this Review. We focus on hormones
where endocrine functions have been most compre-
hensively studied and on recently identified candidates.
Furthermore, factors were selected in a way to represent

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Key points
• White and brown adipocytes secrete many peptide hormones (adipokines), bioactive
lipids (lipokines) and RNA molecules with local (paracrine) and systemic (endocrine)
effects on the brain, pancreatic β-cells, the liver, skeletal muscle and the
cardiovascular system.
• Production and secretion of adipokines and lipokines is dependent on the energy
status of adipose tissues. Through endocrine action, these factors contribute to
systemic energy metabolism by regulating appetite, thermogenesis, glucose
metabolism and lipid metabolism.
• Many peptides that were initially described as adipokines are secreted by endothelial
and immune cells located in adipose tissues, as well as by other organs, which means
the endocrine contribution of adipocytes can be difficult to ascertain.
• In healthy states, white and brown adipose tissues secrete endocrine factors that
maintain organ functions and metabolic homeostasis.
• In obesity, hypertrophic adipocytes and adipose tissue-resident immune cells
accelerate a chronic, proinflammatory profile with altered secretion of adipokines
and lipokines, thereby exacerbating cardiometabolic disease.
• Preclinical and clinical studies show that activating or inhibiting the signalling of
specific adipokines or lipokines could be an approach suitable to treat or prevent the
development of cardiometabolic diseases. However, in almost all cases, efficacy and
safety in humans needs to be proven.
the diverse primary biological functions of these mole-
cules beyond classical peptide hormone signalling. For
each molecule, we critically discuss the level of experi-
mental evidence, important differences between rodents
and humans (if they occur) and the gaps in knowledge
identifying the molecule as a true endocrine factor.
The diversity of adipose tissue depots
White adipose tissue
WAT is the main site of energy storage in the body and
is present in multiple anatomical locations6,7. White
adipo­cytes are the predominate cell type found in WAT,
and contain low amounts of mitochondria and none of
these mitochondria contain uncoupling protein 1 (UCP1).
In the postprandial state (that is, after a meal), white
adipo­cytes take up fatty acids carried by circulating lipo­
proteins, convert them into triglycerides and store these
in a large intracellular lipid droplet. By contrast, between
meals and in other catabolic states, WAT releases free
fatty acids (FFAs) liberated by intracellular lipolysis into
the bloodstream to provide other organs with energy8.
In adipocytes, catecholamines, which originate primar-
ily from the sympathetic nervous system, are the major
lipolytic signalling molecules and increase intracellular
cyclic AMP levels by stimulating β-adrenergic receptors.
Moreover, other hormones, such as natriuretic peptides9,
induce catabolic signalling by elevating intracellular
cyclic AMP or cyclic GMP concentrations. By contrast,
in the postprandial state, insulin inhibits lipolysis and
causes the uptake of fatty acids and glucose into WAT.
Not surprisingly, several endocrine factors released from
adipose tissues are regulated by insulin or sympathetic
Uncoupling protein 1 tone, as described in detail later.
(UCP1). A unique proton During periods of calorie surplus, WAT mass expands
transporter that shuttles by increasing both the size (hypertrophy) and the number
protons back into the of adipocytes (hyperplasia). However, chronic activation of
mitochondrial matrix and
uncouples the electron transfer
this process becomes detrimental, leading to obesity. In
obesity, excessive WAT expansion is accompanied by
chain from ATP synthesis,
a process that generates heat. structural and cellular changes in the tissue, including
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adipocyte hypertrophy and fibrosis10, local inflammation,
infiltration of immune cells, polarization of macrophages
from an anti-inflammatory to a pro-inflammatory pheno­
type (Fig. 2), altered lipid handling in macrophages,
decreased response of adipocytes to insulin (insulin
resistance) and a disturbed metabolism11–14.
Adipocyte insulin resistance leads to insufficient lipid
retention in WAT and, consequently, ectopic lipid accu-
mulation occurs in organs such as the liver and skeletal
muscle. This accumulation is hypothesized to disturb
insulin signalling in those organs and further promote
the development of systemic insulin resistance and type 2
diabetes mellitus (T2DM)15 (Box 2). Importantly, fatty
acids released from white adipocytes, especially satu­rated
fatty acids such as palmitic acid, alter the production
and secretion of inflammatory cytokines and adi-
pokines from hypertrophic WAT, thereby contributing
to obesity-related organ dysfunction (see later)8,10,11.
Of note, not all WAT depots are associated with equal
disease risk in human obesity. The amount of visceral
abdominal WAT, as compared with subcutaneous WAT,
is tightly linked with insulin resistance and metabolic
disease in humans7,16,17. The reason for this association is
not fully clear but might be partially due to the drainage
of visceral fat into the portal vein7. This anatomical situ-
ation means that molecules released from visceral WAT
can reach the liver in higher concentrations than mole­
cules derived from subcutaneous WAT7. Importantly,
unhealthy obesity is associated with intra-abdominal
expansion of insulin-resistant and inflamed WAT16. As
described later, some adipokines are enriched in visceral
WAT and probably have a particular impact on the liver
in the context of visceral obesity.
Brown adipose tissue
BAT is a highly vascularized organ rich in brown adipo­
cytes, which is unique to mammals and functions to gen-
erate heat by metabolizing fatty acids and glucose in a
process called ‘adaptive (non-shivering) thermogenesis’.
In contrast to white adipocytes, brown adipocytes have
multiple small lipid droplets as well as a much higher
content of mitochondria, and, importantly, these mito-
chondria contain UCP1, which shuttles protons back
into the matrix and uncouples the electron transfer chain
from ATP synthesis, thereby generating heat18. The pro-
cess of adaptive thermogenesis is triggered by increased
sympathetic tone or by the action of endocrine hor-
mones such as natriuretic peptides and secretin9,19, which
stimulate intracellular lipolysis in brown adipocytes.
Box 1 | Adipokines and lipokines
In addition to their prominent role in fatty acid and
energy metabolism, adipocytes and other cells in adipose
tissue secrete a large number of different regulatory
peptides (adipokines)8,30,31, as well as regulatory lipid
species (lipokines)8,90,97,104. These factors can act on
neighbouring cells (paracrine action) or on cells in
other organs (endocrine action) to specifically regulate
or modulate diverse processes, including lipid and
glucose homeostasis, energy balance, inflammation
and tissue repair.
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 Reviews

WAT Brain
• Leptin • Adiponectin Leptin • Appetite
• Adiponectin • FABP4 • Temperature
• Adipsin • FAHFAs • Glucose homeostasis
• FABP4 • Palmitoleate
• FAHFAs
• Palmitoleate
Pancreas (β-cells)
• Leptin • Insulin secretion
• Adiponectin • β-Cell survival
• Adipsin
• FAHFAs

Cardiovascular system
Beige WAT
• Leptin • Inflammation
• Adiponectin • Vascular remodelling
• NRG4 • FABP4 • Vascular tone
• NRG4 • 12,13-diHOME • Palmitoleate
• 12,13-diHOME

Liver
• Adiponectin • Glucose metabolism
• FABP4 • Lipid metabolism
• Palmitoleate • Insulin signalling
• NRG4
• 12,13-diHOME
• miR-99b
BAT

• NRG4 Musculature
• 12,13-diHOME • NRG4
• miR-99b • 12,13-diHOME • Adiponectin • Glucose metabolism
• miR-92a • miR-92a • Palmitoleate • Lipid metabolism
12,13-diHOME • Insulin signalling

Fig. 1 | Endocrine effects of adipocyte-secreted factors. Adipocyte-secreted hormones have multiple effects on other
organs. Although most adipose tissue hormones are produced by both white adipose tissue (WAT) and brown adipose tissue
(BAT), only major sites of origin are shown. Adiponectin is downregulated in obesity and is important for maintaining glucose
homeostasis, insulin sensitivity and organ function in chronic inflammatory states. The circulating levels of leptin, which
suppresses appetite, improves peripheral insulin resistance, raises body temperature and regulates hormonal axes, correlate
with total adipose tissue mass. The protease adipsin is an essential component of the alternative complement pathway and
stimulates insulin secretion via C3a receptors on β-cells. In obesity, increased plasma levels of the lipid chaperone fatty
acid-binding protein 4 (FABP4) increase hepatic gluconeogenesis, peripheral insulin resistance and plaque formation in the
arteries. By contrast, levels of the anti-inflammatory fatty acid palmitoleate are decreased in obesity. Fatty acid esters of
hydroxy fatty acids (FAHFAs) are a novel class of lipids that improve glucose tolerance by increasing adipocyte glucose
transport and insulin secretion. Exosomal microRNA (miR)-99b might suppress hepatic fibroblast growth factor 21 production,
whereas miR-92a serves as a biomarker for BAT. Production of the fatty acid derivative 12,13-dihydroxy-(9Z)-octadecenoic
acid (12,13-diHOME) is increased in thermogenic adipose tissues in response to cold exposure to facilitate thermogenesis.
Neuregulin 4 (NRG4) is released from activated thermogenic adipose tissue, acting on hepatocytes to decrease de novo
lipogenesis and prevent liver damage. Dashed arrows indicate paracrine activity; solid arrows indicate endocrine activity.

M2 macrophages
Macrophages polarized by
type 2 immunity-related
cytokines such as IL-4 and
IL-13, which maintain tissue
homeostasis by counteracting
proinflammatory processes
and facilitating tissue
regeneration.
Subsequently, fatty acids that are released from lipid
droplets can allosterically activate UCP1 and are then
combusted in the mitochondria to generate heat18.
In parallel with BAT activation, the replenishment of
energy stores in BAT is initiated, which is a process
regulated by both insulin and β-adrenergic signalling20.
Under prolonged stimulation, BAT adapts by increas-
ing the mass and the number of brown adipocytes18
(Fig. 2). Of note, cold exposure or other catabolic condi-
tions can trigger an adaptive process in WAT in rodents
and humans, which occurs when WAT is continuously
stimulated by the sympathetic nervous system 18,21.
Subsequently, UCP1-containing adipocytes (so-called
beige (or brite) adipocytes) appear among white adipo­
cytes; these beige adipocytes are functionally very sim-
ilar or even identical to brown adipocytes and have
substantial metabolic potential21. Superimposed on the
effects of sympathetic tone, other mechanisms have been
demonstrated to regulate the abundance and function of
brown and beige adipocytes. For example, innate immune
cells such as tissue-resident M2 macrophages have been
shown to induce thermogenesis in both BAT and WAT,
although the mechanisms remain controversial22.
The abundance of BAT differs substantially in human
populations and typically decreases with advanced age
and increasing body weight, thereby suggesting a role in
age-related and obesity-related diseases21. In lean adults,
BAT is present at distinct locations in the upper body,
predominantly in thyroid, supraclavicular, mediastinal,
parathoracic and perirenal depots6. In contrast to mice,
human BAT depots are relatively small. Nevertheless,
owing to the exceptionally high metabolic activity of

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WAT BAT

• Inactivity • Exercise
• Thermoneutrality • Cold exposure
• Caloric excess • Caloric restriction

Hypertrophic WAT and whitened BAT Healthy WAT and active BAT
Saturated FFAs ↑ ↓
Anorexigenic peptide ↑ Leptin ↓ Leptin
Anti-inflammatory lipids ↓ Palmitoleate, FAHFAs ?
Anti-inflammatory peptides ↓ Adiponectin, omentin, NRG4 ↑ Adiponectin, NRG4
Proinflammatory peptides ↑ RBP4, FABP4, resistin, IL-6 ↑ IL-6
Prothermogenic molecules ↓ CXCL14 ↑ CXCL14, 12,13-diHOME

Proinflammatory tissue-resident immune cell Anti-inflammatory tissue-resident immune cell

Fig. 2 | Endocrine factors released by healthy and unhealthy adipose tissues. In response to chronic energy excess,
an infiltration of proinflammatory immune cells can be observed in adipose tissue, which develops a hypertrophic white
adipose tissue (WAT) and whitened brown adipose tissue (BAT) phenotype, a hallmark of unhealthy obesity. In contrast,
energy expenditure or decreased food intake results in healthy WAT and BAT, which is characterized by the presence of
anti-inflammatory immune cells and by active thermogenic brown and beige adipocytes. Both healthy and metabolic
disease states are accompanied by altered secretion of adipose tissue hormones as indicated by the arrows. Overall, the
changes in hypertrophic WAT contribute to insulin resistance, impaired glucose and lipid metabolism and low-grade
systemic inflammation. In catabolic states, thermogenic adipocytes secrete various endocrine factors that ensure
metabolic homeostasis and tissue remodelling. CXCL14, C-X-C motif chemokine ligand 14; 12,13-diHOME, 12,13-­dihydroxy-
(9Z)-octadecenoic acid; FABP4, fatty acid-binding protein 4; FAHFAs, fatty acid esters of hydroxy fatty acids; FFAs, free
fatty acids; NRG4, neuregulin 4; RBP4, retinol-binding protein 4.

BAT, these small amounts of tissue still have an impact
on whole body metabolism21. BAT also produces a num-
ber of endocrine factors (Figs. 1,2). Although the much
larger WAT depots are probably the dominant source
of most circulating adipose tissue factors, especially
in humans, some hormones are selectively induced in
BAT under certain conditions and probably act in an
endocrine fashion, as described later.
Organ-associated adipose tissue depots
Some specialized adipose tissue depots are closely asso-
ciated with other organs and may affect these organs
by contributing to the tissue microenvironment. One
example is bone marrow adipose tissue (BMAT), which
is particularly abundant in the medulla of long bones. The
data available suggest that bone marrow adipocytes have
primarily local functions such as the regulation of bone
turnover23 and haematopoiesis24. In addition, bone mar-
row adipocytes might also have systemic effects through
secretion of the adipokine adiponectin25 (see later).
Arteries and arterioles are surrounded by adipocytes
that share features of brown and beige adipocytes, which
comprise the perivascular adipose tissue (PVAT). These
cells are involved in the regulation of vasodilation, pro-
vide mechanical support to the vessel, buffer excessive
fatty acids and release paracrine hormones26. Of note,
increased inflammation in PVAT is associated with higher
cardiovascular disease risk in humans and increases the
development of atherosclerosis in mice26–28. Analogous to
PVAT, a layer of adipose tissue covers the myocardium and
the coronary arteries of the heart. This epicardial adipose
tissue (ECAT) is functionally similar to PVAT and shares
the microcirculation with cardiomyocytes. Consequently,
ECAT can have a negative impact on the myocardium in
states of metabolic inflammation29. In conclusion, local
adipocytes are closely connected with the cells constitut-
ing the cardiovascular system, conferring both protection
from disease and increased risk of disease.
Of note, most studies investigating adipose tissue
biology focus on classical WAT and BAT depots. As such,

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Lipodystrophy
A genetic or acquired condition
that is characterized by lack of
adipose tissue, insulin
resistance and hyperglycaemia.
Neointima
Pathological thickening of the
subendothelial layer (intima) of
arteries due to atherosclerosis
or other arterial injuries
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Box 2 | Unhealthy adipose tissues
In obesity, adipose tissues can become unhealthy when
adipocytes expand owing to chronic energy excess.
In this state, adipose tissues contain large (hypertrophic)
adipocytes that are insulin-resistant, lose their ability to
adequately store triglycerides and display impaired
energy expenditure8,10,15. Consequently, fatty acids are
released into the circulation and accumulate in other
organs, causing cellular stress and disturbed metabolism,
which is a hallmark of chronic metabolic diseases such as
type 2 diabetes mellitus, cardiovascular disease and
nonalcoholic steatohepatitis8,10,11,15. In addition, the
altered secretion of endocrine factors from hypertrophic
adipose tissues contributes to pathological changes in
other organs8,30.
the relevance of PVAT, ECAT and BMAT for endocrine
hormonal regulation requires further investigation.
A general drawback of studying specific WAT depots is the
lack of genetic intervention tools, for example, mouse
lines deficient for a gene of interest in specific adipose
tissue depots. Currently, depot-specific in vivo research
is based on cumbersome surgical procedures such as
excision and transplantation. For those WAT depots, a
more extensive use of local genetic manipulation (for
example, using adeno-associated virus vectors) might be
useful to decipher the functional role of WAT as source
of paracrine or endocrine factors.
Adipocyte-enriched endocrine factors
Numerous regulatory factors secreted from adipose tis-
sue with impact on adjacent or remote tissues have been
identified30 (Fig. 1; Tables 1,2) and discovery is ongoing5.
Notably, of these factors only leptin and adiponectin
are selectively expressed in adipocytes and also well
established as endocrine hormones that act on specific
receptors in remote target organs. In this section we
describe these two classical adipokines, as well as other
adipokines, lipid hormones and regulatory RNAs that
are predominantly produced by adipocytes or adipose
tissues and that exert a defined endocrine function. For
each factor, we discuss the level of evidence indicating
that it is part of a bona fide endocrine axis.
Leptin and adiponectin
Leptin. The obesity gene (ob) encodes an adipokine,
called leptin, which is almost exclusively expressed
in adipocytes1 (Table 1). Leptin-deficient ob/ob mice
have an extremely obese phenotype, which is currently
explained by the essential role of leptin in suppressing
appetite and promoting energy expenditure through
receptors in the central nervous system31; however, the
latter finding was challenged by a 2017 study demon-
strating that leptin regulates heat loss rather than energy
expenditure32. Importantly, rodents or humans that lack
either leptin or the leptin receptor (LEPR) are not only
very obese but are also hyperglycaemic and extremely
insulin-resistant31,33. These metabolic derangements
are not caused by excessive adipose tissue mass but
are due to the lack of leptin, as hyperglycaemia and
insulin resistance are also present in lipodystrophy, a
condition of very low leptin levels31. In addition to its
Reviews
role in metabolism, leptin has substantial effects on the
hypothalamus–pituitary hormonal axis, the regulation of
fertility, the immune system and bone turnover31.
In healthy conditions in humans and rodents, cir-
culating leptin levels correlate positively with adipose
tissue mass and leptin levels decrease sharply during pro-
longed fasting34, but do not substantially change between
meals35. Thus, low plasma leptin levels can be regarded
as an endocrine signal reflecting depleted adipose tissue
energy stores and high energy demand. In line with this
notion, low plasma leptin concentration not only fosters
increased energy intake but is also causally involved in
starvation-associated alterations such as increased corti-
costerone and decreased thyroid hormone levels, gonadal
hypoactivity and suppression of the immune system36.
Leptin is expressed in all types of adipose tissues, with
a preference for subcutaneous WAT in humans37, and is
predominantly regulated at the transcriptional level38.
In the fasted state, the sympathetic nervous system act-
ing on adipocyte β-adrenergic receptors is the principal
leptin-lowering mechanism39–41. By this mechanism, the
secretion of leptin is tightly coupled to nutritional state
and thus can mediate physiological adaptations.
LEPR is a type I cytokine receptor that is expressed
in many cell types both in the central nervous sys-
tem and in the periphery. In the brain, leptin signal-
ling is important for mediating the metabolic effects
of leptin, as demonstrated by elevated levels of body
fat, glucose and insulin in neuron-specific but not in
hepatocyte-specific LEPR-deficient mice42. Evidence
is accumulating that all the major metabolic effects of
leptin are linked to leptin signalling in specific neurons
or areas of the brain, resulting in increased sympathetic
flow to adipose tissues and subsequent higher energy
expenditure39,43, decreased heat loss32 and the suppres-
sion of appetite44,45, as well as the reduction of hepatic
gluconeogenesis and the prevention of peripheral insulin
resistance46,47. Of note, two distinct neuron classes in the
arcuate nucleus of the hypothalamus have been identi-
fied as key leptin-responsive neurons: the agouti-related
protein neurons and the pro-opiomelanocortin neurons.
Selective knockdown of LEPR in either of these neuron
classes or re-expression on a receptor-deficient back-
ground had substantial metabolic effects47,48. The meta­
bolic phenotype induced by such selective knockdown
is not as pronounced as that associated with systemic
LEPR knockdown, which suggests the importance
of LEPR expressed in other parts of the brain (for example,
the hindbrain)44.
Notably, LEPR signalling in the periphery is also
relevant. For example, leptin could be antiatherogenic,
as indicated by increased neointima formation in an
endothelial cell-specific Lepr-knockout mouse model49.
Leptin signalling also occurs in pancreatic β-cells50,51.
In vitro studies found that leptin signalling inhibits
insulin secretion and increases the survival of β-cells50,51.
However, a 2015 study using a mouse model with LEPR
knockdown restricted to β-cells found no evidence of
hyperinsulinaemia or disturbed glucose homeostasis52.
Thus, leptin signalling in β-cells affects insulin secretion
in vitro, but is seemingly not essential for maintaining
functionality of β-cells in vivo. Overall, leptin signalling
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Table 1 | Major cellular sources of adipose tissue-derived hormones

Factor White Brown and beige Preadipocytes Macrophages Endothelial cells Immune Hepatocytes Other
adipocytes adipocytes cells cells
Adipocyte-enriched endocrine factors
Leptin1,38 ++ ++ – – – – – –
Adiponectin25,53 ++ ++ – – – – – –
Adipsin 72
++ ++ – – – – – –
FABP4 (refs78,79) ++ ++ – ++ ++ – – –
NRG4 (refs 83,84
) – ++ – – – – ++ –
Lipokines
Palmitoleate90 ++ – – – – – – –
DNL FAHFAs97,98 ++ – – – – – – –
12,13-diHOME 104
– ++ – – – – – –
Adipocyte-derived exosomal microRNAs
Exosomal miR-99b108 ++ ++ – – – – – –
Exosomal miR-92b107 – ++ – – – – – –
Adipokines also released by hepatocytes
FGF21 (refs113,114,120,122) ++ ++, + – – – – ++ –
RBP4 (refs 30,129
) ++ ++ – – – – ++ –
IGF1 (ref. ) 197
++ ++, + – ++ – – ++ –
Adipokines also released by immune cells
CXCL14 (refs133,134) – ++ – – ++ ++ – ++
IL-6 (refs136,198) ++ ++ – ++ ++ ++ – –
Resistin 146,149
++ ++ – ++ – – – –
Broadly expressed adipokines
GDF15 (refs151,153,157) + + + + – + + +
eNAMPT159 ++ ++ ++ ++ – ++ ++ ++
Omentin 164,165
– – – ++ ++ – – ++
Vaspin169,199 ++ ++ ++ – – – – ++
+, factor is released from adipocytes under certain conditions; ++, factor is released from cell type; –, factor is not released in major amounts from cell type or
unknown; 12,13-diHOME, 12,13-dihydroxy-(9Z)-octadecenoic acid; CXCL14, C-X-C motif chemokine ligand 14; DNL , de novo lipogenesis; eNAMPT, extracellular
nicotinamide phosphoribosyltransferase; FABP4, fatty acid-binding protein 4; FAHFAs, fatty acid esters of hydroxy fatty acids; FGF21, fibroblast growth factor 21;
GDF15, growth differentiation factor 15; IGF1, insulin-like growth factor 1; NRG4, neuregulin 4; RBP4, retinol-binding protein 4.

in target cells outside the central nervous system has not
been studied as extensively, and more in vivo research is
required to dissect the role of this pleiotropic hormone
in physiology and pathophysiology.
Adiponectin. All adipose tissue depots express adi-
ponectin, which is an adipocyte-specific hormone with
systemic insulin-sensitizing and anti-inflammatory
properties53 (Fig. 1). Plasma levels of this adipokine
are decreased in obese rodents and humans, and
this alteration contributes to the manifestation of
obesity-related cardiometabolic diseases53. The mecha­
nisms causing lower adiponectin secretion in obesity
are still under intensive research and probably involve
hypoxia, inflammation, endoplasmic reticulum stress
and downregulation of β-adrenergic signalling, which
is a positive regulator of adiponectin secretion 54–56.
Subcutaneous WAT and BMAT might be especially
relevant for circulating adiponectin levels. Studies from
2014 and 2016 showed that adiponectin expression is
high in bone marrow adipocytes of rabbits and mice
and that under specific conditions, such as calo-
rie restriction, expanded BMAT mass could explain
increased plasma adiponectin levels as compared with
ad libitum-fed controls25,57.
The action of adiponectin is important for systemic
insulin sensitivity, as demonstrated by the development
of insulin resistance in adiponectin-deficient mice58
and by preserved insulin sensitivity in obese mice over­
expressing adiponectin59. Adiponectin signalling is initi­
ated by adiponectin binding to either of two related cell
surface receptors (ADIPOR1 or ADIPOR2)60, which
is followed by docking of the adaptor protein APPL1
(ref.61) and the stimulation of receptor-intrinsic cerami­
dase activity62. The resulting signalling pathway, which
is mediated through the activation of AMP-dependent
kinase, peroxisome proliferator-activated receptor-α
(PPARα) and other regulatory proteins, leads to meta­
bolic health-promoting alterations such as decreased
hepatic gluconeogenesis, increased fatty acid oxidation

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Table 2 | Regulation, signalling and function of adipose tissue hormones
Endocrine factor Regulation of secretion
Adipocyte-enriched endocrine factors
Leptin • Increased by fat mass
• Decreased by β-adrenergic
signalling
• Decreased by prolonged
fasting
Adiponectin • Increased by β-adrenergic
signalling
• Decreased by endoplasmic
reticulum stress
• Decreased by oxidative stress
• Decreased by obesity
Adipsin • Decreased by insulin
• Decreased by obesity (mice)
FABP4 Increased by obesity
NRG4 • Increased by thermogenic
activation
• Decreased by obesity
Adipocyte-derived exosomal microRNAs
Exosomal miR-99b Unknown
Exosomal miR-92a Decreased by thermogenic
activation
Lipokines
FAHFAs from DNL • Increased by glucose
metabolism
• Increased by DNL
Palmitoleate Increased by WAT DNL
12,13-diHOME • Increased by cold exposure
• Increased by exercise
Adipokines also released by hepatocytes
FGF21 Liver
• Increased by starvation
• Increased by carbohydrate
overfeeding
BAT
• Increased by thermogenic
activation
• Increased by transplantation
• Increased by cellular stress
• Increased by hypertension
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Molecular signalling Physiological functions
(receptor)
Receptor ligand (LEPR) CNS signalling
• Increased starvation response
• Decreased appetite
• Increased energy expenditure
• Decreased heat loss
• Increased hepatic gluconeogenesis
• Decreased insulin resistance
Peripheral signalling
• Decreased insulin secretion
• Decreased atherogenesis
Receptor ligand • Decreased inflammation
(ADIPOR1, ADIPOR2) • Increased insulin sensitivity
• Increased fatty acid catabolism
• Decreased gluconeogenesis
Complement factor D, • Decreased inflammation by
generation of clearance of dead cells
complement factor C3a • Increased inflammation by
chemotaxis
• Increased insulin secretion via
C3a receptor
Cytosolic fatty acid • Increased gluconeogenesis
binding, extracellular • Increased insulin resistance
mechanism unknown • Increased atherogenesis
Receptor ligand (ERBB3, • Decreased hepatocyte DNL
ERBB4) • Decreased hepatocyte death
• Decreased insulin resistance
• Decreased steatohepatitis
• Increased adipose tissue
angiogenesis
• Increased adipose tissue
innervation
Decreased translation Decreased liver FGF21 expression
Decreased translation • Decreased angiogenesis
• Decreased obesity
Receptor ligand • Increased glucose tolerance
(GPR120, GPR40), • Increased GLP1 secretion
others? • Increased insulin secretion
Unknown • Decreased inflammation
• Decreased atherogenesis
• Increased glucose homeostasis
Unknown • Increased BAT activity
• Increased skeletal muscle fatty acid
oxidation
• Increased fatty acid transport
Receptor ligand (FGFR1 Liver
with β-klotho) • Increased hepatic gluconeogenesis
• Increased fatty acid oxidation
• Increased ketogenesis
• Increased sympathetic tone
• Increased insulin sensitivity
BAT
• Improved glucose homeostasis
• Decreased cardiac hypertrophy
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Table 2 (cont.) | Regulation, signalling and function of adipose tissue hormones

Endocrine factor Regulation of secretion Molecular signalling Physiological functions
(receptor)
Adipokines also released by hepatocytes (cont.)
RBP4 Increased by obesity Vitamin A-binding • Increased inflammation
protein, receptor ligand • Increased insulin resistance
(STRA6, TLR4)
IGF1 • Increased by growth hormone Receptor ligand (IGF1R) BAT
• Increased by BAT • Increased glucose homeostasis in
transplantation T1DM
Adipokines also released by immune cells
CXCL14 Increased by thermogenic Receptor ligand • Increased WAT browning
activation (receptor unknown) • Decreased WAT inflammation
IL-6 • Increased by inflammatory Receptor ligand (IL-6RA, • Increased and/or decreased
cytokines glycoprotein 130) inflammation
• Increased by lipolysis • Increased hepatic gluconeogenesis
• Increased by obesity
Resistin Increased by inflammation Receptor ligand (TLR4, • Increased inflammation
others?) • Increased insulin resistance
Ubiquitously expressed adipokines with endocrine potential
GDF15 • Increased by obesity Receptor ligand • Decreased inflammation
• Increased by severe illness (GFRAL) • Increased glucose homeostasis
• Increased by IL-4 and IL-13 • Pleiotropic effects
• Increased by oxidative stress
NAMPT/visfatin • Increased by obesity NAD+-synthesizing • Increased lymphocyte growth
• Increased by insulin resistance enzyme, receptor • Increased inflammation
ligand? • Increased apoptosis
Omentin Decreased by hyperinsulinemia Lectin, receptor ligand? • Decreased insulin resistance
• Decreased atherogenesis
Vaspin Increased by obesity Protease inhibitor Decreased insulin resistance
ADIPOR, adiponectin receptor protein; BAT, brown adipose tissue; CNS, central nervous system; CXCL14, C-X-C motif chemokine
ligand 14; 12,13-diHOME, 12,13-dihydroxy-(9Z)-octadecenoic acid; DNL, de novo lipogenesis; FABP4, fatty acid-binding protein 4;
FAHFAs, fatty acid esters of hydroxy fatty acids; FFA, free fatty acid; FGF21, fibroblast growth factor 21; GDF15, growth differentiation
factor 15; GFRAL, GDNF family receptor-α-like; GLP1, glucagon-like peptide 1; IGF1, insulin-like growth factor 1; LEPR, leptin
receptor; NAMPT, nicotinamide phosphoribosyltransferase; NRG4, neuregulin 4; RBP4, retinol-binding protein 4; T1DM, type 1
diabetes mellitus; TLR4, Toll-like receptor 4; WAT, white adipose tissue.

in liver and skeletal muscle, increased glucose uptake in
muscle and WAT and decreased WAT inflammation53.
Of note, adiponectin also has a protective effect
on pancreatic β-cells. Local inflammation and stress
induced by the deposition of lipotoxic lipids (for exam-
ple, ceramides and diacylglycerols) are important mecha­
nisms causing dysfunction63 and partial β-cell loss
during progression from simple insulin resistance to
T2DM. Adiponectin receptors are expressed by β-cells,
and evidence suggests that adiponectin, in line with its
general anti-inflammatory role, prevents β-cell apoptosis
and dysregulation of insulin secretion in vitro51. Mouse
experiments using a transgenic model of limited β-cell
destruction found that adiponectin was essential to pre-
vent hyperglycaemia and loss of pancreatic islet mass,
in part by decreasing levels of lipotoxic ceramides63.
Notably, adiponectin supports the regeneration of β-cells
in vivo by inducing expression of HNF4A, a master
transcription factor of β-cells63.
Beyond β-cells, adiponectin exhibits strong
anti-inflammatory and antifibrotic activities in many
organs by acting on macrophages and fibrogenic
cells53,64,65. Accordingly, a protective role of adiponectin
could be identified in atherosclerosis66, gestational
diabetes67–69 and nonalcoholic fatty liver disease70,71.
Taken together, the findings show that adiponectin is
an endocrine hormone that is released by adipocytes,
with proven homeostatic functions, particularly in the
context of chronic metabolic stress.
Other adipokines
Adipsin. The first identified adipokine was adipsin,
which was originally described as a secreted serine pro-
tease expressed in mature adipocytes but not in undif-
ferentiated precursors72. Plasma adipsin is derived from
adipose tissues (Fig. 1), which are the major site of its
expression73. Adipsin is also known as complement fac-
tor D, which is a rate-limiting component of the alterna-
tive complement pathway. In humans, the activity of the
alternative complement pathway correlates with adverse
outcomes, for example in cardiovascular disease74,
indicating that adipsin has the potential to modulate
inflammatory events in remote organs. Depending on
the context, the alternative pathway might fuel inflam-
mation by the production of chemotactic molecules, or
might dampen inflammation by opsonization and the
removal of dead cells.
Studies using mouse disease models suggest that
the net outcome of adipsin action depends on dis-
ease severity; models with more pronounced tissue

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damage favour a proinflammatory role of adipsin75.
However, in mouse models of obesity, circulating lev-
els of adipsin progressively decline over time76. In sup-
port of a protective function of adipsin, a 2014 study
found that adipsin-deficient mice fed a high-fat diet
developed glucose intolerance. The phenotype could be
explained by defective insulin secretion in the presence
of unaltered β-cell mass and normal insulin sensitivity76.
Mechanistically, complement factor C3a, which is gen-
erated in an adipsin-dependent manner, was found to
boost glucose-dependent insulin secretion through C3a
receptor-dependent Ca2+ signalling in β-cells76.
In humans, moderately increased adipsin levels
were observed in the plasma of people with obesity
as compared with control individuals77. Intriguingly,
patients with T2DM who required treatment with
recombinant insulin were characterized by lower
plasma adipsin levels76. Thus, a decrease in adipsin lev-
els in the advanced prediabetic state could be involved
in the progression to overt T2DM in humans. However,
as it cannot be ruled out that insulin treatment might
have caused lower adipsin levels in this cohort, more
human studies are required to confirm that lower
activity of endocrine adipsin increases development
of insulin-dependent T2DM.
Fatty acid-binding protein 4. Fatty acid-binding pro-
tein 4 (FABP4) is a small cytosolic protein that binds
fatty acids and structurally related lipids and is abun-
dantly expressed in adipocytes as well as being found
in macrophages and capillary endothelial cells (Table 1).
Genetic deficiency or pharmacological inhibition of
FABP4 decreases insulin resistance in obese mice and
also protects mice from atherosclerosis78. Changes in
intracellular lipid metabolism, in particular decreased
lipolysis and increased de novo lipogenesis (DNL), have
been identified as potential mechanisms protecting
FABP4-deficient mice from insulin resistance (described
later); however, strong evidence also exists for a role of
extracellular FABP4 in cardiometabolic disease78.
FABP4 is released from adipocytes in response to the
induction of lipolysis through non-classical secretory
mechanisms78,79. Obese mice exhibit increased circulat-
ing levels of FABP4, and plasma FABP4 concentration
is increased in conditions of obesity, insulin resis­
tance, T2DM and cardiovascular risk in humans78,80.
Infusion of recombinant FABP4 increases hepatic
gluconeogenesis in FABP4-deficient mice, whereas
antibody-mediated neutralization of FABP4 in obese
mice decreases gluconeogenesis and improves insu-
lin resistance80,81. Furthermore, in vitro, recombinant
FABP4 triggers proatherogenic responses in vascular
smooth muscle and endothelial cells82.
The mechanism of action of FABP4 is unclear; how-
ever, it might involve direct effects through interaction
of the protein with a cell surface receptor, or indirect
effects via FABP4-dependent delivery of lipokines80.
Furthermore, although circulating FABP4 is likely to
originate from adipocytes, potentially other cells (in
particular macrophages or capillary endothelial cells)
can contribute to plasma FABP4. Nevertheless, sev-
eral independent studies indicate that FABP4 exerts
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endocrine functions and accelerates the development of
obesity-related diseases79–81.
Neuregulin 4. Neuregulin 4 (NRG4) is an adipokine
that can counteract chronic inflammation and obesity-
associated metabolic changes in the liver83,84. This pro-
tein is a member of the epidermal growth factor family
and is highly expressed in brown and white adipo­cytes
(Table 1) . In adipose tissue and especially BAT, the
expression of NRG4 is induced in mice on cold expo-
sure, whereas expression is decreased in obese mice and
humans with obesity83.
NRG4 signalling through the epidermal growth
factor receptor homologues ERBB3 and ERBB4 in
mouse hepatocytes in vivo leads to attenuated DNL83 as
well as decreased apoptosis and necrosis in the liver84.
Consistent with these protective cellular mechanisms,
NRG4-deficient mice fed a diabetogenic high-fat diet
have a fatty liver phenotype, gain more weight and are
more insulin-resistant than controls, whereas transgenic
mice overexpressing NRG4 show the opposite pheno-
type83. Moreover, NRG4-deficient mice display exacer-
bated inflammation and fibrosis when fed a diet designed
to induce nonalcoholic steatohepatitis (NASH)84.
Although the contribution of adipose tissue to NRG4
plasma levels needs to be formally proved, this factor
seems to be a hormone that is enriched in thermogenic
adipocytes and that has beneficial effects on hepato-
cytes in the context of obesity-associated cardiometa-
bolic disease. However, evidence indicates that NRG4
has strong paracrine effects on endothelial cells and is
essential for adequate adipose tissue angiogenesis85,86.
Moreover, NRG4 might also be relevant for appropri-
ate BAT innervation87. In addition, although NRG4 is
expressed at a much lower level in the liver than in adi-
pose tissue83, potential exists for hepatic NRG4 to act
in a paracrine fashion. Thus, adipose tissue-derived
NRG4 acting on the liver is probably not the only mech-
anism for how this adipokine confers systemic insulin
sensitivity. Anti-inflammatory effects and a healthy
adipo­kine profile established through local action88 are
probably also relevant for the systemic effects of NRG4.
Tissue-selective knockdown of NRG4 or its receptors
will certainly shed light on the biology of this exciting
novel adipokine, especially to differentiate between its
paracrine and endocrine actions.
Lipokines
Adipose tissues are quantitatively important sites of
fatty acid metabolism. In interplay with other organs, fatty
acids are relevant not only as energy sources or bio-
synthetic precursors but also as regulatory factors. For
example, adipose tissue-derived FFAs induce the expres-
sion of catabolic enzymes in hepatocytes by binding
and activating PPARα, thereby linking WAT lipolysis
to metabolism in the fasting state liver89. Beyond this
and other general fatty acid-related mechanisms, certain
fatty acid species and derivatives produced by adipocytes
have been found to exert defined physiological effects.
Several studies (described later) suggest that these lipid
hormones, referred to in this Review as ‘lipokines’, act in
an endocrine fashion (Box 1).
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Exosomes
Small cytosol-containing
membrane vesicles that are
released by one cell to be
taken up by other cells and
release their content, for
example microRNA.
516 | SEPTEMBER 2019 | volume 15
Palmitoleate. The first lipid that was postulated to act
as an endocrine adipose lipokine was palmitoleate
(16:1Δ9), an abundant monounsaturated fatty acid that
is mostly derived from DNL90 (Fig. 1). Typically, the pal-
mitoleate content of WAT and levels of palmitoleate
in the plasma FFA pool are decreased in obese and
insulin-resistant mice, owing to decreased adipose tissue
DNL8. As palmitoleate exhibits anti-inflammatory and
insulin-sensitizing effects in vitro91,92 and genetic inter-
ventions that increase WAT DNL in obese mice increase
systemic insulin sensitivity90,93, it has been proposed
that palmitoleate is a lipokine that increases metabolic
health90. Supporting this concept, dietary palmitoleate
supplementation reduces atherosclerosis92, improves glu-
cose homeostasis90,94, and suppresses liver inflammation95
in mouse disease models.
Whether a decrease in the palmitoleate content
of WAT is an important step in the development of
obesity-associated insulin resistance in humans is an
open question. In people with obesity and insulin resist-
ance, WAT palmitoleate content is not substantially
altered as compared with healthy control individuals.
This observation can be explained by the finding that,
unlike in mice, the enzyme catalysing the final step in
palmitoleate synthesis, Δ9-desaturase, is not downregu-
lated in WAT of obese humans96. Thus, there is no sys-
temic palmitoleate deficiency in individuals with obesity
and insulin resistance and, consequently, no major con-
tribution to the development of cardiometabolic diseases.
Nevertheless, palmitoleate is probably anti-inflammatory
in humans, and supplementation might have beneficial
effects in chronic inflammatory diseases.
Fatty acid esters of hydroxy fatty acids. Fatty acid esters
of hydroxy fatty acids (FAHFAs) are a novel class of
lipids that are linked to adipose tissue DNL97 (Fig. 1).
Genetic mouse models with suppressed DNL in multiple
organs or selectively in adipocytes have decreased levels
of FAHFA species (containing fatty acids derived from
DNL) in adipose tissues and plasma97,98. In both mice
and humans, WAT and plasma levels of such FAHFAs
correlate with systemic and adipocyte insulin sensitiv-
ity97,99. These results led to the model that the systemic
decrease of the levels of WAT DNL-derived FAHFAs in
obesity contributes to the development of general insulin
resistance and the deterioration of metabolism.
Mechanistic studies performed to provide evidence
for the aforementioned model focused on positional
isomers of palmitic acid hydroxystearic acid (PAHSA),
which are an abundant subgroup of WAT FAHFAs97. For
example, oral gavage of 5-PAHSA or 9-PAHSA improves
glucose tolerance in insulin-resistant mice97,98. At the cel-
lular level, activation of the fatty acid receptor GPR120
increases adipocyte glucose transport. Moreover, GPR40
activation and the secretion of both glucagon-like pep-
tide 1 and insulin from intestinal L cells and pancreatic
β-cells, respectively, were identified as potential mecha­
nisms mediating the beneficial metabolic effects of
PAHSAs97,100. The effects of PAHSAs administered by
oral gavage in mice on oral glucose tolerance were, how-
ever, not observed by another group101. The discrepancy
might be due to differences in the lipid content of the
vehicle and the degree of insulin resistance of the mice
used in the experiments102,103.
Another unresolved issue is the effective concentra-
tion of FAHFAs needed to activate GPR120 and GPR40
in vitro, which is considerably higher than the concen-
tration present in mouse plasma97,98,101. Thus, the role of
FAHFAs as endocrine, antidiabetic regulators remains
controversial, and more research is needed, especially
to identify and corroborate molecular FAHFA targets.
12,13-Dihydroxy-(9Z)-octadecenoic acid. 12,13-
Dihydroxy-(9Z)-octadecenoic acid (12,13-diHOME)
was identified through an unbiased lipidomic approach
as a lipokine the level of which is selectively increased
in the plasma of humans and mice that are exposed to
cold104 (Fig. 1). Notably, BAT was identified as the source
of circulating 12,13-diHOME in mice. This conclu-
sion is based on the observation that the expression
of 12,13-diHOME-synthesizing enzyme, bifunctional
soluble epoxide hydrolase 2, is specifically induced
in BAT depots on cold exposure104. In both mice and
humans, plasma 12,13-diHOME concentration corre-
lated with the volume of active BAT104. Functionally,
12,13-diHOME boosted energy expenditure and stimu­
lated fatty acid uptake in BAT, but not in other organs,
probably through the fatty acid transporters CD36
and FATP1 (ref.104). Together, these data characterize
12,13-diHOME as a BAT-derived lipokine that augments
adaptive thermogenesis in a paracrine fashion.
A 2018 publication found that the concentration of
12,13-diHOME is elevated in the plasma of humans and
mice under conditions of moderate-intensity exercise and
that 12,13-diHOME stimulates fatty acid uptake and oxi-
dation in skeletal muscle105. The study authors showed
that 12,13-diHOME is primarily produced by BAT; how-
ever, the factor also acts on muscle, thereby providing
evidence for an endocrine action. Taken together, the
findings show that 12,13-diHOME is a novel lipokine
that seems to be important for providing fatty acids to
organs under conditions of high energy demand, through
cellular mechanisms that need to be further explored.
Adipocyte-derived exosomal microRNAs
MicroRNAs (miRNAs) are regulatory non-coding
RNAs that are shared between cells primarily through
exosomes 106. Evidence is accumulating for a role of
exosomal miRNAs secreted from WAT and BAT in
metabolic regulation107–109 (Fig. 1). A major proportion
of plasma miRNAs originate from adipose tissues, as
indicated by a decrease in the levels of many miRNA
species in the plasma of mice with adipocytes deficient
in the miRNA-generating enzyme Dicer, which is a
phenotype that can be rescued by adipose tissue trans-
plantation108. Of note, BAT transplantation reversed
the plasma increase of the endocrine hormone fibro-
blast growth factor 21 (FGF21) that was observed in
the Dicer-deficient mice and this effect was linked to
exosomal miR-99b downregulating liver Fgf21 mRNA.
In patients with lipodystrophy, a greater number of
miRNAs in the circulation were found to be downreg-
ulated than upregulated, suggesting that adipose tis-
sue is also an important source of plasma miRNAs in
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humans108. In healthy volunteers exosomal miR-92a is
released by brown adipocytes and plasma levels inversely
correlate with human BAT activity measured by meta­
bolic imaging107, indicating the potential of plasma
miRNAs as a biomarker for BAT activity. In summary,
evidence suggests that WAT and BAT are an important
source of exosomal miRNAs; however, more studies are
needed to understand the cell biology and regulation of
the secretion process, as well as to define the specific
endocrine function of miRNAs in metabolism.
To conclude this section, there are a number of
endocrine factors that are released by white and brown
adipocytes (Fig. 1). These hormones regulate systemic
energy metabolism and influence the development of
cardiometabolic diseases by modulating organ-specific
functions (Figs 1,3).
Factors also secreted by other organs
Most adipose tissue-derived regulatory secreted factors
are not exclusively produced by adipocytes but are also
produced in other organs or by cells of the adipose tissue
stroma–vascular fraction (Table 1). The latter includes
β-Cell dysfunction and/or diabetes mellitus Protective
Adiponectin, adipsin
Detrimental
β-Cell eNAMPT
Obesity, insulin resistance and/or Protective
diabetes diabetes mellitus Leptin, adiponectin, NRG4, palmitoleate,
FAHFAs, 12,13-diHOME, FGF21, IGF1,
Insulin CXCL14, GDF15, vaspin
receptor
Detrimental
FABP4, RBP4, resistin, eNAMPT
Context dependent
Adipocyte IL-6
Nonalcoholic fatty liver disease Protective
Adiponectin, NRG4, palmitoleate
Detrimental
Liver Resistin
Context dependent
IL-6
Cardiovascular disease (atherosclerosis, Protective
cardiac hypertrophy and so on) Leptin, adiponectin, palmitoleate, FGF21,
omentin, vaspin
Blood vessel
Detrimental
FABP4, eNAMPT
Fig. 3 | Functional relevance of adipokines and lipokines in cardiometabolic
diseases. Various adipokines and lipokines have been found to exert either protective or
detrimental effects on the development of cardiometabolic diseases. Causal, disease-
modifying roles of the hormones presented have been demonstrated by genetic or
pharmacological intervention studies in rodents, as described in detail in the text. Of note,
for most of the factors, only a limited number of proof-of concept studies have been
performed. The intensively studied hormone IL-6 displayed variable, context-dependent
results, which can be explained by cell type-specific modulation of inflammatory and
metabolic pathways. CXCL14, C-X-C motif chemokine ligand 14; 12,13-diHOME,
12,13-dihydroxy-(9Z)-octadecenoic acid; eNAMPT, extracellular nicotinamide phosphori-
bosyltransferase; FABP4, fatty acid-binding protein 4; FAHFAs, fatty acid esters of hydroxy
fatty acids; FGF21, fibroblast growth factor 21; GDF15, growth differentiation factor 15;
IGF1, insulin-like growth factor 1; NRG4, neuregulin 4; RBP4, retinol-binding protein 4.
NATuRe RevIeWS | EndOcRInOlOgy
Reviews
endothelial cells, preadipocytes, macrophages and var-
ious immune cell types that are present throughout the
body. Here we describe factors for which an endocrine
function has been demonstrated and that are expressed
to a certain degree also outside adipose tissue. Cytokines
and chemokines are not discussed, as they probably
exert most or all of their functions as paracrine medi-
ators. Exceptions are interleukin-6 (IL-6) and C-X-C
motif chemokine ligand 14 (CXCL14), for which endo-
crine roles are supported by experimental data. As the
contribution of adipose tissue to the effects of the factors
discussed is not self-evident, special focus will be placed
on data that suggest a specific contribution of adipose
tissues versus other organs as the source of the respective
endocrine factor.
Adipokines also released by hepatocytes
Fibroblast growth factor 21. The endocrine hormone
FGF21 has attracted a lot of attention owing to its ben-
eficial pharmacological action on metabolism in obese
rodents and primates. In mice, both adipose tissue and
brain are important target organs that mediate major
metabolic effects (weight loss and decreased plasma
glucose and triglyceride levels) of FGF21 administered
in therapeutic doses110–112. The liver is the primary or
only source of plasma FGF21 under basal conditions
in mice as well as in humans113,114. The production of
hepatic FGF21 is induced on prolonged fasting or pro-
tein restriction, and in this context it increases hepatic
gluconeogenesis, fatty acid oxidation and ketogenesis
via stimulation of the hypothalamus–pituitary–­
adrenal axis and sympathetic tone110,115. Paradoxically,
the production of hepatic FGF21 is also induced by
carbo­hydrate overfeeding, and under this condition
it supports the disposal of dietary glucose via acute
insulin-sensitizing effects mediated through FGF21
receptors in adipose tissue110,116. Thus, FGF21 produced
in the liver fine-tunes metabolism during both fasting
and acute overfeeding by acting on brain and adipose
tissue, respectively.
The role of adipose tissue-derived FGF21 is more
complex and controversial. FGF21 produced in adipose
tissue might not be important in obesity-associated
insulin resistance, as adipose tissue-specific FGF21-
deficient mice that are fed a high-fat diet did not show
decreased circulating FGF21 levels or insulin resistance,
in contrast to liver-specific FGF21-deficient mice114. By
contrast, adipose tissue-derived FGF21 seems to be rele-
vant under thermogenic stimulation. In mice exposed to
cold, FGF21 expression in BAT and subcutaneous WAT
is substantially increased; however, this effect usually
occurs without any increase in plasma FGF21 levels116–118.
A 2017 study that used tissue-specific FGF21 knock-
down indicates that expression and autocrine signalling
of FGF21 in adipose tissue is required for the proper
development of thermogenic beige adipocytes in WAT
of cold-exposed mice119.
Of note, other studies provide evidence for endo-
crine roles of BAT-derived FGF21. One study reports
that the severely dysfunctional BAT of UCP1-deficient
mice showed a strong induction of Fgf21 expression
and elevated plasma FGF21 levels, as compared with
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wild-type controls120. In another study, transplantation
of BAT improved the glucose homeostasis of acceptor
wild-type mice with high-fat diet-induced obesity and
insulin resistance. This phenotype was accompanied by
substantially elevated plasma FGF21 levels as a result of
increased FGF21 expression that was observed in both
transplanted and endogenous BAT. The effect was absent
when donor BAT was deficient in IL-6, indicating an
essential role of this cytokine in FGF21 induction121.
Further evidence for an endocrine role of BAT-derived
FGF21 was provided by a mouse hypertension model,
which had increased plasma FGF21 levels. BAT surgi-
cal removal and BAT-specific knockdowns provided
strong evidence that BAT-derived FGF21 acted on the
heart to diminish cardiac hypertrophy122. Taken together,
BAT can become a source of circulating FGF21 under
severe disease conditions, whereas under milder physio­
logical stress ranging from long-term fasting to obe-
sity, adipose tissue FGF21 seems to act primarily in a
paracrine fashion.
Insulin-like growth factor 1. Under basal conditions, the
liver secretes abundant amounts of insulin-like growth
factor 1 (IGF1) in a growth hormone (GH)-dependent
manner. Of note, IGF1 production is also induced under
basal conditions by GH in WAT and BAT123. However, cir-
culating IGF1 levels and liver Igf1 expression are almost
undetectable in GH receptor-deficient mice124, despite
substantial residual Igf1 expression in BAT and WAT123,
thereby demonstrating liver is the dominant source of
circulating IGF1. Notably, considerably increased plasma
IGF1 levels and improved glucose homeostasis were
observed in BAT transplantation experiments from donor
wild-type mice to an acceptor mouse model of type 1
diabetes mellitus (T1DM)125. Although other hormonal
changes observed in this study could explain the improve-
ment in glucose homeostasis (for example, decreased IL-6
levels as discussed later), this study showed that trans-
planted BAT can be a major source of plasma IGF1 that
probably acts as an endocrine adipokine125.
Serum retinol-binding protein 4. Hepatocytes and adi-
pocytes secrete serum retinol-binding protein 4 (RBP4),
which is the main plasma carrier for retinol (vitamin A).
Plasma RBP4 levels are frequently increased in humans
with obesity and insulin resistance, and they correlate with
RBP4 expression in human visceral WAT16,30,126. RBP4
directly induces insulin resistance in both muscle tissue
and adipocytes, which is mediated through the RBP4
receptor STRA6 (ref.127). This factor also confers systemic
insulin resistance that is mediated by Toll-like receptor 4
(TLR4)-dependent signalling in macrophages128. Thus,
compelling evidence exists that RBP4 is a contributing
factor for insulin resistance in obesity.
One important open question is the extent to which
adipose-derived RBP4 contributes to circulating RBP4.
A 2017 study found that plasma RBP4 levels are unde-
tectable in lean and obese hepatocyte-specific RBP4-
deficient mice129, suggesting that RBP4 is an endocrine
hepatokine but not an adipokine. Decreasing plasma
RBP4 levels achieved with the synthetic retinoid fen-
retinide increases insulin sensitivity in obese mice130.
518 | SEPTEMBER 2019 | volume 15
However, increasing plasma RBP4 levels via hepatic
overexpression does not affect insulin sensitivity in
mice131, whereas adipose tissue-specific overexpression
does not alter plasma RBP4 levels but induces adipocyte
hypertrophy and inflammation in WAT132. Thus, strong
evidence exists for a paracrine action of adipose tissue
RBP4 in insulin resistance, whereas more research is
needed to elucidate the endocrine functions of hepatic
and potentially adipose tissue-derived RBP4.
Adipokines also released by immune cells
C-X-C motif chemokine ligand 14. CXCL14 is a chemo­
kine expressed by various immune and epithelial cells
throughout the body, lacks a known receptor133, and
was proposed in 2018 as a novel endocrine BAT adipo­
kine134. In comparison with controls housed at ambient
temperature, cold-exposed rodents showed increased
expression of CXCL14 in brown and white adipocytes,
as well as increased release of CXCL14 from BAT as
shown by arterial–venous difference. Conversely, plasma
and adipose tissue CXCL14 levels were decreased in
a high-fat diet-induced mouse model134. CXCL14-
deficient mice had compromised adaptive thermogen-
esis and impaired glucose tolerance, whereas systemic
CXCL14 administration increased the thermogenic
capacity of BAT, increased WAT browning and amelio-
rated insulin resistance in obese mice. Adipose tissue
recruitment of anti-inflammatory and prothermogenic
M2 macrophages was found as a mechanism conferring
CXCL14-dependent WAT browning134. In summary,
in rodents, CXCL14 is an adipokine released from
BAT that can increase thermogenic differentiation in
WAT through M2 macrophage polarization. Research
addressing the expression patterns in humans, the
effects of BAT-derived CXCL14 on other organs and
immune cells and metabolic characterization of mice
with adipocyte-specific knockdown of CXCL14 will
help clarify the role of this novel BAT-derived adipokine.
Interleukin-6. IL-6 is a cytokine that is secreted by WAT
and BAT but also by a number of non-adipose tissues,
especially the skeletal muscle in the context of exer-
cise135,136. The signalling pathways of IL-6 are complex
and involve both a transmembrane form and a soluble
form of IL-6 receptor (IL-6RA), which both interact
with the broadly expressed co-receptor glycoprotein
130 (ref.136). IL-6 is released from WAT into the systemic
circulation of humans, as determined by the measure-
ment of arterial–venous differences seen even in healthy
individuals137, and the level of this factor is frequently
elevated in the blood of individuals with obesity and/or
diabetes mellitus.
The secretion of IL-6 is induced in WAT by various
factors, including proinflammatory cytokines and exces-
sive adipocyte lipolysis138,139. Adipose tissue-derived IL-6
has been proposed to act on the liver. This hypothesis
is based on the observation that hepatic insulin resist-
ance and impaired glucose tolerance in obese mice were
accompanied by a strong increase in IL-6 production
in WAT and these detrimental metabolic effects were
abolished by interventions selectively preventing this
IL-6 induction139,140. However, IL-6 and other cytokines
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can also originate from Kupffer cells and other immune
cells in the liver.
Mouse studies using cell type-specific knockdown
of IL-6RA showed variable and unanticipated results.
For example, hepatocyte-specific IL-6RA-deficient
mice showed systemic insulin resistance and pro-
nounced hepatic inflammation, even when fed a nor-
mal diet, demonstrating the anti-inflammatory effects
of IL-6 in the liver141. Similarly, myeloid cell-specific
IL-6RA-deficient obese mice showed a poorer meta-
bolic phenotype than obese controls associated with
WAT macrophages polarized towards a proinflamma-
tory M1 phenotype142,143. By contrast, T cell-specific or
natural killer cell-specific IL-6RA deficiency improved
insulin resistance in obese mice144,145. Thus, IL-6 can act
in both a proinflammatory and an anti-inflammatory
fashion, depending on cell type and context. Given these
complex functions, it is not surprising that the role of
WAT-derived IL-6 in hepatic glucose metabolism and
insulin resistance is still controversial135,136.
Resistin. Resistin is a protein that is secreted from mouse
adipocytes and macrophages, and its level is increased
in the plasma of obese mice as compared with lean con-
trols146,147. Resistin accelerates insulin resistance as well
as the development of inflammatory metabolic diseases,
including NASH, by acting on many cell types, includ-
ing adipocytes, hepatocytes, myocytes, macrophages,
endothelial cells and hypothalamic neurons146. The pat-
tern recognition receptor TLR4 mediates at least some
of the proinflammatory effects of resistin148. However, no
specific receptor has been identified so far, which limits
functional studies of this adipokine.
Importantly, human resistin is derived from circu-
lating monocytes and tissue-resident macrophages,
but not adipocytes146,149. Nevertheless, plasma levels of
the hormone also increase with obesity in humans146.
Notably, a humanized mouse model expressing human
resistin exclusively in macrophages showed increased
insulin resistance and inflammation as compared with
control animals150. Thus, human resistin plays a role in
obesity-associated inflammation and insulin resistance,
but in humans the contribution of adipose tissue to plasma
resistin levels is probably less important than in mice.
Ubiquitously expressed adipokines
Growth differentiation factor 15. Growth differentiation
factor 15 (GDF15; also known as macrophage inhibitory
cytokine 1) is a member of the transforming growth fac-
tor superfamily with anti-inflammatory properties. In
humans, GDF15 plasma levels are increased in many
pathological conditions, including cancer, cardiovascular
disease and kidney failure, and GDF15 levels are positively
associated with the risk of death151. Many organs can pro-
duce GDF15 (for example, liver and skeletal muscle).
However, this factor is not expressed in these organs under
basal conditions and is induced only on oxidative stress,
proinflammatory cytokine action or other stimuli151.
GDF15 is also secreted by preadipocytes and adipo-
cytes152, and serum levels are increased in humans with
obesity and in obese mice. As a downstream effector
of the anti-inflammatory cytokines IL-4 and IL-13, in
NATuRe RevIeWS | EndOcRInOlOgy
Reviews
WAT, GDF15 can prevent excessive inflammation and
improve glucose metabolism153. Studies suggest that
GDF15 mediates metabolic effects by acting on the neuro­
nal brainstem receptor GDNF family receptor-α-like
(GFRAL)154–156. However, in obesity, GDF15 mRNA is
increased not only in WAT but also in the liver and pos-
sibly other organs157. Thus, the contribution of adipose
tissue to circulating GDF15 in this context is not clear,
and overall the status of GDF15 as an endocrine adipo­
kine is not well established. Nevertheless, recombinant
GDF15 infusion reduces body weight and corrects
many obesity-related metabolic derangements in rodent
and primate models of obesity, thereby indicating
therapeutic potential157.
Nicotinamide phosphoribosyltransferase. Nicotinamide
phosphoribosyltransferase (NAMPT; also known as
visfatin) is a protein that functions both intracellularly
and extracellularly. The extracellular function was first
identified through its activity as a bone marrow-derived
B cell growth factor158. In 2005, researchers discovered
that this factor is expressed in human visceral adipose
tissue and renamed it ‘visfatin’159. In the same publica-
tion, the protein was reported to have insulin-mimetic
properties, which could not be confirmed, leading to
the retraction of the article. The visfatin story took an
unexpected turn when scientists discovered that the
protein is NAMPT, which is the rate-limiting enzyme
in the salvage pathway of nicotine amide dinucleotide
(NAD+) synthesis, thereby identifying an important
intracellular function of the protein159.
As NAMPT is widely expressed, it remains unclear
whether adipose tissue is an important source of circu-
lating extracellular NAMPT (eNAMPT). Experiments
to address this question using adipocyte-specific
NAMPT-deficient mice were inconclusive owing to
severe adipose tissue dysfunction in these animals160.
Nevertheless, plasma NAMPT levels are positively
associated with obesity and insulin resistance in many
clinical studies159. Moreover, eNAMPT has various
activities, including some that implicate it in the patho-
genesis of chronic diseases such as atherosclerosis161
and diabetes162.
Importantly, eNAMPT increases the proinflamma-
tory actions of macrophages and neutrophils, boosts the
activation and proliferation of lymphocytes and exerts
detrimental effects on pancreatic β-cells159,162. Of note,
although eNAMPT activates well-established signal-
ling pathways related to inflammation and apoptosis,
a signalling receptor has not yet been identified. It has
been speculated that the enzymatic activity of eNAMPT,
which regulates adenine nucleotide signalling, medi-
ates the observed cellular effects159. More intervention
studies that separate intracellular functions from extra-
cellular functions (for example, using inactivating anti­
bodies162) are needed to understand the role of eNAMPT
in metabolic regulation and cardiometabolic disease.
Omentin. Omentin (also known as intelectin 1) is a
lectin-like protein that is expressed in the small and large
intestine, where it is involved in microbial surveillance163.
Furthermore, omentin is produced by endothelial and
volume 15 | SEPTEMBER 2019 | 519
Reviews
other stroma–vascular cells in various organs. The
name ‘omentin’ is derived from the high expression of
this factor in omental (that is, visceral) WAT compared
with subcutaneous human WAT164. Notably, mice do not
express appreciable amounts of omentin in adipose tis-
sues, which has hampered mechanistic studies address-
ing the physiological role of adipose-derived omentin165.
Observational studies have established that low omen-
tin plasma levels in humans are associated with insulin
resistance and a higher risk of cardiovascular disease165.
Moreover, in humans, adipose tissue production of
omentin is suppressed by insulin, which explains the
decrease of circulating omentin levels in hyperinsuli-
naemic insulin-resistant states166. Although no specific
cell surface receptor has been identified, omentin elicits
distinct downstream signalling events, which explain the
beneficial metabolic effects165 and suggest therapeutic
potential.
Vaspin. Vaspin (also known as serpin A12) is an
insulin-sensitizing protease inhibitor, the level of which
is frequently but not always increased in the circulation
of individuals with obesity16,167. Vaspin was originally
identified as a visceral WAT-specific adipokine in dia-
betic rats167. Subsequent work showed that in humans
vaspin was detectable only in WAT of individuals with
obesity but was not confined to visceral WAT168; vaspin
was also enriched in the stroma–vascular fraction of
adipose tissue169. As vaspin is widely expressed, and
no adipose tissue-specific deficient models have been
reported so far, it remains unclear whether circulating
vaspin is derived from adipocytes. Nevertheless, animal
studies demonstrate promising beneficial roles of vaspin
in diabetes and cardiovascular disease167. Future work
should focus on the mechanism of action of vaspin,
which may involve inhibition of specific proteases
(for example, kallikrein 7)170.
Taken together, the findings show that a large num-
ber of regulatory molecules with divergent activities are
secreted from adipose tissues. Most of these molecules
are also produced by other organs or by other cell types
in adipose tissues (Table 1), and in many cases the exact
contribution of adipocytes needs to be established.
Therapeutic aspects
Leptin-based therapies
As described previously, leptin is a hormone essential
for the regulation of energy metabolism and major
endocrine axes. Accordingly, recombinant leptin can be
used to treat endocrine dysfunctions in hypoleptinae-
mic conditions that are present in extremely lean women
with amenorrhoea171 and also in patients with lipodys-
trophy172. In addition, leptin administration normalizes
plasma glucose levels in rodent T1DM models that have
low leptin levels173. The mechanisms described remain
unclear, but leptin may act by correcting glucagon hyper-
secretion or by suppressing cortisol secretion174, or both.
However, leptin deficiency is less pronounced in human
T1DM, and leptin treatment might not be effective in
patients with T1DM174.
The weight-lowering and insulin-sensitizing effects
of leptin make it an attractive therapeutic approach to
520 | SEPTEMBER 2019 | volume 15
tackle obesity-related metabolic dysfunction. Proving
this concept, leptin treatment was found to be effective
in humans with obesity caused by rare leptin loss-of-
function mutations33. However, one major hurdle in the
development of leptin as a general antiobesity drug is
the presence of leptin resistance in individuals with
obesity and in obese rodents, where typically very high
plasma levels of the hormone are present. Leptin resist-
ance is a complex phenomenon that involves defects in
the uptake of leptin into the cerebrospinal compartment,
as well as the attenuation of leptin signalling in central
neurons175. Notably, potential approaches to overcome
leptin resistance in obesity have been identified, including
treatment with the islet hormone amylin176–178 and agents
that restore leptin signalling by decreasing intracellu-
lar stress in central neurons179. Although the potential
adverse effects of leptin therapy, such as liver fibrosis180,
need to be kept in mind, the leptin signalling pathway
is amenable to pharmacological intervention, and leptin
sensitizing may be a viable option for the treatment of
common metabolic diseases.
Adiponectin-based therapies
Given its pleiotropic beneficial effect in cardiometa-
bolic diseases (as identified in rodent disease models),
adipo­nectin signalling is an attractive therapeutic target.
The levels of circulating adiponectin can be elevated by
pharmacological intervention using PPARγ agonists.
Moreover, adiponectin mediates at least part of the result-
ing positive effects of PPARγ agonist treatment on insu-
lin resistance, development of fatty liver and other organ
disturbances, as comparisons of adiponectin-deficient
and wild-type mice demonstrated181,182. Adiponectin
receptors were also targeted directly in rodents using
AdipoRon, an orally available small-molecule ADIPOR1
and ADIPOR2 dual agonist183. AdipoRon administered
to obese mice not only improved insulin resistance183 but
also slowed the development of inflammatory disorders
such as generalized fibrosis184, providing proof of con-
cept for adiponectin-specific therapies. A general caveat
is that even though high adiponectin levels are strongly
associated with insulin sensitivity and a low risk of devel-
oping T2DM in humans, a causal role of adiponectin and
salutary effects of high adiponectin levels on mortality
could not be confirmed in large genetic studies185. These
findings cast doubt on the general translatability of the
rodent data to humans, and more research is warranted
to resolve this paradox.
Other adipokine-based therapies
Although many adipokines and other adipose tissue hor-
mones are associated with cardiometabolic diseases and
are promising as biomarkers186, none have as yet as much
therapeutic validation as leptin. Therapeutic targeting
of molecules secreted from adipose tissue is generally
difficult, and a potential reason for this is that many
exert pleiotropic, modulatory functions. This fact is not
ideal with regard to therapeutic efficacy, especially in the
context of complex cardiometabolic diseases that require
long-term treatment, as both pleiotropic effects and
sustained dosing increase the risk of adverse effects.
For example, the administration of NRG4 might exert
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 Reviews

beneficial cardiometabolic effects but at the same Conclusions

time increase the risk of breast cancer development
through permanent activation of the receptors ERBB3
and ERBB4 (ref.187). In addition, the development of
oral drugs for peptide factors such as adipokines is
challenging, and thus pharmaceutical efforts to develop
endocrine therapies based on these molecules are
limited so far.
Nevertheless, many adipokines are of great thera-
peutic interest. Treatment with pharmacological doses
of FGF21 corrects elevated plasma levels of glucose and
triglycerides in rodent models, non-human primates
and patients with diabetes mellitus111,112,188. Moreover,
a long-acting analogue of FGF21 was found to reduce
liver steatosis in patients with NASH189. GDF15 is
another promising therapeutic adipokine, as this factor
reduces weight in obese mice and monkey models by
suppressing appetite, even in a chronic setting, proba-
bly through defined areas in the hindbrain157. Several
rodent studies indicate that omentin has various ben-
eficial effects in cardiovascular diseases. For example,
adenoviral or transgenic expression of human omentin
attenuates cardiac hypertrophy, reduces atherosclerosis
and prevents myocardial injury in mouse models190–192.
Recombinant vaspin protects rats against myocardial
ischaemia and reperfusion injury193, as well as alleviat-
ing pulmonary hypertension by inhibiting inflammation
and remodelling of the vascular wall194.
Harmful adipokines and their effect on metabolism
and cardiovascular disease can be neutralized by anti-
bodies, as shown, for example, in the case of FABP4.
Long-term treatment of obese mice targeting extracel-
lular FABP4 resulted in improved glucose homeostasis
and increased insulin sensitivity, and decreased fat mass
as well as liver steatosis81. In summary, administration
of therapeutic adipokines and adipokine-neutralizing
antibodies has provided encouraging results in rodent
models; however, for most of them efficacy and safety
in humans needs to be proven.
A large number of plasma hormones originate from
WAT and BAT, and are secreted depending on the energy
and disease states of these adipose tissues (Fig. 2; Table 2).
The relevance of these factors is especially exemplified
by the presence of hypertrophic adipocytes in obesity,
where adipose tissue-derived proinflammatory mol-
ecules can affect β-cell function, obesity-associated
insulin resistance and the development and progres-
sion of diabetes, NASH and various cardiovascular
diseases (Fig. 3).
Notably, many adipose tissue-derived hormones are
expressed to a substantial degree in other organs, and
their endocrine versus paracrine contribution is fre-
quently not defined. This issue could be addressed by
more frequently using in vivo technologies that are based
on arterial–venous or microdialysis sampling, thereby
allowing quantification of secretion from adipose tissue
depots in rodents and humans. Moreover, more
research using cell type-specific genetic manipulation
of these hormones and their receptors is needed to dis-
sect systemic and pleiotropic effects. Furthermore, the
combination of global interventions such as constant
adipo­kine or lipokine infusion, or neutralizing antibodies
combined with organ-specific receptor knockdown
would advance our understanding of adipocyte-derived
hormone endocrine functions. The role of specific cell
types can also be investigated by novel nucleic acid-
based intervention methods. For example, adenovirus-
associated virus vectors and small interfering RNAs
encapsulated by a glucan shell can be used to target
adipocytes and WAT-resident macrophages, respec-
tively195,196. Finally, it will be important to translate the
proof of concept generated in rodent models to the clini­
cal setting and demonstrate feasibility as well as effi-
ciency of therapies based on endocrine signalling of
adipose tissue hormones in humans.
Published online 11 July 2019

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Acknowledgements
The authors acknowledge the support of grants from the
Deutsche Forschungsgemeinschaft (SCHE522/4-1),
Collaborative Research Center (SFB 1328) and Heisenberg
Professorship (HE3645/10-1).
Author contributions
The authors contributed equally to all aspects of the article.
Competing interests
The authors declare no competing interests.
Peer review information
Nature Reviews Endocrinology thanks D. Langin and the other,
anonymous, reviewer(s) for their contribution to the peer
review of this work.
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