Adiponectin A Promising Target For The Treatment o
Adiponectin A Promising Target For The Treatment o
Adiponectin A Promising Target For The Treatment o
Review
Adiponectin: A Promising Target for the Treatment of Diabetes
and Its Complications
Mahmuda Begum 1 , Mayank Choubey 2 , Munichandra Babu Tirumalasetty 2 , Shahida Arbee 3 ,
Mohammad Mohabbulla Mohib 4 , Md Wahiduzzaman 2 , Mohammed A. Mamun 5,6 ,
Mohammad Borhan Uddin 7 and Mohammad Sarif Mohiuddin 2, *
1 Department of Internal Medicine, HCA-St David’s Medical Center, 919 E 32nd St, Austin, TX 78705, USA;
[email protected]
2 Department of Foundations of Medicine, NYU Grossman Long Island School of Medicine, 101 Mineola Blvd,
Mineola, NY 11501, USA; [email protected] (M.C.); [email protected] (M.B.T.);
[email protected] (M.W.)
3 Institute for Molecular Medicine, Aichi Medical University, 1-Yazako, Karimata, Aichi,
Nagakute 480-1103, Japan; [email protected]
4 Julius Bernstein Institute of Physiology, Medical School, Martin Luther University of Halle-Wittenberg,
Magdeburger Straße 6, 06112 Halle, Germany; [email protected]
5 CHINTA Research Bangladesh, Savar 1342, Bangladesh; [email protected]
6 Department of Public Health and Informatics, Jahangirnagar University, Savar 1342, Bangladesh
7 Department of Pharmaceutical Sciences, North South University, Dhaka 1229, Bangladesh;
[email protected]
* Correspondence: [email protected]; Tel.: +1-832-908-3977
the three main groups of diabetes, which include type 1 diabetes mellitus (T1DM) and
gestational diabetes, type 2 diabetes is the most prevalent form [4]. The primary cause of
T2DM is a gradual decline in insulin secretion by pancreatic β-cells, typically occurring
against a backdrop of pre-existing insulin resistance in skeletal muscle, liver, and adipose
tissue [5,6]. According to the World Health Organization (WHO), diabetes stands as a
primary contributor to conditions such as blindness, kidney failure, heart attacks, stroke,
and lower limb amputations [7]. Diabetes is linked to both microvascular (diabetic retinopa-
thy, neuropathy, and nephropathy) and macrovascular (cardiovascular disease or CVD)
complications [8]. Individuals with diabetes face an elevated risk of CVD, encompass-
ing conditions like coronary heart disease (CHD) [9], hypertension, increased levels of
low-density lipoprotein-cholesterol (LDL), and obesity [5,10].
Adiponectin, the most prevalent peptide released by adipocytes, plays a prominent
role in the intricate connection between adiposity, insulin resistance, and inflammation [11].
Levels of adiponectin are inversely correlated with adiposity, meaning an increase in body
fat reduces adiponectin levels and a reduction in fat accumulation increases adiponectin
levels [12]. Adiponectin shows its biological action through several mechanisms such
as enhancing insulin sensitivity in the peripheral cells [13–15], anti-inflammatory actions
by reducing the production of inflammatory molecules [16], breakdown of fatty acids
and inhibiting the production of fatty acids in the liver [17], maintaining the health and
flexibility of blood vessels [18,19], etc. Adiponectin also plays a role in appetite regulation
and energy expenditure [20,21].
Today, there are several treatment options for T2DM. However, treating T2DM is
very challenging due to its complex nature and the diversity of factors involved. T2DM
is a progressive disease as the production of insulin is reduced day by day irrespective
of the treatment of diabetes. Insulin resistance is another challenge in treating diabetes.
Lifestyle modifications including diet and exercise play a crucial role in diabetes. However,
sustaining these alterations can be arduous. Moreover, chronic conditions like T2DM have
significant effects on emotional health.
Recent studies have shown that a reduction in plasma adiponectin concentration is closely
associated with the development of type 2 diabetes mellitus (T2DM) and obesity [22,23]. Both
animal and experimental research have demonstrated that adiponectin enhances insulin sensi-
tivity, suggesting that it may serve as a preventive measure against the onset of T2DM [24].
In the current review, we will discuss recent advancements in studying the pathophys-
iological functions of adiponectin and its receptors in relation to insulin resistance, type 2
diabetes, and metabolic syndrome.
2. Adiponectin: An Overview
Adiponectin, alternatively referred to as AdipoQ, APM1, or ACRP30, is a single-chain
adipokine composed of 244 amino acids, possessing a molecular weight of around 26 kilo-
daltons (kDa) secreted by white adipose tissue. The adiponectin protein is encoded by
the AdipoQ gene located on the chromosome locus 3q27. Adiponectin consists of sev-
eral distinct structural components. It includes an NH2-terminal hyper-variable region,
a collagenous domain consisting of 22 Gly-XY repeats, and a COOH-terminal C1q-like
globular domain. When secreted into the bloodstream, adiponectin forms three oligomeric
complexes: a trimer, a hexamer, and a high molecular weight multimer [25]. Adiponectin
primarily binds to seven transmembrane receptors known as AdipoR1 and AdipoR2 to
regulate a range of physiological functions including whole-body energy balance, inflamma-
tory responses, insulin sensitivity, and the process of fat metabolism [26]. Unlike traditional
G-protein coupled receptors, these receptors possess a cytoplasmic NH2 terminus and an
extracellular COOH terminal domain. AdipoR1 is most abundantly expressed in skeletal
muscle, whereas AdipoR2 is predominantly expressed in the liver [27]. In humans and mice,
AdipoR1 is situated on chromosome 1p36.13-q41, while AdipoR2 is found on chromosome
12p13.31 and 6 F1. The molecular structure of both forms of the receptor exhibits significant
homology, featuring an internal N-terminus and an external C-terminus [28]. AdipoR1
chromosome 12p13.31 and 6 F1. The molecular structure of both forms of the receptor
exhibits significant homology, featuring an internal N-terminus and an external C-termi-
Life 2023, 13, 2213 nus [28]. AdipoR1 and AdipoR2 (Figure 1) are adiponectin receptors that stimulate3 of AMP-
16
activated kinase (AMPK) and PPAR activity, regulating glucose and lipid metabolism.
Adiponectin-induced complete AMPK activation requires both Ca2+/CaMKK and
AMP/LKB1 [29]. (Figure 1) are adiponectin receptors that stimulate AMP-activated kinase
and AdipoR2
(AMPK) and PPAR activity, regulating glucose and lipid metabolism. Adiponectin-induced
complete AMPK activation requires both Ca2+ /CaMKK and AMP/LKB1 [29].
FigureFigure 1. A presentation
1. A presentation demonstrating
demonstrating thethe diversepathways
diverse pathways through
through which
whichadiponectin
adiponectin receptors
receptors
exert functions.
exert their their functions. Adiponectin
Adiponectin engages
engages with
with itsitsreceptors
receptorstoto initiate
initiate various
varioussignaling
signaling pathways.
pathways.
AdipoR1 enhances calcium influx, leadingtotothe
theactivation
activation of 2+
AdipoR1 enhances calcium influx, leading ofCa
Ca2+/calmodulin-dependent
/calmodulin-dependent protein
protein
kinase kinase β (CaMKKβ) and subsequent downstream kinases.
kinase kinase β (CaMKKβ) and subsequent downstream kinases. AdipoR1- and R2-dependent sig- AdipoR1- and R2-dependent
nalingsignaling are mediated
are mediated by adaptor
by adaptor proteinprotein phosphotyrosine
phosphotyrosine interaction (APPL)
interaction (APPL) 1, 1,which
whichallows
allows LKB1
LKB1
to translocate from the nucleus to the cytoplasm and activate AMPK, ceramidase
to translocate from the nucleus to the cytoplasm and activate AMPK, ceramidase activity, and pe- activity, and peroxi-
someproliferator-activated
roxisome proliferator-activated receptor-alpha
receptor-alpha (PPAR-α).
(PPAR-α). Activation of AMPK
Activation reduces reduces
of AMPK gluconeogenesis,
gluconeo-
oxidative
genesis, stress,
oxidative and inflammation.
stress, and inflammation.On the other
On the hand, activation
other of PPAR-α reduces
hand, activation of PPAR-α lipotoxicity
reduces and
lipo-
inflammation
toxicity and increases
and inflammation andfatty acid oxidation.
increases fatty acid Alloxidation.
these effectsAll
ultimately improve
these effects glycemic status.
ultimately improve
glycemic status.
Adiponectin stimulates glucose uptake and fatty acid oxidation in skeletal muscle after
binding to AdipoR1, which is mediated by the recruitment of the adaptor protein with the
Adiponectin stimulates glucose uptake and fatty acid oxidation in skeletal muscle
pleckstrin homology domain, phosphotyrosine domain, and leucine zipper domain (APPL).
after APPL
binding to AdipoR1,
binding which is mediated
to the intracellular domain ofby the recruitment
AdipoR1 activates Rab5,of thea adaptor
small GTPase protein
with the
that enhances GLUT4 membrane translocation and glucose absorption in muscle. APPLdo-
pleckstrin homology domain, phosphotyrosine domain, and leucine zipper
main also
(APPL).
bindsAPPL
to PI3binding
kinase and to the
Akt,intracellular
showing thatdomain of AdipoR1
adiponectin can boost activates Rab5, a small
insulin signaling as
GTPasewell that enhances
[30]. GLUT4between
The interaction membrane APPL translocation
and AdipoR1and glucose
activates absorption in
AMP-activated muscle.
protein
APPLkinase (AMPK),
also binds which
to PI3 inhibits
kinase andacetyl-CoA
Akt, showing carboxylase (ACC) andcan
that adiponectin promotes
boost fatty
insulinacidsig-
oxidation—adipoR-mediated activation of AMPK leads to
naling as well [30]. The interaction between APPL and AdipoR1 activates AMP-activated higher fatty acid oxidation and
protein kinase (AMPK), which inhibits acetyl-CoA carboxylase (ACC) and promotes in
decreased obesity. AMPK activation increases glucose absorption and lactate generation fatty
muscle while suppressing gluconeogenesis. Together, the adiponectin signaling pathways
acid oxidation—adipoR-mediated activation of AMPK leads to higher fatty acid oxidation
underscore the relevance of adiponectin in glucose and lipid metabolism (Figure 2) [31].
and decreased obesity.
Adiponectin AMPKand
activates activation
enhances increases
the productionglucose of absorption
PPAR ligands andvialactate
AdipoR2, genera-
as
tion in muscle while suppressing gluconeogenesis. Together,
well as fatty acid combustion and energy consumption. This is accomplished in part by the adiponectin signaling
pathways underscore
enhanced expression the
ofrelevance
the ACO and of UCP
adiponectin
genes, which in glucose
include theandperoxisome
lipid metabolism
proliferator(Fig-
ure 2)response
[31]. element (PPRE) in their promoter regions [32].
Life 2023, 13, x FOR PEER REVIEW 4 of 18
Life 2023, 13, 2213 4 of 16
3.9. Aging
As individuals age, there is a decrease in the activity of brown adipose tissue, a decline
in sex hormone levels, and an expansion of abdominal adipose tissue. This is accompanied
by a shift of lipids from the subcutaneous fat compartment to the visceral fat compartment.
This eventually results in reduced production of adiponectin [55].
meta-analysis showed that the administration of metformin led to a notable rise in serum
adiponectin levels [58].
Figure 3.
Figure 3. AApresentation
presentationillustrating
illustratingthe
themechanism
mechanismthrough which
through adiponectin
which functions
adiponectin as an
functions as an-
an
tidiabetic agent.
antidiabetic agent.
5.
5. Insulin Resistance and Adiponectin
Insulin
Insulin resistance has
hasaahereditary
hereditarycomponent
componentthatthat
is is
notnot fully
fully understood
understood andand is
is fre-
frequently passed down through generations. Furthermore, obesity has a significant
quently passed down through generations. Furthermore, obesity has a significant heredi-
hereditary component
tary component that inevitably
that inevitably worsensworsens
insulininsulin resistance.
resistance. As a obesity
As a result, result, obesity and
and insulin
insulin resistance
resistance are often
are often present
present for many
for many years
years before
before additionalalterations
additional alterationssuch
such as
as high
high
blood pressure, dyslipidemia, T2DM, and cardiovascular disease develop [19,60]. It was
discovered that, in both mice and humans, a reduction in adipose tissue leads to increased
levels of circulating triglycerides and fatty acids. The presence of insulin resistance pro-
vides further substantiation for the pivotal role played by adipose tissue in governing sys-
temic metabolism by lipid storage [61–63]. Additionally, the appropriate release of adi-
Life 2023, 13, 2213 7 of 16
blood pressure, dyslipidemia, T2DM, and cardiovascular disease develop [19,60]. It was
discovered that, in both mice and humans, a reduction in adipose tissue leads to increased
levels of circulating triglycerides and fatty acids. The presence of insulin resistance provides
further substantiation for the pivotal role played by adipose tissue in governing systemic
metabolism by lipid storage [61–63]. Additionally, the appropriate release of adipokines
like leptin and adiponectin, which improve insulin sensitivity, depends on the amount of
adipose tissue. Lipodystrophies affect adipokine secretion in humans and mice.
The first study to demonstrate that adiponectin actively affects insulin sensitivity was
reported in 2001. A C-terminal globular adiponectin fragment can lower plasma glucose
levels by boosting fatty acid oxidation in muscle [14,64,65]. Globular adiponectin appears to
function in conjunction with AMP-activated protein kinase (AMPK) (and later by inhibiting
acetyl-CoA carboxylase) and PPAR-α (peroxisome proliferator-activated receptor alpha) to
create its metabolic action in the muscles. Ceramidase silencing can inhibit AMPK phos-
phorylation in C2C12 myotubes, indicating a function for sphingolipid metabolism with
adiponectin signaling in this tissue. Adiponectin binding increases glucose uptake (through
GLUT4 translocation) and non-oxidative glycolysis while decreasing intramyocellular tri-
acylglycerol concentration and boosting fatty acid oxidation. Furthermore, adiponectin
affects the number of mitochondria and the kind of oxidative fibers [64]. Adiponectin’s
actions on skeletal muscles are diminished in disease situations. Obese and insulin-resistant
rats had poorer binding of globular and full-length adiponectin, which may be attributed
to a lower density of adiponectin receptors. Human investigations, on the other hand,
have not shown changed levels of Adipor1/Adipor2 mRNA related to insulin resistance
states [66].
Figure 4. Diagram depicting the investigated pathways illustrating the impacts of adiponectin on
Figure 4. Diagram
pancreatic β-cells. depicting the investigated pathways illustrating the impacts of adiponectin on
pancreatic β-cells.
Adiponectin knockout mice exhibit compromised glucose tolerance, even in the pres-
enceAdiponectin
of normal or lower-than-normal
knockout mice exhibit insulincompromised
levels [80]. Transgenic
glucoseob/ob mice even
tolerance, expressing
in the pres-
the globular domain of adiponectin demonstrate heightened insulin sensitivity
ence of normal or lower-than-normal insulin levels [80]. Transgenic ob/ob mice expressing and ele-
vated insulin secretion in comparison to nontransgenic mice [32,81,82] In vivo experiments
the globular domain of adiponectin demonstrate heightened insulin sensitivity and ele-
conducted in C57BL/6 mice revealed that intravenous administration of adiponectin leads
vated insulin secretion in comparison to nontransgenic mice [32,81,82] In vivo experi-
to an augmentation in insulin secretion [76].
mentsAn conducted in C57BL/6
observational mice revealed
study involving that intravenous
Asian children administration
found that adiponectin of adiponec-
levels exhibit
tin
anleads
inverseto relationship
an augmentation in insulin
with body weight,secretion
body mass[76]. index, and proinsulin levels in both
boysAnand observational
girls. Moreover,study involving
in girls, Asian
there is children
an inverse found that
association adiponectin
between adiponectinlevels ex-
levels
hibit anand insulin
inverse concentration
relationship withas body
well as the homeostasis
weight, body mass model assessment
index, of insulin
and proinsulin levels in
resistance
both boys and(HOMA-IR) [83]. Studies
girls. Moreover, have
in girls, demonstrated
there is an inversea positive correlation
association between between
adiponectin
adiponectin
levels levelsconcentration
and insulin and insulin sensitivity.
as well asConversely, there ismodel
the homeostasis an inverse correlation
assessment of insulin
between adiponectin levels and fasting proinsulin concentration, as well as the proinsulin-
resistance (HOMA-IR) [83]. Studies have demonstrated a positive correlation between ad-
to-insulin ratio, which serves as a marker of β-cell failure [84]. Furthermore, it has been
iponectin levels and insulin sensitivity. Conversely, there is an inverse correlation be-
suggested that the decrease in adiponectin levels is longitudinally linked with a reduced
tween adiponectin levels andfor
ability of β-cells to compensate fasting
insulinproinsulin
resistance inconcentration,
women with a as wellofasgestational
history the proinsulin-
to-insulin ratio,
diabetes [85]. Inwhich serves
overweight as a marker
Hispanic of β-cell
adolescents, failure [84]. Furthermore,
a cross-sectional study affirmeditthathas been
suggested that the decrease in adiponectin levels is longitudinally linked with a reduced
ability of β-cells to compensate for insulin resistance in women with a history of gesta-
tional diabetes [85]. In overweight Hispanic adolescents, a cross-sectional study affirmed
that both leptin and adiponectin are individually linked to insulin sensitivity, while they
do not exhibit an association with insulin secretion [86].
Life 2023, 13, 2213 9 of 16
both leptin and adiponectin are individually linked to insulin sensitivity, while they do not
exhibit an association with insulin secretion [86].
its generation in skeletal muscle, particularly during intense exercise, is considered ad-
vantageous [103]. The examination of mice with specific deletion of the IL-6 receptor in
hepatocytes has further fueled the debate, as these mice appear to be shielded from both
local and systemic insulin resistance [104].
A number of experimental studies with genetic loss-of-function manipulations indi-
cate that ablation of adiponectin contributes to diet-induced insulin resistance, increased
vascular remodeling in response to injury, and severe cardiac damage under ischemic condi-
tions [105]. A sequence of in vitro experiments has shown that adiponectin has the capacity
to impede the production and effects of TNFα, which is a pivotal proinflammatory cytokine.
This effect has been observed in different types of cells, including cardiac and vascular
cells [106]. Devaraj et al. provided evidence that adiponectin can inhibit the production
of CRP induced by high glucose levels. This inhibition occurs through adiponectin’s ca-
pacity to suppress the activation of nuclear factor-κ B (NF-κB). These findings align with
earlier research that demonstrated adiponectin’s ability to mitigate TNF-α-induced NF-κB
activation in endothelial cells. This, in turn, leads to decreased expression of cell adhesion
molecules and interleukin (IL)-8 [107].
Figure5.
Figure Single-cell UMAP
5. Single-cell UMAPvisualization
visualization depicting the cellular
depicting landscape
the cellular comparison
landscape of Early db/db
comparison of Early
vs. Control
db/db (A) and(A)
vs. Control Lateand
db/db
Latevs.db/db
Early vs.
db/db (B)db/db
Early of pancreatic
(B) of islet cells. The
pancreatic differential
islet cells. Theexpression
differential
expression of critical
of critical genes genes in adiponectin
in adiponectin signaling,β-cell
signaling, apoptosis, apoptosis, β-cell
function, function,
oxidative oxidative
stress, stress, in-
inflammation,
flammation,
and cellularand cellular
growth growth in
are depicted arecolor
depicted in color
indications (C).indications (C).
12. Conclusions
In conclusion, the significance of adiponectin in diabetes management cannot be over-
stated. Its pivotal role in regulating glucose metabolism and insulin sensitivity highlights its
potential as a promising therapeutic target. As research in this sector advances, tapping the
full potential of adiponectin may lead to novel and successful diabetes therapies. Further
research, including clinical trials and in-depth molecular investigations, will be critical
in achieving the full therapeutic potential of this unique hormone. With ongoing effort
and scientific study, the road to improving diabetes management with adiponectin-based
therapy holds enormous potential.
Author Contributions: Conceptualization, M.B. and M.S.M.; methodology, M.C., M.B.T. and M.A.M.;
software, M.C. and M.B.; validation, M.W., S.A. and M.M.M.; resources, M.W.; writing—original draft
preparation; M.B. and M.S.M.; writing—review and editing, M.C., M.B. and S.A.; visualization, M.C.,
M.M.M. and M.B.U.; supervision, M.S.M.; project administration, M.C. and M.S.M. All authors have
read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: No new data were created.
Acknowledgments: The authors want to thanks Mihreema Mohib Ruwaizah for her outstanding
inspiration for this work.
Conflicts of Interest: The authors declare no conflict of interest.
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