Jurnal 29

Biochimie 204 (2023) 92e107
Contents lists available at ScienceDirect
Biochimie
journal homepage: www.elsevier.com/locate/biochi
Adipokines from white adipose tissue in regulation of whole body

energy homeostasis
Bijayashree Sahu, Naresh C. Bal*
School of Biotechnology, KIIT University, Bhubaneswar, Odisha, 751024, India
a r t i c l e i n f o a b s t r a c t
Article history: Diseases originating from altered energy homeostasis including obesity, and type 2 diabetes are rapidly
Received 31 January 2022 increasing worldwide. Research in the last few decades on animal models and humans demonstrates that
Received in revised form the white adipose tissue (WAT) is critical for energy balance and more than just an energy storage site.
8 August 2022
WAT orchestrates the whole-body metabolism through inter-organ crosstalk primarily mediated by
Accepted 1 September 2022
cytokines named “Adipokines”. The adipokines influence metabolism and fuel selection of the skeletal
Available online 7 September 2022
muscle and liver thereby fine-tuning the load on WAT itself in physiological conditions like starvation,
exercise and cold. In addition, adipokine secretion is influenced by various pathological conditions like
Keywords:
WAT
obesity, inflammation and diabetes. In this review, we have surveyed the current state of knowledge on
Adipokine important adipokines and their significance in regulating energy balance and metabolic diseases.
Batokine Furthermore, we have summarized the interplay of pro-inflammatory and anti-inflammatory adipokines
Energy homeostasis in the modulation of pathological conditions.
Obesity © 2022 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights
Insulin resistance reserved.
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
2. Role of WAT as a secretory organ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
2.1. Leptin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
2.2. Adiponectin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
2.3. Omentin-1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98
2.4. Visfatin/NAMPT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98
2.5. Tumour necrosis factor-alpha (TNF-a) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98
2.6. Interleukin-6 (IL-6) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
2.7. Plasminogen activator inhibitor-1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
2.8. Monocyte chemoattractant protein 1 (MCP-1) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
2.9. Secreted frizzled-related protein 5 (SFRP5) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
2.10. Fatty acid binding protein 4 (FABP-4) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
2.11. Chemerin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
2.12. Vaspin or serpinA12 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
2.13. Fibroblast growth factor 21 (FGF21) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
2.14. Retinol-binding Protein-4 (RBP4) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
2.15. Cardiotrophin-1 (CT-1) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
2.16. Acylation-stimulating protein (ASP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
2.17. Lipocalin-2 (LCN2) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
2.18. Resistin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
3. Future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
* Corresponding author.
E-mail addresses: bijayashree.ksbt@gmail.com (B. Sahu), naresh.bal@kiitbiotech.
ac.in (N.C. Bal).
https://doi.org/10.1016/j.biochi.2022.09.003
0300-9084/© 2022 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.
B. Sahu and N.C. Bal Biochimie 204 (2023) 92e107
Data availability statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102

Authors’ contributions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
Declaration of competing interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
Abbreviations Nonesterified fatty acids (NEFA)

Tumour necrosis factor receptor (TNFR)
White adipose tissue (WAT) Transmembrane TNF-a (tmTNF-a)
Adipose tissue (AT) Interleukin-6 (IL-6)
Beige adipocytes, Free fatty acid (FFA) Stromal vascular fraction (SVF)
Fatty acid (FA), Central nervous system (CNS) Glycoprotein 130 (gp130)
Skeletal muscle (SkM) IL-6 receptor (IL-6R)
Cardiovascular disease (CVD) Janus kinase (JAK)
Subcutaneous WAT (SAT) signal transducer and activator of transcription (STAT)
Neuropeptide Y (NPY) Phosphoinositide 3-kinase (PI3K)
g-aminobutyric acid (GABA) A strain k thymoma/transforming protein kinase (AKT)
Corticotropin-releasing hormone (CRH) Metabolic syndrome (MS)
Triglyceride (TG) JAK/Tyk and STAT
insulin receptor substrate1 (IRS-1 Glycoprotein 130 (gp130)
Glucose transporter (GLUT) 4 IL-6 receptor (IL-6R)
Insulin resistance (InR) CeC motif chemokine receptor (CCR2)
Suppressor of cytokine signalling-3 (SOCS-3) AT macrophages (ATMS)
Type 2 diabetes mellitus (T2DM) Secreted Frizzled-Related Protein 5 (SFRP5)
Streptozotocin (STZ) Wingless-related integration site (Wnt)
NAD-dependent deacetylase sirtuin-1 (SIRT1) Fatty Acid Binding Protein 4 (FABP-4)
Forkhead box transcription factors 1 (FOXO1) Glucose-dependent insulin secretion (GSIS)
Diabetes mellitus (DM) Chemokine-like receptor 1 (CMKLR1)
Stromal vascular fraction (SVF) G-Protein coupled Receptor (GPR1)
Visceral adipose tissue (VAT) Chemokine CeC motif (CCRL2)
Proliferator-activated receptors (PPAR) Mitogen-activated protein kinase (MAPK)
PPAR-g coactivator-1a (PGC-1a) lipoprotein lipase (LPL)
Adiponectin (ADIPOQ) lipopolysaccharide (LPS)
Mechanistic target of rapamycin (mTOR) Gestational diabetes mellitus (GDM)
AMP-activated protein kinase (AMPK) Fibroblast Growth Factor 21 (FGF21)
Nitric oxide (NO) Brown adipose tissue (BAT)
Extracellular regulated protein kinases (ERK) Uncoupling protein 1 (UCP1)
Nuclear factor kappa-light-chain-enhancer of activated B Retinol-Binding Protein-4 (RBP4)
cells (NF-kB) High-density lipoprotein (HDL)
c-Jun N-terminal Kinase (JNK) Cardiotrophin-1 (CT-1)
cyclooxygenase-2 (COX-2) Acylation-Stimulating Protein (ASP)
Basal metabolic index (BMI) High-fat diet (HFD)
Nicotinamide adenine dinucleotide (NADþ) Lipocalin-2 (LCN2)
Nicotinamide mononucleotide (NMN) Neutrophil gelatinase-associated lipocalin (NGAL)
Nicotinamide phosphoribosyltransferase (NAMPT) CCAAT/enhancer-binding protein (C/EBP)
Tissue inhibitor of metalloproteinase 3 (TIMP3) Secreted Frizzled-Related Protein 5 (SFRP5)
A disintegrin and metalloprotease 17 (ADAM17) Peptidase M20 Domain Containing 1 (PM20D1)
Inhibitor Of Nuclear Factor Kappa B Kinase (IKKB) neuregulin 4 (NRG 4)
1. Introduction high substrate requirement such as exercise, cold, and starvation

[1]. It maintains the whole-body energy homeostasis by acting as a
Recent studies on white adipose tissue (WAT) are highlighting metabolic sink for excess food intake and promoting energy
its role beyond a classical energy storage site to a biologically dy- expenditure by converting substrate to heat termed as “Adaptive
namic organ. In contrast to the traditional belief, adipose tissue (AT) Thermogenesis” [2]. Several factors regulate its functionality,
is metabolically active and regulates body function like energy including thyrods, steroids, stress, and several cytokines [3e5]. As a
expenditure through immunological, nervous and endocrine fac- metabolic coordinator, WAT regulates the energy intake via acting
tors in an autocrine, paracrine and endocrine manner [1]. It takes on the orexigenic and anorexigenic centers of the brain [6]. It
the central stage of metabolism by serving as the energy supplier in synthesizes and secretes endocrine hormones like leptin and adi-
the form of free fatty acids (FFA) during physiological conditions of ponectin that target muscle and liver to efficiently utilize substrates
93
such as glucose and fatty acids (FAs). It further coordinates the translocation and reduces insulin resistance (InR). The leptin
metabolism of vital organs of the body by secreting an array of signaling is inhibited by increased expression of the protein-
cytokines, interleukins and peptides, not only from adipocytes but tyrosine phosphatase 1B (PTP-1B) and suppressor of cytokine
also from residing immune cells, altogether recognized as adipo- signaling-3 (SOCS-3) which are also propose to induce a form of InR
kines [7]. From the physiological standpoint, adipokines are known [14]. Thus, leptin regulates energy metabolism and its therapeutic
to act both systemically and locally by inducing several receptors, significance in obesity and type 2 diabetes mellitus (T2DM) has
thereby permitting the central nervous system (CNS) and other been assessed. Exogenous leptin administration has been shown to
hormonal networks of afferent and efferent signaling. Adipokines normalize hyperglycemia, lipodystrophy associated with InR
maintain the typical body metabolic homeostasis by their action [15e18]. Additionally, leptin evokes fat oxidation and reduction in
through several possible routes such as 1) directly acting on target body weight by triggering AMPK in non-adipocytes and conse-
organs such as skeletal muscle (SkM), heart, pancreas, liver or, 2) quentially improve insulin sensitivity [19].
indirectly via hypothalamus and/or CNS or, 3) acting synergistically
with the major metabolic hormone, insulin [8]. The metabolic ho- 2.2. Adiponectin
meostasis is altered by the sedentary lifestyle that is closely asso-
ciated with the adipokines. These adipokines have an additional Encoded by the ADIPOQ gene located on chromosome 3, adi-
role in inflammation and are suggested to mediate morbid obesity, ponectin, secretion is mainly determined by adipocyte size in SAT
and cardiometabolic complications [9]. The emerging discoveries modulating insulin sensitivity. Contrary to leptin, adiponectin
on adipokines as prognostic markers and their therapeutic concentration attenuates the degree of InR and is reduced before
administration provide new insight into the treatment of metabolic the onset of obesity InR [20e22]. The adiponectin undergoes post-
diseases. Here we have summarized the various types of adipo- translational modifications as well as proteolytic cleavage. After
kines, their mechanism of action and role in metabolic regulation in cleavage, the globular domain stimulates fat oxidation in the SkM,
mammals, especially humans. We have also accessed the pro- while the full-length adiponectin decreases hepatic glucose output.
gressing phases of therapeutic interventions originating from adi- It is interesting to note that adiponectin exhibit both pro-
pokine administration for reshuffling energy homeostasis to inflammatory and anti-inflammatory properties. As a pro-
counter diseases. inflammatory factor, adiponectin induces secretion of NF-kB and
inflamatory cytokines in monocytic, macrophages and C2C12
2. Role of WAT as a secretory organ myocytic cells [23,24]. Adiponectin is shown to induce M1 type
macrophage cells in human [25]. As anti-inflammatory agent, adi-
Although the concept of adipokines has been put forward during ponectin reduces chronic inflammation in target organs by
the early 1990s, this term is now used to cover all secretory prod- switching macrophage phenotype to M2 type and decreasing TLR4
ucts from WAT [10]. These secretory factors regulate hypertrophy expression. Many studies in human and rodents demonstrated that
and hyperplasia of the AT and modulate adipocyte activity by adiponectin shows anti-inflammatory action in diabetes mellitus
regulating substrate utilization, vascularization, and innervation (DM), non-alcoholic fatty liver disease (NAFLD) and cardiovascular
during various pathophysiological conditions. The adipokines are disease [26]. Adiponectin decreases TNF-a induced inflammation in
implicated in substrate (glucose and lipid) metabolism, inflamma- the liver of NAFLD-mice model [27].
tory phenomenon, and regulating the function of many other or- Adiponectin action in above condition mediated by interaction
gans [9]. The distortion in the WAT secretion also influences the with its receptors: AdipoR1 (ubiquitously expressed, but more
development of insulin resistance (InR), hyperglycemia, dyslipide- abundant in SkM) and AdipoR2 (exclusively in the liver), and T-
mia, and cardiovascular diseases (CVDs). In this section, we sum- cadherin-CDH13 (localized in SkM and cardiac muscle) [28,29].
marize all the important adipokines described so far (Table 1). Deletion of AdipoR1 and 2 leads to lipodeposition in various tissues,
glucose intolerance, and InR. Adiponectin binding and its receptors
2.1. Leptin themselves can induce ceramidase activity and hydrolyzed to
sphingosine thereby form antiapoptotic metabolitedsphingosine-
Leptin, one of the first adipokines to be identified in 1994, is the 1-phosphate (S1P) [30]. In diet induced diabetic model adiponectin
product of the OB or Lep gene and is a 16 kDa peptide primarily lowers ceramide-lengths and formation of deoxyceramides. In liver,
produced from subcutaneous WAT (SAT) [10]. Its secretion is AdipoR2 expression results in production of S1P that induces sig-
directly proportional to WAT mass and nutritional status and serves nificant AMPK expression [31]. In the liver, adiponectin activates fat
as a communicator about energy status between CNS and periph- oxidation and reduces gluconeogenesis by inhibiting the hepatic
eral tissues. Hence, leptin plays a major role in energy homeostasis phosphoenol pyruvate carboxylase decreasing glucose output [32].
of the body by regulating satiety & food intake, glucose meta- In SkM, adiponectin induces insulin sensitivity via AMPK-mediated
bolism, atherogenesis, and body weight [11]. Leptin can act on the fat oxidation and GLUT4-mediated glucose uptake. Adiponectin is
hypothalamic appetite center by inhibiting orexigenic neuropep- suggested to work through peroxisome-proliferator-activated re-
tide Y (NPY), g-aminobutyric acid (GABA) neurons thereby stimu- ceptor (PPAR) a and g and PPAR g-coactivator-1a (PGC-1a) in the
lating the anorexigenic center. In addition to reduced food intake, liver and SkM, and regulates insulin signaling in vivo [33,34]. This
leptin stimulates energy expenditure through its action on adipokine also indirectly boosts insulin sensitivity by rising hepatic
corticotropin-releasing hormone (CRH) expression from the hy- insulin receptor substrate1 (IRS-1) expression via a macrophage-
pothalamus [11]. Leptin not only targets the hypothalamus but also derived interleukin (IL) 6 dependent pathway [35,36]. Adipo-
has receptors in adipocytes and pancreatic b cells, thereby exerting nectin has also been shown to act on endothelial cells and mediate
some of the pleiotropic effects. In WAT, leptin acts as an autocrine nitric oxide production increasing angiogenesis and protecting
factor and provokes oxidization of stored triglycerides (TGs), and vascular walls [37]. Adiponectin receptors expression in pancreatic
increases mitochondrial energy expenditure in adipocytes [12]. In b-cells and their upregulation by exposure to FFA, signifying its
the pancreas, leptin regulates glucose homeostasis by inhibiting involvement in insulin secretion [38]. Studies have shown that
insulin biosynthesis and secretion, while insulin shows a positive during DM, the adiponectin/AdipoR1 signaling is impaired in
feedback loop for leptin secretion [13]. Recent studies demonstrate muscles (cardiac and SkM), WAT and liver. In the heart of the
leptin action on SkM, where it boosts glucose transporter (GLUT) 4 streptozotocin (STZ) -treated DM model, the adiponectin/AdipoR1
94
Table 1
A representation of the function and pathological significance of various secretory factors of WAT.
Adipokines Site of Secretion Target Site Genetic characteristics Targeting Functional Altered Anomalies Administration effect
Molecule Characteristics
Leptin WAT AT OB or Lep gene NPY [ vascular [ Leptin resistance and Normalize hyperglycemia
Enterocytes Pancreas GABA adhesion elevated circulating and, lipodystrophy
Hypothalamus CRH molecules leptin in human associated with InR in
SkM GLUT4 Stimulate [ InR. STZ-induced diabetic rats
AKT platelet- and human respectively
AMPK dependent [15e18].
thrombosis Rapidly Improves Glucose
[AMPK Homeostasis in leptin-
mediated insulin deficient (ob/ob) mice
sensitivity in [280].
non-ATs.
Adiponectin WAT Liver ADIPOQ gene AMPK [ fat oxidation Adiponectin/adipor1 Y weight and amelioration
Placenta SKM GLUT4 Y signaling and adipor1- of InR in obese men [42].
PPARa gluconeogenesis Caveolin-3 are Y blood glucose, insulin
PGC-1a [ angiogenesis impaired in STZ levels and hepatic
IRS-1 and protecting induced treated dia- gluconeogenesis in high-
vascular wall betic mice [39,40]. fat, high-sucrose (HFHS)
Mediate nitric fed mice [43].
oxide
production.
Omentin-1 VAT WAT Omentin 1 gene IRS Y TNF-a. Y in the serum and VAT Lower contractile
SAT Endothelial Mtor Y JNK activation of obese and diabetes dysfunction and InR in
Epicardial AT cells JNK in vascular human [33,35,36,46 cultured cardiomyocytes
ERK endothelial cells e49]. [282].
/NF-kB YAMPK/enos/NO Y Cardiovascular
AMPK pathways dysfunction in DM
besides lower patients [281].
TNF-a
TNF-a VAT AT TNF-a gene NF-kB Y lipogenesis [ the rate of Y inflammation in rats
Immune cells Liver PPAR-g and adipocytes atherosclerosis in [ fatty Liver disease
SkM Endothelium IRS-1 Alters the APOE*3-Leiden trans- protection in rat [81].
Smooth muscle AKT expression genic mice [94]. Ydiet-induced obesity and
adiponectin and [ endothelial InR in mice [82]
IL-6 dysfunction and
Y storage of atherogenesis in mice
glucose and [94].
NEFAs Augmenting
Y GLUT4 endothelium
expression and permeability in vitro
lipoprotein [90]
lipase ((LPL)
[ activation of
JNK-1 and IKKB/
NF-kB pathway
[ synthesis of
cholesterol and
fatty acids
[apoptosis
[InR and
lipolysis
Yinhibition of
insulin-
stimulated
glucose
transport
[ Inhibitory Ser
phosphorylation
of IRS-1.
IL-6 AT Liver IL-6gene IRS-1 Y Insulin [ circulating IL-6 in Administered peripherally
VAT WBC SOCS-3 signaling men [101] [ triglycerides, glucose
SkM JAK/STAT3 Regulates [ fatty acid oxidation and InR in rodents [100]
STAT1 glucose in both healthy men Centrally leads [ energy
ERK homeostasis and type-2 DM patient expenditure in rodents
PI3K [ Apoptosis [126,140]. [106,108].
AKT regeneration
and hepatic
acute phase
reactions.
PAI-1 Liver pancreas PAI-1 gene JAK/STAT3 Ynegative [Degree of InR, Not tested
WAT Kidney STAT1 regulator of adiposity, and body
Endothelium SkM ERK fibrinolysis weight in mice [149].
VAT Liver PI3K
(continued on next page)
95
Table 1 (continued )
AKT YPPARg Y adiponectin in type 2

expression is diabetes patients with
downregulated MS [151]
[accumulation
lipids in
nonadipose
tissue
Visfatin VAT Liver NAMPT gene SIRT1 Y b-cell [ Levels of circulating [ hepatic insulin
SkM apoptosis. visfatin in obese sensitivity in HFD-
Neutrophils women [64]. induced T2DM patient and
Bone marrow rat and in-vitro studies
[56,59e61].
IGF1-induced steroido-
genesis and IGF1 receptor
signalling through SIRT1 I
in vitro [68] .
MCP-1 VAT WBC CCL2 Gene JAK/STAT3 Leucocyte [obesity-induced InR Ameliorate InR without
Immune cells Liver STAT1 recruitment to [ TNF-a, IL1b and affecting macrophage
AT ERK inflammation RANTES infiltration into AT in mice
PI3K sites Y insulin-stimulated [164].
AKT Recruitment of AKT phosphorylation
AT macrophages in gastrocnemius mus-
[direct lipid cle of Mice and diabetic
accumulation in obese patient
hepatocytes [161,162].
SFRP5 WAT Adipocyte SFRP5 Gene Wnt Yinflammation YSerum SFRP5 in Not tested
Y insulin human [170,171]
sensitivity and Yglucose clearance
Y Wnt signalling [171]
[Wnt5a-mediated
inflammationobesity
and adipocyte
atherosclerosis in
human subject
[168,277].
FABP-4 Adipocytes AT FABP4 Gene [Circulating FABP4 [ insulin secretion in
Macrophages Heart levels in in diabetes human [178].
[173].
[InR in HL-1 cardiac
cells and HFD mice
[176].
Diabetes and
hypertension
[173,177]
[adipocyte
atherosclerosis [174]
Impaired myocardial
contractility in
cardiovascular patient
[174,175].
Chemerin WAT Skin Retinoic acid receptor MAPK Y [abdominal visceral [ InR in human skeletal
Liver BAT responder protein 2 ERK1/2 steroidogenesis fat accumulation, InR, muscle cells in-vitro and
Lung WAT (RARRES2) gene AKT Promoted and cholesterol levels Y glucose uptake in 3T3-
SkM AMPK insulin- in rat [183] L1 adipocytes [184]
brain glycogen dependent [ chemerin level in in
lower in heart synthase glucose uptake serum and adipocytes
Liver kinase 3 in adipocytes in obesity and T2DM
Pancreatic b- Improved patient [187,188]
cells glucose [Activation ICAM-1
NK cells tolerance in and E-selectin in
macrophages pancreas adipocyte in vitro [184,
Regulates 189]
adipogenesis and [atherosclerosis and
adipocyte cardiovascular disease
metabolism in T2DM patient [191].
Vaspin Liver Hypothalamus Serpina12 gene NPY Improve ER [ Serum vaspin Improve glucose
SkM POMC stress insulin concentration in metabolism in rodents
Pancreas sensitivity and obesity and/or T2DM [205].
Stomach maintain glucose [196e198,200e202].
Skin load
VAT Y
SAT gluconeogenesis
Y food intake
FGF 21 WAT Liver FGF21 gene. В-Klotho
96
BAT WAT AKT Regulate energy Y Serum FGF21 levels [ glucose uptake in
Beige ERK1/2 homeostasis in overweight rodents human [219]
WAT AMPK Induced during and human [214]. Y gluconeogenesis [208]
Liver PGC1-a adipogenesis Y blood glucose and
PPAR g [UCP1- triglycerides to near
dependent ther- normal levels in mice
mogenesis in [208,212].
human [ pancreatic b-cell
function in vitro as well
as rodent models
[283,284]
NRG 4 WAT WAT NRG4 Gene STAT5 [ lipogenesis in Y in T2DM, NAFLD in Not tested
BAT BAT ERBB3 liver rodents and obese
Beige fat Liver ERBB4 [ angiogenesis patient [285,286].
blood vessel Y in patient with
gestational DM and
coronary artery
diseases [271,287]
Slit2-C Beige Fat WAT SLIT2 Gene. The Ucp1 [ energy Y Obesity and DM in improve whole body
Ing WAT extracellular matrix Dio2 expenditure human [275] energy expenditure and
protein Slit2 cleaved to Cidea improve glucose glucose homeostasis in
c terminal part. PRDM16 homeostasis HFD fed obese mice [276]
PKA
EGFR
ERK1/2
CT-1 Liver Adipocyte CTF1 Gene AKT Maintain glucose [ in human and [glucose utilization
Kidney SkM cAMP homeostasis murine steatotic liver in vitro [227]
SkM PKA [ insulin- [228,233]. Chronic administration Y
Heart stimulated phos- adipocyte size, and
Adipocyte phorylation of lipogenesis and [ lipolysis
Lung AKT and fatty acid oxidation in
Brain mice [227,231]
Testis Eliminate hepatic
steatosis in obese mice
[230]
Y intestinal sugar
absorption in obese
patient [231,234].
ASP WAT WAT C3 gene. PKC [ lipogenesis in [ Plasma ASP in [ the clearance of FFAs
Cleaved from C3 adipocytes hyperlipidemia and and triglycerides from the
obesity in both mice circulation after oral fat
and human [236e238]. administration in mice
[adipocyte [240e242].
inflammatory response
leading to high-fat diet
((HFD)-induced InR in
mice [240]
Resistin WAT WAT RETN Gene SOCS-3 interfere with Trigger systemic InR in induces InR [265,266]
Liver Liver AMPK insulin- mice [264]. [ hepatic glucose
peripheral gluconeogenic stimulated Y insulin-assisted production and glycemia
blood enzymes glucose uptake glucose uptake in adi- leptin-deficient (ob/ob)
mononuclear by SkM pocytes [264] and HFD-induced obese
cells ((PBMCs) induces InR in [ hepatic InR [265] mice [258,260,268]
macrophages human [serum concentration
hepatocytes of resistin in humans
and rodents [258,262].
LCN2 AT BAT LCN2 Gene. MC4R Increase [ inflammation, InR Long-term LCN2
WAT NF-kB and C/EBP UCP1 oxidative [249e251] administration
binds to LCN2 PGC1-a metabolism and [Serum LCN2 levels in suppresses appetite and
promoter and BAT activation obese women [254] body weight gain in mice
regulates LCN2 [ insulin secretion [288]
expression and promote b- [ whole body glucose
cell proliferation metabolism [248]
Plays a role in [ energy expenditure
adipocyte obese mice [243]
remodeling
[ fat oxidation
promotes
metabolic
homeostasis
Yage-related
ectopic
(continued on next page)
97
adiposity in
Liver
activate MC4R-
dependent
anorexigenic
pathway
Apelin Placenta Hypothalamus APLN gene CAMP Modulating [InR and [ Insulin Sensitivity in
Kidney Pre-Pro-Apelin is ERK1/2 glucose entry Hyperinsulinemia in Skeletal Muscle and AT in
SkMs cleaved by PI3K into tissues via mice [273] Diabetic Patient [274].
Heart Endopeptidase to AKT NO
Stomach Generate of Mature P70s6 Kinase; Promotes
Lung C-Terminus AMPK and glucose uptake
Mammary (Apelin. Fragment eNOS mainly through
Gland AMPK pathway
Stimulation of
Nitric Oxide
Synthase ((NOS);
and Mobilization
of Calcium.
[ represents upregulation or improvement, Y represents downregulation or reduction.
signaling and AdipoR1-Caveolin-3 are impaired [39,40]. In adipo- neutrophils [56,57]. Conversely, the intracellular form of visfatin act
cytes, NAD-dependent deacetylase sirtuin-1 (SIRT1) induces adi- as the crucial enzyme in the Nicotinamide adenine dinucleotide
ponectin upregulation through forkhead box transcription factors1 (NADþ) salvage pathway and plays a significant role in nicotin-
(FOXO1) and SIRT1 protects against InR damage but is impaired in amide mononucleotide (NMN) biosynthesis as a nicotinamide
DM [41]. Animal studies have demonstrated significant and sus- phosphoribosyltransferase (NAMPT) where as its extracellular form
tainable weight reduction and amelioration of InR by adiponectin is cytokine-like. Administration of NMN, a product of the NAMPT
infusion [42,43]. However, the clinical trial of adiponectin has not reaction enhances glucose intake and hepatic insulin sensitization
been transcended. in a high-fat diet (HFD)- stimulated T2DM suggests visfatin act as
an insulin-mimetic hormone [58,59], but these data remain
2.3. Omentin-1 controversial [60,61]. Not only intracellular NAMPT ameliorates
aging-induced T2DM but also NAMPT- mediates SIRT1 to promote
It is also known as intelectin 1 consisting of 313 amino acids insulin sensitization in peripheral tissues [62], but its role is still
transcribed from the omentin 1 gene in chromosome1. Omentin-1 controversial. It would contribute to the prevention of high-calorie
is copiously expressed in the stromal vascular fraction (SVF) of the intake as well as aging-dependent obesity and T2DM [63]. Not only
visceral adipose tissue (VAT) whereas tremendously down- circulating visfatin concentration reflects the adiposity but also is
regulated in the SAT and mature adipocytes of VAT [44]. In hu- associated with InR and T2DM [62,64]. Visfatin transcription was
man adipocytes, inhibition of the mTOR signaling pathway by modified by glucocorticoids, TNFs, and IL-6. Elevated circulating
omentin-1 activates insulin receptor substrate (IRS) and enhances visfatin concentration was reported in inflammatory diseases
insulin-stimulated glucose uptake [44,45]. Omentin-1 levels are supporting the concept of visfatin and inflammatory factors
significantly lessened in the serum as well as VAT of overweight, affecting each other [65]. It is suggested to mediate proinflamma-
obese and T2DM patients [33,35,36,46e51]. Omentin-1 plays an tory signaling for macrophage differentiation, and monocyte-
anti-inflammatory role by preventing the TNF-a-induced COX-2 induced lymphocytes responses [66]. Additionally, visfatin played
expression, JNK activation apparently via activation of AMPK/ a profound role in b-cell proliferation and function by suppressing
eNOS/NO pathways in vascular endothelial cells besides lower TNF- b-cell apoptosis [67], but elevated in serum with progressive b-cell
a [52,53]. Another study in human umbilical vein endothelial cells deterioration [68]. Inclusively, as a proinflammatory intermediate,
suggests omentin may hinder TNF-a-induced adhesion molecules visfatin can exert constructive changes depending on the nutri-
expression in endothelial cells via blocking ERK/NF-kB pathway tional and physiological conditions such as NAMPT-mediated NMN
[54]. It exerts a negative correlation with inflammation, obesity, production. Since evidence of a straight forward link between vis-
InR, and basal metabolic index (BMI) and has an optimistic effect on fatin genotype and human T2DM is puzzled, more physiological,
exercise-induced insulin sensitivity [50e52,55]. A study on human molecular and clinical studies are necessary for vivid evaluation of
models demonstrated that altered equilibrium between chemerin visfatin role in the etiology of T2DM.
and omentin1 (increased chemerin and decreased omentin-1
levels) is correlated with InR, oxidative stress, and chronic 2.5. Tumour necrosis factor-alpha (TNF-a)
inflammation in morbidly obese patients [49]. Based on the above
studies, omentin-1 could be considered a new prognostic marker TNF-a performs its physiological actions following cleavage of
for predicting the severity of metabolic disorders linked to obesity 26-kDa transmembrane protein by ADAM-17 to its active 17-kDa
and T2DM. polypeptide form. Beyond the traditional view of its inflamma-
tory role, studies suggest its participation in energy homeostasis,
2.4. Visfatin/NAMPT InR and positively correlated with obesity. Tissue inhibitor of
metalloproteinase 3 (TIMP3) inhibited ADAM-17 action, that pro-
Visfatin, derives its name from its predominant expression in tein is reduced in obesity, InR, and DM thereby increasing soluble
VAT adipocytes encoded by the NAMPT gene and acts as a growth TNF-a level [69e71]. The manner of TNF-a action in negative
factor for B cell precursors in the liver, SkM, bone marrow, and metabolic regulation is more intricate. On one hand, TNF-a directed
98
genomic level modulation within metabolically dynamic AT and of circulating IL-6 is secreted from AT and implicated in the etiology
liver modulation of gene expression within metabolically active AT of obesity and InR [98,99]. Many studies have reported that IL-6
and liver [72]. Within AT, TNF-a dampens the genes regulating secretion and expression are positively integrated with different
lipogenesis, adipogenesis, the inflow as well as the deposit of phases of obesity, glucose uptake, and InR [100]. Circulating IL-6
glucose and NEFAs, and in the other hand, it alters the action of concentration is proportional to weight, as increases with weight
adiponectin and IL-6. In adipocytes, TNF-a mediated lipopolysac- gain and decreases upon weight loss and disturbs the energy ho-
charide (LPS) induced leptin secretion whereas dampens the adi- meostatic in obesity [101]. Peripherally, IL-6 impairs insulin action
ponectin secretion, thereby promoting InR [69,73,74]. It induces via down-regulating the insulin receptor substrate 1 (IRS-1)
atherogenic dyslipidemia not only by increasing the expression of expression [100] and inducing the expression of SOCS-3 [102].
hormone-sensitive lipase but also by simultaneous decreasing li- Additionally, IL-6 represses adiponectin expression and deviates its
poprotein lipase (LPL) action [75]. On the other hand, TNF-a impairs advantageous properties on metabolism [72].
insulin signaling by activating stress- kinases protein JNK and the Centrally, decreased IL-6 defines an antagonistic interaction
IKKB/NF-kB pathway in adipocytes and hepatocytes thereby play- with bodyweight [97,103]. This divergence between the activities in
ing a central role in the chronic inflammatory state present in both peripheral and central administration of IL-6 is most probably
obesity [37,76e79]. In both differentiating and mature adipocytes, verified by the infusion of IL-6 in these peculiar regions. IL-6
TNF-a hinders the phosphor- caveolin-1 expression and eventually treatment results in elevated TGs, glucose, and subsequent InR in
dampens insulin action [80]. Besides, TNF-a represses genes for peripheral tissues [104,105]. However, central IL-6 administration
glucose metabolism and FFAs oxidation in the liver [81,82]. How- assisted in enhanced energy expenditure while lessening fat mass
ever, TNF-a simultaneously enhances the expression of genes [103,106e108]. It has a common feature of linking the classic IL-6
involved in cholesterol and FAs synthesis in hepatocytes [82,83]. pathway with extracellular glycoprotein 130 (gp130) via specific
Furthermore, TNF-a has also been related to the escalating rate of 80 kD IL-6 receptor (IL-6R) in hepatocytes, neutrophils, monocytes,
atherosclerosis, a secondary complication amplified in obesity, by and inactive lymphocytes [109e111]. The anti-inflammatory IL-6
inducing the expression of adhesion molecules in the endothelium from muscle and myeloid cells followed the classic pathway and
of the blood vessels [84]. activates JAK/STAT3, STAT1, PI3K, ERK, and AKT cytoplasmic mole-
The interaction between TNF-a and its receptors (TNFR1 and cules. It regulates glucose homeostasis, apoptosis, regeneration,
TNFR2) mediates apoptosis and inhibits insulin-stimulated glucose and hepatic acute phase reactions. Although central IL-6 adminis-
uptake by inhibitory Ser phosphorylation of IRS-1 [81,82], con- tration diminished adiposity [97,108], it should be demonstrating
firming the link among inflammation, obesity, and InR [76,85]. The any encouraging properties that arise in clinical trials. In adipocytes
preclinical TNF-a infusion also shows variable outcomes. Studies in of obese individuals, IL-6 secretion is higher in hypertrophic adi-
obese Zucker rats show that anti-TNF treatment had a neutral effect pocytes in comparison to smaller adipocytes and linking obesity to
on insulin signaling or altered lipid profile [75,86]. Antagonistically inflammation. In disease conditions, Adam 17 cleaved soluble form
in some other rodent experiments, TNF-a antibody administration of IL-6R (sIL-6R) binds to IL-6 and activate gp130, it mediates trans-
resulted in inhibition of inflammatory reactions, improved fatty signaling in IL-6R deficient cells leading to inflammation through
liver disease, protection against InR, and diet-induced obesity NF-kB activation [111e113]. In a comparative view, we can say
[81,82]. Therefore, the TNF-a effect on insulin signaling in patients ADAM17 acts as a molecular switch between canonical and trans-
with T2DM needs to be studied to enlighten the path for selecting signaling pathways and leading to adipose tissue specific micro-
new therapeutic targets. phase infiltration [114,115]. The meticulous metabolic IL-6 role is in
Even though it was initially assumed that the major site of TNF-a dispute due to complex tissues specific action on metabolism, in-
in obesity were adipocytes, now it is identified that residing M1 sulin signaling, and inflammation [115,116]. These effects depend
macrophages residing in AT are accountable for the augmented on stimulus frequency (acute vs. chronic), target tissue (liver or
concentration of this cytokine [81,82]. Still, TNF-a was the former muscle), or the source secretion (AT or SkM) [111,117]. Chronic
adipokine to stand for the link among inflammation, obesity and -elevation of IL-6 has been reported to be positively related to
T2DM [87e89]. Studies in the last two decades show that TNF-a metabolic syndrome (MS) conditions such as DM, and InR
induces the activity of proliferative, procoagulant, and proi- [111,118,119]. Also, IL-6 mediates partial hepatic InR due to the
nflammatory genes in endothelial cells [87]. During obesity, the inactivation of insulin receptors and IRS-1 [116,117] mediated by IL-
production of TNF-a disrupts the equilibrium of pro and anti- 6 classic rather than a trans-signaling pathway [120]. The binding of
inflammatory molecules, vasodilators and vasoconstrictors, inhib- IL-6 to its low-affinity receptor, IL-6 receptor-a (IL-6Ra, expressed
itor and stimulator factors as well as coagulating factors [87,90e92] in macrophages, neutrophils, myocytes, and hepatocytes), forms a
and can be considered as an instigator of endothelial dysfunction high-affinity hexameric complex with two gp130 proteins to acti-
(foremost result in atherogenesis) in part by STAT induction [93,94]. vate the JAK/Tyk and STAT pathways [121].
Furthermore, the activity of endothelium and upregulated adhe- It is interesting to mention that the potency of IL-6 in T2DM does
sion molecules expression by TNF-a can be suppressed by adipo- not have consistency [122]. As per reports, IL-6 activated SOCS-1
nectin [95]. Interestingly, transmembrane TNF-a (tmTNF-a) and -3 proteins leading to InR in the hepatocytes [123e125].
facilitates glucose uptake by GLUT4 and boosts insulin-dependent However, another study reported that IL-6 increased SOCS-3 in
phosphorylation of IRS-1 and AKT. It also down-regulates the murine myotubes showing tissue-specific differences in glucose
production of proinflammatory IL-6 and MCP-1 via NF-kB and uptake. The myotube shows increased glucose uptake rather than
upregulates adiponectin expression through the PPAR-g pathway decreased [126]. It was shown that prolonged IL-6 exposure leads
[96]. to InR in both differentiating and mature simultaneous decreased
expression of PPAR-g [127]. Additionally, treatments of differenti-
2.6. Interleukin-6 (IL-6) ating preadipocytes with IL-6 profoundly reduce both glucose up-
take and lipogenesis. Studies support that, IL-6 can also down-
IL-6 is a 185 amino acid protein transcribed from the IL-6 gene in regulate adiponectin secretion and insulin signaling in 3T3-L1 ad-
chromosome 1. It is a prominent cytokine that modulates the im- ipocytes [128,129]. Another study reported that the global deletion
mune system [97]. It is now well-defined that both adipocytes and of IL-6 speed up liver inflammation, maturity-onset obesity and
the SVF of VAT act as the major site of IL-6. Surprisingly around 35% whole body InR in vivo [130]. Regarding the mechanism in in vivo
99
and in vitro studies, IL-6 was shown to regulate energy expenditure AT as well as involved in an inflammatory response similar to
by enhancing fatty acid oxidation via AMPK [126,131e133]. In the obesity as well as establishes a connection of InR to thrombosis
contrary, some studies reported no significant alteration in the [160]. Monocytes recruitment into AT by CCR2 activation also
glucose metabolism with acute administration of IL-6 might be due promotes secretion of TNF-a, IL-6, and MCP-1, which enhances the
to the signaling through the gp130 receptor [134e137]. In muscle, inflammation and InR in AT InR by both autocrine and paracrine
chronic elevation of IL-6 levels also impaired the insulin-dependent interactions between adipocytes and monocytes [160,163]. Mice
glucose metabolism whereas acute IL-6 secretion from SkM during lacking MCP-1 or the CCR2 are resistant against high-fat diet (HFD)-
exercise, show enhanced glucose uptake, efficient insulin signaling associated InR [157] and demonstrating MCP-1/CCR2 signaling is a
and AMPK-mediated fatty acid oxidation [126,138e140]. Not only key for obesity-linked InR and CCR2 antagonists able to mitigate
in insulin signaling but also its clearance from blood is regulated by the detrimental effects without aff ecting macrophage infiltration
IL-6. Insulin-degrading enzymes, a 110 kDa zinc-metalloprotease into AT [164,165]. However, it is crystal clear that MCP-1 corrobo-
associated with insulin clearance and amyloid b in liver and SkM rates macrophage infiltration into AT and obesity to InR short-term
and lower expression leads to hyperinsulinemia in obesity and DM. insulin therapy lower MCP-1 and NF-kB expression in serum can
A contradiction to all, a recent study in IL-6 KO mice suggest that IL- ameliorate increased inflammation reaction in T2DM [165,166].
6 might improve the insulin signaling pathway by enhancing the Importantly, under high glucose concentration, MCP-1 is upregu-
expression and production of insulin-degrading enzyme (IDE) in lated in mesangial cells of the kidney relating to glomerulosclerosis
obesity and DM [141]. The IL-6 and IDE are higher in plasma and and diabetic nephropathy [167].
SkM after acute physical exercise and reduce hyperinsulinemia. All
these finding refers to controversial pleotropy of IL-6 in glucose 2.9. Secreted frizzled-related protein 5 (SFRP5)
metabolism. Further research should be done to elucidate the
mechanism with proper stimuli and use this pleiotropic molecule SFRP5 is recently discovered as a new adipokine that is abun-
as a therapeutic target for alleviating InR and DM [142]. dantly expressed in WAT than BAT or beige fat. It is known for its
significance on insulin signaling and chronic inflammation in AT
2.7. Plasminogen activator inhibitor-1 [168]. It negatively impacts the Wnt signaling by close interaction
with the Wnt protein [169]. Reduced SFRP5 increases Wnt5a
Plasminogen activator inhibitor-1 (PAI-1) or serpin E1 is a 45- regulated inflammation, adipocyte atherosclerosis, and obesity
kDa glycoprotein mostly expressed in endothelial cells, adipo- [168,169]. Moreover, decreased SFRP5 level increases the macro-
cytes, and hepatocytes [9]. PAI-1 is secreted chiefly in VAT in phage amount and the proinflammatory factor in mouse adipocytes
comparison to SAT [143]. It acts as a key negative regulator of and impairs insulin-mediated glucose utilization [168]. Lesser
fibrinolysis by acting as an antagonist for plasminogen activator, serum SFRP5 has been reported in obesity and T2DM can be
this indicates PAI-1 is positively associated with CVD [144]. Its associated with altered insulin signaling [170,171]. These demon-
expression is mainly regulated at the transcriptional level by strate that lower SFRP5 in serum can be used as a prognostic
several hormones (aldosterone), cytokines (TNF-a), VLDL, glucose, biomarker for T2DM.
and endotoxin [145e148]. Presently, the mechanisms intertwining
PAI-1 with obesity is still beyond the limelight. It is suggested that 2.10. Fatty acid binding protein 4 (FABP-4)
the initial rise in PAI-1 is due concurrent increase in TNF-a [149]
and a rise in both adipokine levels impairs PPARg expression FABP4 (also known as A-FABP or aP2) is principally released
[145,150]. Additionally, ablation of PAI-1 prevents TNFa-mediated from adipocytes and macrophages and has a pivotal role in InR,
lower glucose uptake in adipocytes, signifying that PAI-1 mediates atherosclerosis, and inflammatory response in adipocytes [172].
inflammation-influenced InR [145,151]. The secreted adipocytic FABP4 contributes to a higher fraction of
PAI-1 serves as a crucial link for CVD to obesity and InR [72]. A adipokine level in the serum [172]. Circulating FABP4 is integrated
recent case-control study Ghana reported that PAI-1 hyper- with obesity-associated complicacy such as InR, hypertension,
coagulation can be prevented by good glycemic control in T2DM adipocyte atherosclerosis, and distorted myocardial contractibility
patients [152]. Its direct inhibition has been identified as a fasci- [173e176]. Further, the circulating FABP4 level is directly propor-
nating area of research. Tiplaxtinin (PAI-039), an oral antagonist of tional to adiposity and body fat percentage while it negates plasma
PAI-1 results in an array of positive effects such as antithrombosis, adiponectin level [177]. A part of higher circulating insulin in
reduction in InR, and adiposity [153]. obesity is correlated to enhanced insulin secretion from the
pancreas by induction of b-cell by FABP4. Interestingly, FABP4
2.8. Monocyte chemoattractant protein 1 (MCP-1) administration promotes insulin secretion while increased blood
FABP4 concentration promotes glucose-dependent insulin secre-
MCP-1 (chemokine CeC motif ligand 2, CCL2) is the introductory tion (GSIS) in humans [178].
discovery in human CC chemokine. It interacts with its CeC motif Conversely, insulin shows negative feedback to FABP4 secretion
chemokine receptor (CCR2) and is intricate in T lymphocytes, by AT in vitro as well as in rodent models and humans [178,179]. All
monocytes, and natural killer cells recruitment during Inflamma- these findings are suggesting that FABP4 mediates insulin release
tion [154e157]. The binding between MCP-1 to CCR2, is key for the during obesity, as an adaptive measure of pancreatic cells. It in-
recruitment of AT macrophages (ATMs) and guiding obesity- dicates that FABP4 can be considered for detectable prognostic
induced InR [157]. MCP-1 is chiefly secreted from AT and causes biomarker that can portrait obesity and adiposity.
AT inflammation without macrophages as well induces direct lipid
accumulation in hepatocytes [158,159]. MCP-1 from AT is crucial in 2.11. Chemerin
intensifying InR in AT in obesity [160]. The MCP1-mediated sig-
nificant level of macrophage markers (CD68 and CD11c), elevates Chemerin is considered a pioneer adipokine since 2007 which is
pro-inflammatory chemokines such as TNF-a and IL1b and the activated from inactive prochemerin by inflammatory and coagu-
chemokine RANTES and attenuates insulin-stimulated AKT phos- lating serine proteases such as plasmin, elastase, and cathepsin G to
phorylation in gastrocnemius muscle in Mice and diabetic obese active form while further cleaved to chemerin-F154 by chymase to
[161,162]. Remarkably, chronic MCP-1 leads to adipocyte atrophy in block functionality. Chemerin has three G protein-coupled
100
receptors as chemokine-like receptor 1 (CMKLR1), GPR1 or expression and secretion of FGF21 via the b3-adrenergic pathway
chemokine-like receptor 2 (CMKLR2), and chemokine CeC motif [207,209]. Omega-3 polyunsaturated fatty acids induce GPR120
(CCRL2). CMKLR2 is a ubiquitous and higher expression in skin, BAT, activation in brown and beige adipocytes that enhance FGF21
WAT, SkM, brain, and lower in heart, and liver [180]. CMKLR1 or release to blood in mice [210]. Enhanced FGF21 boosts energy
ChemR23 is prominent in NK cells, macrophages, and WAT, which catabolism by promoting glucose uptake by GLUT1 as well as
might diminish steroidogenesis by phosphorylation of MAPK, suppressing lipid metabolism by activating lipolysis and reducing
ERK1/2, AKT, as well as increase blood pressure by AMPK through lipogenesis [208,211e214]. It was also confirmed that FGF21
Gi, but how Gi regulates the whole mechanism yet to explore inducing uncoupling protein 1 (UCP1)- mediated thermogenesis in
[181,182]. Further, serum chemerin levels are correlated with BAT and beige adipocytes [215,216]. In accounting for its beneficial
cholesterol levels, BMI, InR, and abdominal fat [49,183]. Chemerin effects on energy expenditure and metabolism, the activity of
in binding with the ChemR23 receptor promotes insulin-mediated FGF21 was reevaluated in humans and revealed preferential
glucose influx in adipocytes [184]. Deprivation of ChemR23 has expression in human beige fat [211,217,218]. Supplementary to the
shown diminished chemerin action leading to amplified LPS- above study, mild cold exposure enhances serum FGF21 with
elicited inflammatory neutrophil infiltration and accumulation in activation of BAT in the neck and shoulders of adults [209,219].
tissue [185]. More Over, neonates uphold an astronomical quantity of BAT
Chemerin action through the ChemR23 receptor enhances together with high serum FGF21 levels [218,220].
pancreatic b-cell functionality and GSIS that means improves
glucose sensitivity [186]. Chemerin regulates adipogenic events, 2.14. Retinol-binding Protein-4 (RBP4)
and adipocyte metabolism and promotes InR as remarkable
elevation was seen in serum and adipocytes in obesity, T2DM as RBP4 is a vitamin A transporter, expressed in hepatocytes, WAT,
well in ob/ob and db/db mouse models [187e190]. Chemerin reg- and interestingly expressed in BAT in response to cold exposure or
ulates the activation of endothelial factors (ICAM-1 and E-selectin), b3-adrenergic signaling [221]. Its abundance in WAT shows an
adipocyte atherosclerosis, and the events of CVD in T2DM [188,191]. antagonistic correlation with blood pressure, cholesterol, TGs, and
Although the CCRL2 (high in the lungs and minute in the liver) is low levels of HDL [222,223]. RBP4 expression within VAT is dras-
not showing any signaling in InR, it promotes Ca2þ mobilization tically magnified in obesity and T2DM patient. The VAT RBP4 level
and chemotaxis in response to chemokines (CCL2, CCL5, and CCL8) is reciprocally related to GLUT4 expression and shows positive
and suppresses chemotaxis and invasion in human breast cancer cooperation with T-helper cell polarization and adipocytic inflam-
cells [192,193]. Studies on pregnant women manifest that mation concomitant with InR. Another study suggests the RBP4-
decreased serum omentin-1 can be indicative of glucose and lipid linked T2DM risk shows sexual dimorphism and is higher in fe-
metabolic disorder and InR, and a simultaneous rise in serum male patients [224]. In response to the above stimuli, RBP4 is also
chemerin and leptin level indicates hyperlipidemia and chronic synthesized and released by the BAT through PGC1-a coactivation
inflammation, supporting a role in gestational diabetes mellitus of PPAR signaling [225]. Nevertheless, the BAT secreted RBP4 con-
(GDM) [194,195]. tributes only a minimum share to the whole circulating RBP4 and
its metabolic importance is yet to elucidate.
2.12. Vaspin or serpinA12
2.15. Cardiotrophin-1 (CT-1)
Recently, Visceral adipose tissue-derived serpin (vaspin), as well
as serum vaspin, was suggested as a key marker for obesity and CT-1 belongs to the IL-6 cytokine family and is considered a
T2DM [196e198]. It is produced abundantly in different tissues, crucial regulator of energy metabolism correlating obesity with InR
including the adipocytes, SkM, liver, pancreas, and stomach, and [226e228]. CT-1 expression is high in the heart, adipocytes, liver,
23% in mature adipocytes of VAT as well as 15% in SAT [199]. Its kidney, SkM, and lung while least in the brain and testis [229,230].
higher level in serum in overweight, obese, and T2DM patients, is CT-1 recruited lipolysis in adipocytes was implemented via the
predicated on the body attempting to compensate for obesity and cAMP/PKA pathway [231,232]. Despite diminished food intake, CT-
T2DM deviations [197,200e202]. Vaspin reduces ER stress while 1 depleted mice showed InR, and high cholesterol levels in circu-
improving insulin sensitivity and maintaining glucose load by lation correlating loss of CT1 with a downfall in energy expenditure
reducing gluconeogenesis [197,203]. Further, vaspin administration [233]. In contrast, chronic CT-1 administration condensed the adi-
markedly suppresses food intake by modulating the hypothalamic pocytes size through downregulating lipogenic genes and simul-
POMC and NPY nuclei [204]. A protease called kallikrein 7 catalyzes taneously upregulating lipolysis and fatty acid oxidation,
the cleavage and degradation of insulin chains in serum, which is eventually modulating the activity of metabolic intermediates
inhibited by vaspin leading to the stabilization of insulin in circu- within murine WAT [65,227]. Moreover, CT-1 promotes glucose
lation [205]. Therefore, vaspin or with its recombinant adminis- utilization by insulin-mediated AKT phosphorylation in myotubes
tration can improve glucose metabolism, leading to longer insulin and adipocytes thereby evidence in improving glucose homeostasis
availability to the body. in SkM and fat [65,227]. Interestingly, chronic and acute infusion
with CT-1 maintains hypoglycemic condition through diminished
2.13. Fibroblast growth factor 21 (FGF21) intestinal sugar absorption that will be beneficial for inhibition of
excess energy load in obese person [231,234].
Several batokines (brown adipose tissue or BAT-derived adipo-
kines) are known to act as positive or negative regulators of ther- 2.16. Acylation-stimulating protein (ASP)
mogenic genes. One elucidated batokine, FGF21 belongs to the FGF
family and is widely studied in rodents and humans. It is considered ASP is a cleaved product of complement 3 (C3) genes in WAT. It
to regulate lipid and glucose metabolism contributed to energy acts as an autocrine factor that promotes lipogenesis from FFA and
homeostasis. It is predominantly expressed in the liver and recent glucose in adipocytes [235]. Multiple experimental findings suggest
reports suggested that BAT and beige WAT secrete FGF21 that plasma ASP concentration is elevated in hyperlipidemia and
[206e208]. When exposed to relevant stimuli such as cold, obesity and that positively related to higher TG content [236e238].
norepinephrine, or CL-316243, BAT or beige WAT upregulates the However, weight loss and fasting reduce ASP levels as well as lower
101
TG concentration [239]. Further, administration of ASP increases 3. Future directions

inflammatory response in adipocytes and enhances HFD-induced
InR [240]. In cooperation with insulin, ASP increases fatty acid Research on adipokines is enhancing the horizon of our
uptake and inhibits fat oxidation in adipocytes [241]. Also, the knowledge regarding energy homeostasis as well as the patho-
absence of C3 was associated with ASP deficiency, and subse- genesis of metabolic diseases. A vast range of regulatory cytokines
quently priming reduced leptin concentration and low WAT mass from vital organs and the residing immune cells of AT modulate the
[241]. In addition, loss of ASP delays clearance of postprandial TGs secretion of a vast range of adipokines. Many external stimuli such
and FAs [242]. as exercise, diet, and cold exposure induce the WAT and also lead to
the secretion of several adipokines. The action of adipokines also
crosstalks with other organs like SkM, liver, heart, pancreas, and
2.17. Lipocalin-2 (LCN2) brain. Each adipokine has not only a regulatory effect on other
peripheral organs but also an autocrine role in regulating the action
LCN2 is also recognized as neutrophil gelatinase-associated of other adipokines either synergistically or antagonistically. Some
lipocalin (NGAL) and is produced copiously in the adipocytes adipokines (IL-6, TNF-a) are also secreted from myofiber with
[243e245]. Its production along with secretion is enhanced by proper stimulations (mainly exercise) and modulate the adipokine
various proinflammatory molecules such as LPS and IL1b action on insulin signaling. The disturbance of adipokine concen-
[246e248]. Particularly, NF-kB and CCAAT/enhancer-binding pro- tration and the ratio of different adipokines such as (omentin to
tein (C/EBP) binds to the consensus motif on the LCN2 promoter chemerin) associated with metabolic diseases like obesity, InR and
and govern LCN2 production [247]. It promotes inflammation, InR, DM. Accounting all the role of adipokines, type 2 DM can be
and involves the transformation of adipocyte physiology in HFD- regarded as a chronic inflammatory disease. Not only with pro-
induced obesity [249e251]. In severely obese women, serum gression of DM but also adipokines modulate progression of
LCN2 concentration correlates with BMI and obesity [252e254]. microvascular and macrovascular complications such as retinop-
Furthermore, LCN2- deficient adipocyte impedes aging and athy, neuropathy, and nephropathy. Extensive studies should be
obesity-induced InR by constraining TNF-a and 12-lipoxygenase required to understand the pathways of recently discovered adi-
(catalyzing metabolization of arachidonic acids) [255,256]. pokine (IGF binding protein-2, Neuregulin-4, Chemokine (C-X-C
Another study confirmed that LNC2 regulates oxidative metabolism motif) Ligand 14 and SFRP5) in DM related secondary vascular
and browning of BAT without reliance on adrenergic stimuli [257]. complications. The studies in inflammatory adipokines (PAI, MCP-
1and TNF-a) are mostly confined in preclinical models. The clin-
ical studies on these adipokines might provide new insight to fight
2.18. Resistin with MS and related pathophysiology.
Proinflammatory resistin is a cysteine-rich secretory factor, Data availability statement

which is related to InR showing different expression patterns in
humans and rodents [258e260]. Both genetic and HFD-induced No raw data is associated with the study since this is a review
obesity is positively correlated with circulating resistin concentra- article.
tion but reduced in rosiglitazone treated WAT [261e263]. Recom-
binant resistin triggers systemic InR in mice while decreasing Authors’ contributions
insulin-dependent glucose utilization in adipocytes [264]. Studies
reported that resistin infusion in rodents provoked glucose pro- B Sahu and N C Bal participated in drafting, editing, and writing
duction, and triggered severe InR in the liver [265]. In fasting, lesser the manuscript. B Sahu designed the table.
resistin partially reduced hepatic gluconeogenesis by AMPK acti-
vation and simultaneously obstructing the gluconeogenesis, and Funding
recovered obesity-linked hyperglycemia [266,267]. Further, lack of
resistin in leptin-deficient (ob/ob) and HFD-induced obese mice This work was supported by the Council of Scientific and In-
showed improvement in glycogenolysis and gluconeogenesis in the dustrial Research (CSIR), India [File no.09/1035 (0011)/2017-EMR-
liver and glucose uptake in peripheral tissue [268]. Resistin I]; the Science and Engineering Research Board (SERB), DST, India
recruited SOCS-3 regulates both glucose and lipid metabolism [Grant number ECR/2016/001247]; and DBT, India [Grant Number
[269,270]. BT/RLF/Re-entry/41/2014 and BT/PR28935/MED/30/2035/2018].
Some recently identified adipokines (insulin growth factor-1,
IGF binding protein-2,apelin, NRG 4, and chemokine (C-X-C Declaration of competing interest
motif) ligand 14) consider for having their role in glucose meta-
bolism either by activating glucose utilization (in SkM and liver) or The authors declare no conflict of interest.
uptake and oxidation of fat [9,271e274]. The beige cell adipokine
slit2-C promotes thermogenesis and the PKA pathway, revealing an References
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Biochimie 204 (2023) 92e107

Contents lists available at ScienceDirect

Adipokines from white adipose tissue in regulation of whole body

Data availability statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102

Abbreviations Nonesteriﬁed fatty acids (NEFA)

1. Introduction high substrate requirement such as exercise, cold, and starvation

AKT YPPARg Y adiponectin in type 2

[ represents upregulation or improvement, Y represents downregulation or reduction.

TG concentration [239]. Further, administration of ASP increases 3. Future directions

Proinﬂammatory resistin is a cysteine-rich secretory factor, Data availability statement

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