Download Role of adiponectin in the regulation of carbohydrate and lipid

JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY 2006, 57, Supp 6, 103–113
www.jpp.krakow.pl
J. KARBOWSKA, Z. KOCHAN
ROLE OF ADIPONECTIN IN THE REGULATION
OF CARBOHYDRATE AND LIPID METABOLISM
Department of Biochemistry, Medical University of Gdansk, Gdansk, Poland
Adiponectin,
an
adipocyte-derived
plasma
protein,
has
been
shown
to
play
an
important role in the regulation of fatty acid and glucose metabolism. Adiponectin
enhances fatty acid oxidation both in skeletal and cardiac muscle as well as in the
liver, thus reducing triglyceride content in these tissues. Moreover, it stimulates
glucose uptake by skeletal and cardiac muscle, and inhibits glucose production by the
liver; consequently decreasing blood glucose levels. This review focuses on the
molecular mechanisms underlying adiponectin effects on carbohydrate and lipid
metabolism in skeletal muscle, cardiac muscle and liver.
Key
w o r d s : adiponectin, adiponectin receptor, glucose metabolism, fatty acid oxidation,
muscle, heart, liver
ADIPONECTIN, THE ADIPOCYTE-DERIVED HORMONE
Adiponectin is an adipocyte-derived plasma protein which was identified by
four research groups independently in the mid-1990s and was named AdipoQ,
apM1
-
adipose
most
abundant
gene
transcript
1,
GBP28
-
gelatin-binding
protein, or Acrp30 - adipocyte complement-related protein 30 (1 - 4). Human
adiponectin
is
encoded
by
the
ADIPOQ
gene
(previously
named
APM1
or
ACDC), which spans 17 kb on chromosome locus 3q27 (5, 6). Interestingly,
human chromosome 3q27 has been identified as a region carrying susceptibility
genes for type 2 diabetes and metabolic syndrome (7, 8). The gene for human
adiponectin contains three exons, with the start codon in exon 2 and stop codon
in exon 3 (5, 6).
Adiponectin
nevertheless,
its
is
expressed
expression
and
and
secreted
serum
predominantly
levels
decrease
by
with
adipose
obesity
tissue;
and
are
104
positively associated with whole-body insulin sensitivity (1, 9, 10). Moreover,
weight loss significantly elevates plasma adiponectin levels (10). In the plasma of
non-obese subjects adiponectin levels lie in the range from 2 to 17
µg/ml
(9).
Plasma adiponectin levels in men are significantly lower than in women among
non-obese and obese subjects (9). Although the ADIPOQ gene is expressed
mainly in adipocytes, recent studies have found that adiponectin gene expression
can be induced in hepatocytes (11), in myotubes (12), and in skeletal muscle (13).
Moreover,
adiponectin
expression
occurs
in
bone-forming
cells
(14)
and
cardiomyocytes (15).
REGULATION OF ADIPONECTIN GENE EXPRESSION
Regulation of adiponectin gene expression remains to be elucidated. Several
studies have shown that adiponectin is induced during adipocyte differentiation
and its secretion is stimulated by insulin (1, 4, 16). It has also been observed that
IGF-1
up-regulates
adiponectin
gene,
whereas
TNF-
α
and
glucocorticoids
decrease adiponectin gene transcription (16 - 18). Recently, a functional PPARresponsive element (PPRE) in the promoter region of the human adiponectin gene
has
been
identified
(19).
Moreover,
proliferator-activated receptor
γ
γ
it
has
been
shown
that
peroxisome
(PPAR ), which is a well-known transcriptional
activator of many adipocyte-specific genes, is required for adiponectin gene
γ
induction (19). Up-regulation of PPAR
accompanied
by
an
increase
in
gene expression in rat adipose tissue is
adiponectin
gene
expression
(20,
21).
γ activators, thiazolidinediones (TZD), which are widely used
Furthermore, PPAR
to ameliorate insulin sensitivity and glucose tolerance in type 2 diabetes, increase
adiponectin expression and secretion by adipocytes, elevating plasma adiponectin
γ plays a
levels (17, 22, 23). These experimental observations suggest that PPAR
significant role in the transcriptional activation of adiponectin gene expression
via the PPRE in its promoter; however, the exact mechanism of adiponectin gene
induction needs further investigation.
PROTEIN STRUCTURE OF ADIPONECTIN
Secreted
region
adiponectin
followed
by
a
consists
conserved
of
an
N-terminal
collagenous
species-specific
domain
highly
variable
homologous
in
sequence to collagen VIII and collagen X, and a C-terminal globular domain
which shows significant sequence similarity with the complement factor C1q (2,
24). Circulating adiponectin forms a wide range of multimers, including trimers,
hexamers and high molecular weight (HMW) multimers (25, 26). The globular
domains of adiponectin form homotrimers (24, 25). The crystal structure of the
α
adiponectin globular trimer reveals an unexpected homology to trimeric TNF-
(24). Both proteins feature the ability to trimerise via key conserved hydrophobic
residues. Higher order structures of adiponectin are formed through the collagen
like region (24, 25). Non-reducing gel electrophoresis analysis of human plasma
105
demonstrated that HMW multimers of adiponectin are less abundant in male than
in female subjects (25). These results suggest that not only the total adiponectin
concentration
but
also
multimer
distribution
are
different
in
two
genders.
Moreover, Fruebis et al. showed the presence of a truncated form of adiponectin,
containing
only
the
globular
head,
in
human
plasma
(27).
Mutations
in
the
ADIPOQ gene result in an impaired multimerization and/or impaired secretion of
adiponectin from adipocytes, both linked to the development of insulin resistance
and type 2 diabetes.
ADIPONECTIN RECEPTORS
A few years ago, Yamauchi et al. cloned two different isoforms of adiponectin
receptor, AdipoR1 and AdipoR2 (28). Both isoforms are expressed in many cell
types,
including
adipocytes
(20,
28,
29).
Since
adiponectin
receptors
are
expressed in fat cells, adiponectin may play an important role in the regulation of
adipose
tissue
metabolism
via
autocrine
and/or
paracrine
manner.
In
human
tissues AdipoR1 is expressed mainly in skeletal muscle, whereas AdipoR2 is
predominantly expressed in the liver (28). Moreover, it has been demonstrated
that two types of adiponectin receptor have different binding affinity for globular
and full-length adiponectin, AdipoR1 is a high-affinity receptor for globular
adiponectin but a very low-affinity receptor for full-length adiponectin, whereas
AdipoR2
is
an
intermediate
affinity
receptor
for
globular
and
full-length
adiponectin (28). In vitro studies have revealed that both isoforms of adiponectin
receptor
can
mediate
increased
AMP-activated
protein
kinase
(AMPK)
α activity by adiponectin binding, thus activating fatty
phosphorylation and PPAR
acid oxidation and glucose uptake (28).
Transcriptional regulation of genes encoding adiponectin receptors has not yet
been clarified. So far, it has been shown that in human macrophages adiponectin
receptor gene expression is regulated by PPAR (30) and that the induction of
AdipoR1 in adipose tissue is correlated with an increase in the expression of
γ (20). These observations suggest that the AdipoR1 encoding gene may be
PPAR
regulated by PPARs.
EFFECTS OF ADIPONECTIN ON CARBOHYDRATE AND LIPID
METABOLISM IN SKELETAL MUSCLE
Adiponectin
has
potent
effects
on
carbohydrate
and
lipid
metabolism
in
skeletal muscle (Fig. 1). Numerous studies have shown that treatment with the
globular domain of adiponectin improves fatty acid utilization, both in isolated
muscle as well as in cultured skeletal muscle cells (27, 31, 32). The action of
adiponectin
in
muscle
is
mediated
by
adiponectin
receptors,
AdipoR1
and
AdipoR2. In human skeletal muscle, AdipoR1 is expressed at the highest level,
with lower levels of AdipoR2 (28). The binding of globular and full-length
106
Fig. 1. Effects of adiponectin on carbohydrate and fatty acid metabolism in skeletal muscle.
α
adiponectin to adiponectin receptors increased PPAR
activity and stimulated
glucose uptake and fatty acid oxidation in myocytes (28).
The
molecular
mechanisms
underlying
adiponectin-dependent
increase
in
muscle fatty acid oxidation include up-regulation of several genes involved in
muscle lipid metabolism, such as fatty acid translocase (FAT/CD36); acyl-CoA
oxidase
(ACO),
the
rate-limiting
enzyme
of
the
β-oxidation
pathway
in
peroxisomes (33); and mitochondrial uncoupling protein 2 (UCP2), accompanied
α gene expression and increase in PPARα activity (28,
α is required for transcription of many genes
by the induction of PPAR
32). The nuclear receptor PPAR
involved in fatty acid oxidation pathway (34), thus its activation by adiponectin
may improve fatty acid utilization in muscle. Additional effect of adiponectin on
skeletal muscle is an increased phosphorylation of AMP-activated protein kinase
(AMPK)
(28,
31).
Moreover,
activation
of
AMPK
has
been
shown
to
be
107
necessary for adiponectin effects on fatty acid oxidation in skeletal muscle cells
(27, 31, 35). AMPK activation triggers many metabolic changes that act to restore
energy balance in muscle cells, such as increased glucose uptake and metabolism,
and increased oxidation of fatty acids (36). Regulation of fatty acid oxidation
pathway by AMPK involves phosphorylation of acetyl-CoA carboxylase (ACC),
which leads to the inhibition of ACC activity followed by a decrease in malonylCoA levels (36). Adiponectin-dependent AMPK activation in skeletal muscle
was associated with an increase in ACC phosphorylation and a decrease in the
concentration of malonyl-CoA (28, 31). Malonyl-CoA is an allosteric inhibitor of
carnitine palmitoyl transferase 1 (CPT-1), an enzyme responsible for the transport
of fatty acids into mitochondria, where fatty acid oxidation occurs (37). Thus a
decrease in malonyl-CoA concentration after adiponectin treatment may be the
reason for increased fatty acid oxidation in muscle (31).
In skeletal muscle, the pathways of glucose metabolism include glycogen
synthesis, glucose oxidation and lactate production. Globular adiponectin has
been reported to stimulate glucose transport both in isolated skeletal muscle as
well
as
in
cultured
myocytes
(31,
35,
38).
Ceddia
et
al.
have
recently
demonstrated that globular adiponectin increases glucose uptake into skeletal
muscle
cells
via
enhanced
translocation
of
glucose
transporter
4
(GLUT4)
molecules to the cell membrane (39). Adiponectin also reduced the basal and
insulin-stimulated rates of glycogen synthesis in muscle cells (39). Since AMPK
can directly phosphorylate and inactivate glycogen synthase (36), the reduction of
glycogen synthesis upon adiponectin treatment may be mediated by activation of
AMPK. Moreover, it has been demonstrated that in adiponectin-treated myocytes
glucose metabolism is shifted toward lactate production (39).
ADIPONECTIN IS INVOLVED IN CARDIAC CARBOHYDRATE AND FATTY
ACID METABOLISM
Both isoforms of adiponectin receptor, AdipoR1 and AdipoR2, are expressed
in the myocardium (Fig. 2). In recent years, Furuhashi et al. have provided
indirect
evidence
demonstrating
for
that
the
serum
binding
of
adiponectin
adiponectin
levels
in
to
the
these
receptors
coronary
sinus
by
are
significantly lower than in the aortic root (40). The gradient of adiponectin
concentrations existing across the heart indicates that adiponectin binds to its
receptors in the myocardium and/or accumulates in vascular walls. This finding,
together with the observation that adiponectin receptors are expressed in the
myocardium, suggests specific effects of adiponectin in the heart. Indeed, it has
recently been reported that adiponectin treatment significantly enhances glucose
and fatty acid uptake by cardiomyocytes (15). Moreover, adiponectin induces
phosphorylation of AMPK in cultured cardiac myocytes (15, 41). Since AMPK
is known to stimulate glucose uptake and translocation of the cardiomyocyte
glucose transporter GLUT4 to the cell surface (42), it seems possible that the
108
Fig. 2. The expression of both isoforms of adiponectin receptor in rat myocardium. AdipoR1 and
AdipoR2 gene expression was measured by the real-time RT-PCR in the myocardium of control
(n=8) and clenbuterol-treated male Lewis rats (cardiac hypertrophy, n=10).
adiponectin-dependent increase in glucose uptake in cardiomyocytes is mediated
by
activation
of
AMPK
impairment
of
glucose
exacerbation
of
heart
(Fig.
3).
Adiponectin
metabolism,
failure
(43).
deficiency
insulin
is
resistance
Interestingly,
associated
and
AdipoR1,
the
with
subsequent
predominant
isoform of adiponectin receptor in the myocardium, is induced during cardiac
hypertrophy
(Fig.
2);
suggesting
increased
adiponectin
signalling
in
this
condition.
Adiponectin is also involved in cardiac fatty acid metabolism. Treatment with
the globular domain of adiponectin significantly increases fatty acid oxidation in
the heart (26). It has been proposed that this effect is independent of AMPK
activation (26); however, the exact mechanism by which adiponectin increases
fatty acid oxidation in cardiac muscle remains to be elucidated.
ADIPONECTIN MODULATES CARBOHYDRATE AND LIPID METABOLISM
IN THE LIVER
The liver, where adiponectin receptor AdipoR2 is expressed, is one of the
adiponectin
modulates
target
hepatic
organs
(28).
carbohydrate
Several
and
studies
lipid
have
shown
metabolism
that
(Fig.
4).
adiponectin
Long-term
treatment with adiponectin improved insulin sensitivity and reduced triglyceride
content in the liver (32). Adiponectin suppresses hepatic glucose production by
down-regulation of phosphoenolpyruvate carboxykinase (PEPCK) and glucose6-phosphatase (G6Pase) gene expression, thus decreasing plasma glucose levels
(35, 44, 45). An inhibitory effect of adiponectin on gluconeogenesis is probably
mediated by AMPK phosphorylation. In the liver, AMPK activation is necessary
109
Fig. 3. Effects of adiponectin on carbohydrate and fatty acid metabolism in cardiac muscle.
for adiponectin-dependent inhibition of PEPCK and G6Pase gene expression and
glucose production (35). Adiponectin has no effect on glycogen content and
synthesis, glucose uptake or glycolysis in the liver (44, 45).
CONCLUSIONS
Over recent years, adipose tissue has been shown to secrete a variety of protein
factors
and
hormones
involved
in
many
aspects
of
organs
physiology.
Adiponectin, an adipocyte-specific secretory protein, plays an important role in
the regulation of glucose and lipid metabolism. In skeletal muscle, adiponectin
improves fatty acid utilization and stimulates glucose uptake through activation
110
Fig. 4. Effects of adiponectin on carbohydrate and lipid metabolism in the liver.
of AMPK (27, 28, 31, 32). Since skeletal muscle accounts for 80-90% of the
insulin-stimulated glucose disposal (46), adiponectin-induced increase in glucose
uptake may be beneficial in subjects with type 2 diabetes. Adiponectin has also
been shown to enhance glucose and fatty acid uptake by cardiomyocytes, and to
increase fatty acid oxidation in the heart (15, 26). Moreover, in various animal
models adiponectin inhibits hepatic glucose production (35, 44, 45). In general,
adiponectin increases insulin sensitivity and improves glucose tolerance (27, 44).
In
humans,
plasma
adiponectin
concentrations
are
positively
correlated
with
whole-body insulin sensitivity (9). Recently, an association between adiponectin
concentrations
in
plasma
and
risk
of
type
2
diabetes
in
apparently
healthy
individuals has been reported (47). Moreover, there is increasing evidence that
genetic
variants
in
the
adiponectin
gene
itself
and/or
in
genes
encoding
111
adiponectin
regulatory
proteins,
such
γ
as
PPAR ,
are
associated
with
hypoadiponectinaemia, insulin resistance and type 2 diabetes. These observations
suggest that adiponectin is probably a major insulin-sensitising hormone secreted
by adipose tissue and may play an important role in the prevention and treatment
of diabetes through modulation of insulin sensitivity and direct regulation of lipid
and glucose metabolism.
Acknowledgements: This work was supported by the State Committee for Scientific Research
Grant 3 P05A 098 23 and ST-41.
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R e c e i v e d : September 15, 2006
A c c e p t e d : October 2, 2006
Author’s address: Dr. Zdzislaw Kochan, Department of Biochemistry, Medical University of
Gdansk, ul. Debinki 1, 80-211 Gdansk, Poland. Phone/fax: +48583491465.
E-mail: [email protected]