Open Access | Review
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Mechanisms of autophagy regulation by adiponectin
* Correspondence to: Xin Xu
Mailing address: Department of Geriatrics, Guangzhou First
People's Hospital, Guangzhou, Guangdong Province, 51000,
China.
Email: eyxuxin@scut.edu.cn
Received: 29 November 2021 / Accepted: 20 December 2021
DOI: 10.31491/APT.2021.12.072
Abstract
Adiponectin is a multifunctional adipocytokine produced predominantly by adipocytes, with potent antiinflammatory, insulin-sensitizing, and cytoprotective properties. Autophagy is a lysosome-dependent self-degradative process that mediates the degradation of damaged organelles, invading pathogens and protein aggregates, thus maintaining cellular homeostasis. Adiponectin performs different biological functions by regulating autophagy. This review attempts to elucidate the biological responses and potential mechanisms underlying adiponectin-induced autophagy, with an aim to guide the identification of new therapeutic targets of related diseases.
Keywords
Adiponectin, adiponectin receptors, autophagy
Introduction
Adiponectin is a healthy adipokine with positive metabolic
effects, such as insulin-sensitizing, anti-inflammatory,
antitumor, and cardiovascular protective functions. Adiponectin
and its receptors play a vital role in regulating
autophagy.
Autophagy is a highly conserved lysosome-dependent
self-degradation process that mediates the degradation of
damaged organelles, invading pathogens, and protein aggregates,
thus maintaining cellular homeostasis. Autophagy
dysregulation occurs in various pathologic conditions,
including cancer, neurodegenerative disorders, and metabolic
diseases [1]. A recent study indicated that inhibition
of autophagy in mice through knockdown of autophagyassociated
proteins significantly reduced the degradation
of lipid droplets in brown adipose tissue [2]. Another study
demonstrated that adiponectin induces autophagic flux in
skeletal muscle cells and diminishes insulin resistance by
alleviating ER stress, indicating that adiponectin mediates
antidiabetic effects in an autophagy-dependent manner
[3]. Furthermore, globular adiponectin induces Beclin-1
phosphorylation, inhibiting Beclin-1/Bcl-2 combination
and mediates the induction of autophagy in macrophages [4]. In this review, we describe the function of
adiponectin
and its receptors in the process of autophagy and the
underlying molecular signaling pathways.
We hope to provide a better understanding of the interrelation
between adiponectin and autophagy, which may
provide novel therapeutic directions for the treatment of
related diseases.
Adiponectin and adiponectin receptors
Adiponectin, also known as AdipoQ, apM1, and GBP28,
is primarily secreted by white adipose tissue [5]. It is a
30-kDa complement C1q-related protein with a globular
C-terminal domain and a collagenous N-terminal domain,
which usually circulates in oligomeric complexes as trimers,
hexamers, and multimers [5, 6]. It regulates multiple
molecular and cellular events, including maintaining
energy homeostasis, lipid metabolism, insulin sensitivity,
immune response, and inflammation [7].
Adiponectin carries out its diversified functions through
two widely expressed receptors, AdipoR1 and AdipoR2,
which are found in skeletal muscle, liver, and endothelial
cells [8]. AdipoRon is an orally active adiponectinreceptor
agonist; it can bind to AdipoR1 and AdipoR2 and
activate AMP-activated protein kinase (AMPK) [9]. The
function of these receptors varies depending on the target
tissue.
Adiponectin and autophagy induction
Autophagy plays a critical role in maintaining cellular homeostasis and easing intracellular stress, including inflammation response, oxidative stress, and endoplasmic reticulum stress. Impairment of autophagy may exacerbate diabetes-related metabolic disorders in insulin target tissues, including the liver, adipose tissue, skeletal muscle, and pancreatic β-cells [10, 11]. Adiponectin plays a critical role in autophagy regulation in various types of cells or tissue, thus exerting different biological effects. It inhibits high-glucose-induced angiogenesis of RF/6A cells by suppressing autophagy [12]. Thus, autophagy may be one of the key mechanisms through which adiponectin and its receptors regulate various biological responses.
Effects of adiponectin on inflammation modulation during autophagy induction
Adipose tissue secretes adipokines and hormones, many
of which are involved in inflammation, glucose homeostasis,
and lipid metabolism. Autophagic flux is an important
mechanism for various beneficial biological responses
by adiponectin [13]. For example, autophagy affects
lipid metabolism in adipose tissue and regulates cellular
energy and nutrient storage [2]. Furthermore, the antiinflammatory
effects of globular adiponectin may be mediated
through autophagy induction. Globular adiponectin
suppresses lipopolysaccharide-primed inflammasome
activation and generation of active IL-1β in murine peritoneal
macrophages by upregulating autophagy and active
AMPK signaling [14]. On the contrary, inhibition of
autophagy in adipocytes was associated with a significant
upregulation of adiponectin expression and a decrease in
proinflammatory markers [15]. Defects of autophagy-related
genes such as Atg3 and Atg16L1 in fully differentiated
adipocytes cause inflammation, insulin resistance, and
mitochondrial dysfunction. Moreover, Atg3 and Atg16L1
are required for proper mitochondrial function in mature
adipocytes, yet postdevelopmental ablation of autophagy
causes peripheral insulin resistance regardless of diet or
adiposity [16]. This evidence indicates that autophagy is
critical for lipid accumulation and adipocyte differentiation
factors [17].
Adiponectin is generally considered to possess cytoprotective
properties. For example, adipocyte-specific gene
Atg5 knockout mice had increased circulating levels of
adiponectin and protected against alcohol-induced adipose
atrophy and liver injury [18]. Moreover, adiponectin has
cytoprotective and antiinflammation properties by inhibiting
autophagy. An in vitro study showed that globular
adiponectin contributes to Beclin-1 phosphorylation and
Bcl-2 mRNA destabilization in macrophages and exerts an
anti-inflammatory effect. The interaction between Beclin-1
and Bcl-2 is regarded as a critical step in the regulation
of autophagy induction; inhibition of such an interaction
is a plausible mechanism for the initiation of autophagy.
Consistently, another study observed that adiponectin
caused Bcl-2 mRNA destabilization and consequently
activated autophagy in macrophages [19]. A study further
determined the effects of globular adiponectin on Beclin-1
phosphorylation and Bcl-2 mRNA stability, and investigated their role in suppressing inflammatory mediators.
Interestingly, globular adiponectin was found to suppress
the inflammation response by inhibiting the formation of
Beclin-1 and Bcl-2 complexes and inducing macrophage
autophagy [4]. Adiponectin exhibits protective effects
against hepatotoxicity; ER stress leads to inflammasome
activation in hepatocytes. For instance, globular adiponectin
significantly suppressed expression of ER stress marker
genes and promoted inflammasome activation, hence
protecting hepatocytes against cell death by autophagy induction,
indicating that adiponectin possesses hepatocyte
protection, at least in part, via autophagy induction [20].
Adiponectin potently suppresses the production of inflammatory
mediators and promotes autophagy by inhibiting
inflammatory responses, thus exhibiting cytoprotective
properties. Further research should explore the effects
of adiponectin on inflammasomes, which can help in the
treatment of inflammatory-related diseases.
Effects of adiponectin on autophagy induction by regulating the AMPK signaling pathway
AMPK is a central regulator of energy homeostasis. In
many cases, adiponectin-induced autophagy is related to
the AMPK signaling pathway [21]. Autophagy dysregulation
is responsible for various diseases, including type 2
diabetes, myocardial injury, and renal damage; deficiency
in autophagy is associated with metabolic disorders [22,
23]. Otherwise, regulated autophagy is a critical component
of a healthy skeletal muscle mass [24].
Cardiomyocyte autophagy is vital for maintaining cardiac
function. Decreased myocardial autophagic flux results in
cardiac dysfunction and cardiomyocyte death. By contrast,
it activates autophagy by globular adiponectin in myoblasts
and promotes myoblast survival and apoptosis via
an AMPK-dependent mechanism [25]. A study confirmed
that adiponectin increases autophagic flux through promotion
of AMPK phosphorylation. Adiponectin deficiency
could aggravate the downregulation of myocardial AMPK
phosphorylation, autophagic flux, and cardiac function.
By contrast, exogenous administration of adiponectin
reverses the decline of AMPK phosphorylation and autophagic
flux and eventually reduce cardiomyocyte death
[26]. AdipoRon, as an adiponectin receptor agonist, inhibits
myeloma cell proliferation and induces apoptosis, and
AMPK/autophagy pathway may be one of its mechanisms
[9]. Moreover, AdipoRon is a cardioprotective molecule;
deficiency of ADIPOQ markedly increases myocardial
ischemia-reperfusion (MI-R) injury. Hypoadiponectinemia
in a diabetic model impairs autophagic flux, and consequently
enhances MI-R injury. Additionally, adipoR activation
restores AMPK-mediated autophagosome formation
and antioxidant-mediated autophagosome clearance,
manifesting a novel intervention effective against MI-R
injury in diabetic conditions [27]. In vitro studies have
demonstrated that AdipoRon promotes autophagic flux through activation of AMPK/ULK1 pathway, thus inhibiting
renal fibrosis [28]. Adipose tissue specifically secretes
autophagy protein Becn1, and then facilitates the secretion
of adiponectin [29]. Furthermore, Becn1 regulates AMPK
activity and improves insulin sensitivity by promoting
adiponectin secretion [30]. In addition, adiponectin
knockout (Ad-KO) in mice induces insulin resistance and
autophagy, and exogenous adiponectin unregulates the expression
of autophagy-related genes LC3-II and Beclin1.
In vitro, adiponectin enhanced autophagic flux in cultured
muscle cells in an AMPK-dependent manner. Taken together,
the study demonstrated that adiponectin stimulated
skeletal muscle autophagy and alleviated HFD-induced
insulin resistance and metabolic dysfunction in skeletal
muscle [31]. Moreover, adipoRon upregulated LC3-II/
LC3-I level, downregulated p62 protein level in multiple
myeloma cells, and significantly inhibited MM cell proliferation
and increased their expression of apoptosis-related
proteins. Moreover, AdipoRon upregulated p-AMPK and
its downstream p-ACC in MPC-11. Globular adiponectin
induces autophagy in chondrocytes by increasing the formation
of Beclin-1 and LC3B and P62 degradation, thus
exhibiting an antiapoptotic effect, indicating that global
adiponectin possesses antiapoptotic properties by inducing
autophagy. In this study, the authors demonstrated
that global adiponectin induced a high expression of p-
AMPK accompanying a high expression of Beclin-1 and
LC3-Ⅱ in chondrocytes. Furthermore, the application of
the inhibitor of AMPK significantly blocked the global
adiponectin-induced autophagy in chondrocytes [32].
To investigate the therapeutic value of AdipoRon, an
adiponectin
receptor agonist, and the molecular mechanism
on chondrocyte calcification, an in vitro study investigating
the effect on autophagy by AdipoRon in chondrocytes
revealed that adiponRon decreased calcification and ALP
activity by promoting autophagy. However, these activities
were blocked by the AMPK inhibitor [33]. Epidemiological
studies have revealed that patients with breast
cancer generally have low levels of circulating AdipoQ,
which indicates a poor prognosis. Moreover, elevated expression
of AdipoQ in breast tissue is closely associated
with advanced stages of the disease. Globular adiponectin
upregulated microtubule-associated protein 1 light chain 3
beta (LC3B)-II and intracellular LC3B puncta, which are
indicators of autophagosome formation, suggesting that
adiponectin contributes to autophagic induction, hence
promoting the migration and invasion abilities of breast
cancer cells [34]. Consistently, Chung et al. reported that
ADIPOQ/adiponectin induces accumulation of autophagosomes
in breast cancer cells, inhibiting breast cancer
growth and inducing apoptosis. Otherwise, AMPK-inhibition
abrogates ADIPOQ/adiponectin-induced ULK1-activation,
LC3B-turnover, and p62-degradation, yet AMPK
activation reverses those effects [21]. These data indicate
that ADIPOQ/adiponectin induces autophagy in breast
cancer cells through the modulation of the AMPK-ULK1
axis. Collectively, the results suggest that by adiponectin
modulation autophagy via the AMPK signaling pathway.
Effects of adiponectin on autophagy induction by regulating oxidative stress and ER stress
Adiponectin is reported to possess cardioprotective properties,
and studies have shown that the mechanism may
be related to modulation of mitochondrial function or ER
stress. ER stress promotes cardiac lipotoxicity in cardiac
myocytes. Globular adiponectin (gAcrp) significantly
upregulates the expression of various ER stress markers
in macrophages, and inhibition of ER stress prominently
suppresses gAcrp-induced autophagy [35]. Pretreatment
with exogenous APN inhibited ER stress and activated autophagy,
thereby protecting cardiomyocytes against apoptosis
through AMPK activation [36]. Similarly, another
study showed that exogenous administration of adiponectin
significantly reduced oxidative stress and increased the
expression of anti-oxidative enzymes, resulting in autophagy
stimulation, hence inhibiting apoptosis and diminishing
brain tissue injury [37].
Globular CTRP9 (gCTRP9), a newly identified adiponectin
paralog, increases the ratio of LC3II/I and upregulate
autophagy-related gene ATG5, and decrease the level of
P62, which is vital to autophagosome formation. Moreover,
gCTRP9 restored the loss of mitochondrial membrane
potential, suppressed ROS generation, and reduced
myocyte death. These results suggest that adiponectin
paralog protects against oxidative stress-mediated damage
in cardiomyocytes by enhancing autophagy [38]. Shi et al.
demonstrated that in the testes of diabetic mice, globular
adiponectin upregulated the expression of autophagyrelated
protein while inhibiting the expression of NAD(P)
H-quinone oxidoreductase 1, heme oxygenase-1, and superoxide
dismutase, suggesting that globular adiponectin
exhibits a protective effect on diabetic mice by inhibiting
oxidative stress and ER stress and inducing autophagy
[39]. In conclusion, adiponectin exerts a cytoprotective effect
likely by inducing autophagy through the modulation
of oxidative stress and ER stress.
Selective form of autophagy induced by adiponectin
Adiponectin targets specific forms of autophagy: mitophagy,
lipopagy, and endoplasmic reticulum autophagy
(ER-phagy). Herein, we elucidate the association and the
underlying mechanism involved as follows.
The elimination of damaged mitochondria is critical for
ensuring energy supply and maintaining mitochondrial
quality. Mitochondrial autophagy (mitophagy), characterized
by selectively excluding damaged mitochondria
via a specific autophagic pathway, is one of the catabolic
processes by which dysfunctional mitochondria are degraded
[40]. It is crucial for mitochondrial quality control
and moderating mitochondrial homeostasis and plays a
critical role in cytoprotection [41, 42]. Adiponectin modulates
insulin responsiveness by regulating mitophagy and
maintains mitochondrial homeostasis, but the underlying mechanisms remain unknown. It also promotes mitophagy
and improves lung functional recovery in type 2 diabetic
rats, suppressing oxidative damage, decreasing inflammation
response, diminishing cell apoptosis, and preserving
mitochondrial function [43]. Chronic intermittent
hypoxia causes disturbances of genioglossal mitophagy,
while supplementation of exogenous adiponectin alleviated
the damage to mitochondrial structure and function
by increasing mitophagy [44]. An in vitro study demonstrated
that adiponectin suppressed the over-production
of ROS by activating the Nrf2/HO-1 pathway, suppressed
H2O2-induced mitophagy, and partially inhibited the
colocalization of autophagosomes/lysosomes with mitochondria.
Otherwise, adiponectin downregulates the
expression of both Bax and Bax/Bcl-2 protein induced
by oxidative stress [45]. These findings suggest that APN
moderately regulates oxidative stress-induced mitophagy
and suppresses apoptosis. Similarly, globular adiponectin
upregulates mitophagy while reducing the rate of hepatocyte
apoptosis induced by intermittent hypoxia [46]. In
summary, adiponectin may protect against tissue damage
by upregulating mitophagy, but the concrete underlying
mechanisms remain unclear.
Lipophagy is another selective form of autophagy characterized
by selective degradation of lipid droplets (LDs). It
is beneficial in maintaining lipid homeostasis. Increased
lipophagy is potent in decreasing abnormal lipid accumulation
by removing ectopic LDs, thus alleviating insulin
resistance and β-cell impairment [47]. Disturbances in
lipophagy have been linked to Nonalcoholic fatty liver
disease (NAFLD)and hepatic triglyceride accumulation,
obesity, liver steatosis, and atherosclerosis [48, 49].
Similarly, in a recent study, the authors observed that
lipophagy deficiency in the tubular cells of patients with
diabetic nephropathy and db/db mice was accompanied by
significantly ectopic lipid deposition, oxidative stress, and
apoptosis. Furthermore, AdipoRon administration moderated
these damages by increasing lipophagy, and the
effects were blocked partially by AdipoR1 siRNA, an autophagy
inhibitor, and enhanced by AMPK activator [50].
The results indicated that AdipoRon can reduce intrarenal
lipotoxicity-associated renal injury by upregulating lipophagy
by activating the AdipoR1/AMPK pathway.
ER-phagy enables protein and lipid synthesis, ion homeostasis,
and organelle communication via constant ER turnover
and modulation [51]. Globular adiponectin upregulates
ER-phagy to alleviate ER stress and attenuates H9C2
cardiomyocyte apoptosis induced by CIH through AMPK
activation [52]. Interruption of the adiponectin signaling
pathway mimics perturbed or inadequate nutrient intake,
triggers catabolic processes such as selective forms of
autophagy, including ER-phagy and lipophagy, to acquire
and mobilize internal nutrient stores, enhances survival,
and promotes longevity in C. elegans [53].
Table1.
Effects of adiponectin on autophagy regulation.
Experimental models | Biological responses | References |
---|---|---|
L6 skeletal muscle cells | Adiponectin-induced autophagy in skeletal muscle cells and alleviated ER stress and insulin resistance. | Ahlstrom, P., et al. (2017) |
Breast cancer cells | Adiponectin induces autophagic cell death in breast cancer, and inhibits breast cancer growth and induces apoptosis. | Chung, S. J., et al. (2017) |
Chondrocytes | Globular adiponectin protected chondrocytes by inducing autophagy via AMPK/mTOR signal-pathway activation. AdipoRon alleviates the calcification of chondrocytes via activating AMPK-mTOR signaling to promote autophagy. | Hu, J., et al. (2017) Duan, Z. X., et al. (2020) |
Macrophages | Adiponectin inhibits LPS-primed inflammasomes activation via autophagy induction and AMPK signaling activation. Gene silencing of p62 prevented gAcrp-induced increases in autophagy-related genes and autophagosome formation. Enhanced interaction of Bcl-2 with Beclin-1 prevented gAcrp-induced autophagy activation. | Kim, M. J., et al. (2017) Tilija Pun, N., et al. (2017) Shrestha, A., et al. (2018) |
C2C12 myoblasts | Adiponectin protected C2C12 myoblasts against oxidative stress-induced apoptosis and suppressed H(2)O(2)-induced mitophagy. | Ren, Y., et al. (2017) |
Adipoq knockout (adipoq(-/-)) mice | Hypoadiponectinemia impairs autophagic flux, contributing to enhanced MI-R injury in the diabetic state. gAcrp protects hepatocytes against cell death by modulating ER stress and inflammasome activation via autophagy induction. gAPN alleviated mitochondrial injury and hepatocyte apoptosis by upregulating Pink1/ Parkin-mediated mitophagy. | Wang, Y., et al. (2017) Kim, E. H. and P. H. Park (2018) Ding, W., et al. (2021) |
hepatocyte | APN inhibited ER stress and activated autophagy through AMPK activation, thus alleviating HL-1 apoptosis. gAPN upregulated ER-phagy to extenuate ER stress, and mitigated cardiomyocytes apoptosis through AMPK activation. gCTRP9 protects cardiomyocytes through enhanced autophagic flux. | Li, B., et al. (2020) Zhang, Q., et al. (2020) Zuo, A., et al. (2020). |
Diabetic mice | Adiponectin protects the testes of diabetic mice by inducing autophagy and inhibiting ER stress and oxidative stress. Adiponectin attenuated oxidative stress, inflammation, apoptosis and mitochondrial dysfunction via activation of mitophagy in diabetic lung IR injury. | Shi, W., et al. (2020) Jiang, T., et al. (2021) |
Conclusions
In summary, adiponectin is a healthy adipocytokine that has anti-inflammatory and antiapoptotic properties, favorable effects on intermediary metabolism, and cardiovascular, renal, and liver protection (Table 1). Adiponectin has multibiological effects on a wide variety of metabolic pathways, many of which are mediated via autophagy induction. Inflammation response, AMPK activation, oxidative and ER stress, and related signaling pathways are the main pathways by which adiponectin modulates autophagy. However, most current research has focused on molecular or cellular biological reactions. Future studies should elucidate the precise mechanisms by which adiponectin/ adipoRs regulate autophagy and its potential physiological functions, as well as evaluate autophagy regulation and implicated biological responses by adiponectin in vivo. A better understanding of the regulation of autophagy by adiponectin can guide preclinical and clinical studies in the treatment of metabolic diseases and cancer.
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Conflicts of interest
Xin Xu is a member of the Editorial Board of Aging Pathobiology and Therapeutics. All authors declare no conflicts of interest and were not involved in the journal's review or desicions related to this manuscript.
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