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1

Signaling mechanisms underlying the

insulin-sensitizing effects of adiponectin

Kenneth K.Y. Cheng, PhD, Research Assistant Professor in

Endocrinology and Metabolism a,

b, Karen S.L. Lam, MD, ChairProfessor and Head of Medicine a,b, Baile Wang, BSc, MPhilStudent a, Aimin Xu, PhD, Professor in Endocrinology andMetabolism a,b,c,*

a Department of Medicine, The University of Hong Kong, Hong Kongb Research Centre of Heart, Brain, Hormone and Healthy Aging, The University of Hong Kong, Hong Kongc Department of Pharmacology & Pharmacy, The University of Hong Kong, Hong Kong

Keywords:APPL1

adiponectin

insulin

diabetes

obesity

Adiponectin is an insulin-sensitizing adipokine with protectiveeffects against a cluster of obesity-related metabolic and cardio-

vascular disorders. The adipokine exerts its insulin-sensitizing ef-

fects by alleviation of obesity-induced ectopic lipid accumulation,

lipotoxicity and chronic inammation, as well as by direct cross-

talk with insulin signaling cascades. Adiponectin and insulin

signaling pathways converge at the adaptor protein APPL1. On the

one hand, APPL1 interacts with adiponectin receptors and medi-

ates both metabolic and vascular actions of adiponectin through

activation of AMP-activated protein kinase and p38 MAP kinase.

On the other hand, APPL1 potentiates both the actions and

secretion of insulin by ne-tuning the Akt activity in multiple in-

sulin target tissues. In obese animals, reduced APPL1 expression

contributes to both insulin resistance and defective insulin secre-

tion. This review summarizes recent advances on the molecular

mechanisms by which adiponectin sensitizes insulin actions, and

discusses the roles of APPL1 in regulating both adiponectin and

insulin signaling cascades.

2013 Elsevier Ltd. All rights reserved.

* Corresponding author. Department of Medicine, The University of Hong Kong, L8-39, 21 Sassoon Road, Hong Kong. Tel.:

852 2819 9754; Fax: 852 2816 2095.

E-mail address: amxu@hku.hk(A. Xu).

Contents lists available atSciVerse ScienceDirect

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Endocrinology & Metabolismj o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / lo c a t e / b e e m

1521-690X/$ see front matter 2013 Elsevier Ltd. All rights reserved.

http://dx.doi.org/10.1016/j.beem.2013.06.006

Best Practice & Research Clinical Endocrinology & Metabolism 28 (2014) 313

mailto:amxu@hku.hkhttp://www.sciencedirect.com/science/journal/1521690Xhttp://www.elsevier.com/locate/beemhttp://dx.doi.org/10.1016/j.beem.2013.06.006http://dx.doi.org/10.1016/j.beem.2013.06.006http://dx.doi.org/10.1016/j.beem.2013.06.006http://dx.doi.org/10.1016/j.beem.2013.06.006http://dx.doi.org/10.1016/j.beem.2013.06.006http://dx.doi.org/10.1016/j.beem.2013.06.006http://www.elsevier.com/locate/beemhttp://www.sciencedirect.com/science/journal/1521690Xhttp://crossmark.crossref.org/dialog/?doi=10.1016/j.beem.2013.06.006&domain=pdfmailto:amxu@hku.hk

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diseases[7]. A recent human Mendelian randomization study provides direct evidence that high level

of adiponectin contributes to increased insulin sensitivity in men[8].

The insulin-sensitizing action of adiponectin in mice was rstly reported by three independent

research groups in 2001[911]. Treatment with recombinant adiponectin or transgenic expression of

adiponectin results in lower glucose level and alleviates insulin resistance in obese mice, and such

effects are independent of plasma levels of insulin[9

12]. In contrast, genetic depletion of adiponectininduces insulin resistance and aggravates hyperglycemia in high-fat diet (HFD)-induced obese mice

[1315]. Adiponectin exerts its insulin-sensitizing actions via both direct and indirect mechanisms

(Fig. 1). In the liver, adiponectin reduces glucose production by inhibiting the gene expression of

gluconeogenic enzymes via the AMP-activated protein kinase (AMPK) pathway [10,15], though a recent

study argues that the suppressive effects of adiponectin on hepatic glucose production are AMPK-

independent [16]. Adiponectin also directly strengthens hepatic insulin signaling by upregulating

IRS-2 expression through a macrophage-derived interleukin (IL)-6-dependent pathway [17]. In skeletal

muscle, full-length or globular domain of adiponectin causes increase in glucose uptake by promoting

the translocation of the glucose transporter 4 (GLUT4) to the plasma membrane[9,18].

In addition to aforementioned direct effects, adiponectin augments insulin sensitivity by reducing

plasma level of free fatty acids and ectopic lipid content in liver and skeletal muscle through induction offatty acid oxidation [9,19]. Chronic treatment with recombinant adiponectin signicantly reduces hepatic

lipid content, thereby alleviating fatty liver disease and hepatic insulin resistance in dietary and genetic

obese mice[20,21]. In skeletal muscle, adiponectin stimulates mitochondrial biogenesis and decreases

oxidative stress, which also leads to enhanced insulin sensitivity [22]. Recent evidence suggest that

skeletal insulin resistance is a result of defective insulin signaling not only in myocytes per sebut also in

endothelial cells, which in turn impairs insulin-stimulated vasodilatation, thereby restricting the supply

of insulin and glucose[23]. In this connection, adiponectin can improve endothelium-dependent vaso-

dilatation by inducing endothelial nitric oxide (NO) production via activation of both the AMPK and Akt

signaling cascades[24]. Furthermore, adiponectin also promotes insulin actions through its effects on

pancreaticbcells by potentiating insulin secretion, increasing the expression of the insulin gene, pre-

venting cytokine/lipid-induced apoptosis and inducing cell proliferation[25,26].

Fig. 1. A proposed model for the role of APPL1 in mediating both adiponectin and insulin signaling cascades. Adiponectin stimu-

lation leads to increased interactions between APPL1 and adiponectin receptors (AdipoR1 and AdipoR2), which in turn initiate the

activation of the downstream targets, thereby modulating glucose and lipid metabolism as well as vascular functions. On the other

hand, APPL1 regulates both the action and secretion of insulin by ne-tuning Akt signaling. Abbreviations: adiponectin receptors

(AdipoRs), endothelial nitric oxide synthase (eNOS), glucose-6-phosphatase (G6PC), glucose transporter 4 (GLUT4), I kappa B kinase

(IKK), insulin receptor (IR), liver kinase B 1 (LKB1), peroxisome proliferator-activated receptor-alpha (PPARa), phosphoenolpyruvate

carboxykinase (PEPCK), nuclear factor-kappa B (NFkB), soluble N-ethylmaleimide-sensitive factor attachment protein receptor

(SNARE) and Tribble-3 (TRB3).

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As an anti-inammatory adipokine, adiponectin can antagonize the inhibitory effects of pro-

inammatory adipokines/cytokines on insulin signaling. Adiponectin suppresses the release of

numerous pro-inammatory cytokines such as tumor necrosis factor-alpha (TNF-a) and IL-6 from

adipocytes and stromal-vascular cells[27]. Transgenic expression of adiponectin reduces inltration of

macrophages into adipose tissue and hence impacts systemic insulin sensitivity, despite extreme

obesity[28]. Adiponectin also exerts its anti-inammatory effect in a paracrine manner by inhibitingthe growth and differentiation of early B lineage progenitors from bone marrow and by modulating

inammatory response in macrophages [29]. Treatment with adiponectin attenuates the release of

lipopolysaccharide-induced pro-inammatory cytokines via inhibition of nuclear factor-kappa B

(NFkB) activation[30]. On the other hand, adiponectin induces the release of anti-inammatory cy-

tokines, such as IL-10[31]and causes polarization of macrophages toward the anti-inammatory M2

phenotype[32]. Taken together, adiponectin may improve whole-body insulin sensitivity indirectly by

reducing adipose tissue inammation.

Cellular pathways underlying the insulin-sensitizing actions of adiponectin

The discovery of adiponectin receptors (AdipoRs) by Kadowaki and colleagues has facilitated the

elucidation of the molecular mechanisms underlying the multiple actions of adiponectin[7,33]. Adi-

poR1 and AdipoR2 are two close homologs, which share 67% identity in amino acid sequences [33,34].

Unlike classical G-protein coupled receptors, the AdipoRs exhibit intracellular NH2-terminal and

extracellular COOH-terminal domains [33,34]. Adiponectin receptor 1 (AdipoR1) is predominantly

expressed in skeletal muscle, whereas adiponectin receptor 2 (AdipoR2) is abundantly expressed in the

liver[33,34]. Genetic disruption of AdipoR1 results in augmented gluconeogenesis and diminished

AMPK activation, whereas deletion of AdipoR2 causes impairment of glucose uptake accompanied with

decreased peroxisome proliferator-activated receptor-alpha (PPAR-a) activity in the liver [35]. In

contrast, hepatic overexpression of AdipoR1 and AdipoR2 improves insulin sensitivity and alleviates

diabetic phenotypes in leptin receptor-decient obese mice [35]. Furthermore, overexpression of

AdipoR1 in skeletal muscle increases glucose uptake and glycogen synthesis as well as insulin sensi-

tivity [36]. Apart from the AdipoR1/AMPK and AdipoR2/PPAR-a signaling axes, Scherer and his col-

leagues recently dened a distinct mechanism underlying the benecial actions of adiponectin[25].

They found that adiponectin promotes the ceramidase activity, which in turn leads to increased for-

mation of spingosine-1-phosphate, thereby protecting pancreatic b cells and cardiomyocytes from

lipid-induced apoptosis. Such an anti-apoptotic effect of adiponectin is mediated by AdipoR1 and

AdipoR2 but appears to be independent of AMPK[25]. Furthermore, adiponectin has been reported to

regulate peroxisome proliferator-activated receptor coactivator-1a and mitochondria biogenesis via

modulation of calcium signaling and the AdipoR1-AMPK-silent mating type information regulation 2

homolog (SirT1) dependent pathway [22]. Adiponectin has also been reported to sensitize insulin

signaling by inhibition of p70-S6 Kinase 1 (S6K1) [37], which is able to induce insulin resistance by

increasing serine phosphorylation of IRS-1. Adiponectin activates LKB1/AMPK/tuberous sclerosiscomplex 1/2 (TSC1/2) signaling pathway, resulting in the suppression of S6K1 and the subsequent

reduction in serine phosphorylation of IRS-1, thereby improving insulin sensitivity in skeletal muscle

[38]. Indeed, skeletal muscle specic deletion of AdipoR1 results in diminished phosphorylation of

AMPK and increased S6K1 activation[22].

Participation of APPL1 in both adiponectin and insulin signal transduction

In light of the insulin-sensitizing activity of adiponectin, there is a growing interest in characterization

of intracellular signaling components proximal to the AdipoRs that transmit adiponectin signaling to its

distal metabolic effects. The adaptor protein APPL1, which contains an NH2-terminal Bin/Amphiphi-physin/Rvs (BAR) domain, a central pleckstrin homology (PH) domain and a COOH-terminal phospho-

tyrosine binding domain (PTB), has recently been identied as a key scaffold protein to mediate the

metabolic and vascular actions of both insulin and adiponectin. APPL1 has been implicated in the insulin-

sensitizing activities of adiponectin in skeletal muscle, hepatocytes and endothelial cells[39].

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APPL1 as a scaffold protein involved in multiple signaling cascades

APPL1 was originally found as an interacting partner of the protein kinase Akt2 in a yeast two hybrid

system[40]. Subsequent studies demonstrated that this adaptor protein is functionally involved in a

number of fundamental processes (such as transcriptional regulation, proliferation and cell survival)

through interacting with a myriad of plasma membrane receptors and intracellular signaling proteins[39]. In response to epidermal growth factor (EGF) stimulation, APPL1 transmits its signal from the

plasma membrane to nucleus through the cytoplasmic signaling cascades [41]. Additionally, APPL1

shuttles between different subcellular organelles such as the endosomes, phagosomes and aggres-

somes upon various stimulations[4245].Phosphatidylinositol 3-phosphate has been shown to act as

a switch that controls endosomal trafcking and signal transduction of APPL1, which is important for

the proliferative activity of EGF[46].

Structure, post-translational modications and expression of APPL1

APPL1 contains a highly conserved BAR-PH domain, which is essential to its endosomal localization

and membrane binding ability [47]. Triple mutations in the BAR domain of APPL1 can disrupt itsendosomal localization and biological functions [47,48]. The BAR domain of APPL1 exhibits the crescent-

shaped dimer with the PH domain located at the distal ends of the dimers [49,50]. The negative charge in

the concave surface of the BAR domain of APPL1 participates in membrane binding. On the other hand,

the PTB domain of APPL1 adopts a folding with a seven-stranded b sandwich and a COOH-terminal a

helix that caps one of the open ends of the sandwich [49,50]. Of note, the PTB domain of APPL1 has been

shown to interact with various transmembrane receptors through an unidentied mechanism[49,50].

Several post-translational modications have been identied in APPL1. Several serine/threonine

and tyrosine phosphorylation sites are found in the BAR, PH and PTB domains of APPL1 [51]. Phos-

phorylation at serine 430 is augmented in hepatocytes with endoplasmic reticulum stress [52].

Furthermore, APPL1 undergoes lysine-63 linked ubiquitination, and this ubiquitination is indispensible

for its subcellular localization and solubility [44]. However, the physiological functions of thesemodications in regulating adiponectin and insulin signaling remain unclear at this stage.

APPL1 is abundantly expressed in several adiponectin and insulin target tissues, including liver,

skeletal muscle, endothelium, white adipose tissues and pancreatic islets, and its expression is altered

by a number of physiological and pathological factors, including exercise, hyperglycemia and obesity

[5356]. The expression of APPL1 is dramatically decreased in pancreatic islets and vascular endo-

thelium in several rodent models of diabetes and obesity[54,55]. Likewise, APPL1 level is signicantly

reduced in adipose tissue, skeletal muscle and liver of diet-induced obese mice, but this change can be

reversed by exercise training[53]. Interestingly, overexpression of AdipoR1 up-regulates APPL1 in rat

skeletal muscle, which is accompanied with enhanced insulin sensitivity [57]. In human, the expres-

sion level of APPL1 is paradoxically increased in skeletal muscles of type 2 diabetic and obese subjects

compared to lean controls, and its expression is reduced in obese subjects with weight loss[58]. Thesendings highlight that the expression of APPL1 is associated with obesity and insulin sensitivity, and

altered expression of APPL1 may contribute to the development of T2DM. However, the conicting

ndings in human and animal studies warrant further investigation.

APPLs as downstream effectors of adiponectin receptors

Several AdipoR interacting partners have been identied, including protein kinase C1[59], protein

kinase CK2b subunit[60], lymphotoxin-b endoplasmic reticulum protein 46[61]and APPL1[55,62].

Among them, APPL1 is therst downstream effector of AdipoR being identied by bothyeast two hybrid

and proteomic analysis, and has been extensively studied for its role in adiponectin actions[55,62].

APPL1 directly associates with the NH2-terminal intracellular regions of AdipoR1 and AdipoR2 via thePTB domain, and these associations are enhanced by adiponectin stimulation [55,62,63]. Of note,

tyrosine phosphorylation in AdipoR1 and AdipoR2 is not required for its binding to APPL1 [50]. In

cultured skeletal muscle cells, suppression of APPL1 attenuates adiponectin-induced glucose uptake,

GLUT4 translocation and fatty acid oxidation, accompanied with decreased phosphorylation of AMPK,

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acetyl coenzyme A carboxylase (ACC) and p38 MAPK[62]. In contrast, overexpression of APPL1 poten-

tiates these adiponectin actions, which appears to be mediated via the small GTPase Rab5. Over-

expression of an inactive Rab5 mutant completely abolishes adiponectin-mediated glucose uptake and

GLUT4 translocation in AMPK-dependent pathway[62]. Furthermore, the synergistic action of insulin

and adiponectin on glucose uptake is also attenuated in skeletal muscle cells with suppression of APPL1.

In endothelial cells, knockdown of APPL1 abolishes adiponectin-stimulated NO production bysuppression of both AMPK and Akt-evoked activation of endothelial nitric oxide synthase (eNOS)

pathways[55]. These changes are attributed to a signicant reduction of complex formation between

heat-shock protein 90 and eNOS, which is essential for maximal activity of eNOS. The expression of

APPL1 is signicantly reduced in arteries from db/dbdiabetic mice[55]and Zucker diabetic fatty rats

[56], suggesting that reduced APPL1 may be causally associated with endothelial dysfunction in obesity

and diabetes. Adiponectin can antagonize the pro-apoptotic effect of IL-18 in endothelial cells, and such

benecial action of adiponectin is also mediated by APPL1[64]. Likewise, the anti-apoptotic effect of

adiponectin on neuroblastoma is lost when APPL1 is reduced by RNAi-mediated knocking down [65].

APPL1 also regulates the anti-inammatory properties of adiponectin. In macrophages, the inhibitory

ability of adiponectin on lipid accumulation and NFkB activation are reduced by suppression of APPL1

expression [66]. There is also considerable evidence for the role of APPL1 in regulating adiponectinsignaling in several other cell types, including mouse cardiomyocytes, human embryonic kidney cells

and rat cardiac broblasts[6769].

Recent studies have elucidated how APPL1 modulates adiponectin-mediated AMPK activation via

its upstream kinase liver kinase B 1 (LKB1) [70,71]. Upon adiponectin stimulation, APPL1 interacts with

both protein phosphatase 2A (PP2A) and protein kinase C (PKC)-zeta, resulting in activation of PP2A

and dephosphorylation of PKC-zeta [71]. The inactivated PKC-zeta causes a dramatic reduction of

serine phosphorylation of LKB1, leading to LKB1 translocation from nucleus to cytosol, where LKB1 can

interact with APPL1 and activate AMPK [71]. Sweeney and colleagues also found that adiponectin

induces the complex formation of LKB1, AMPK and APPL1 in cardiomyocytes, which can be disrupted

by leptin treatment [72]. In addition to AMPK signaling pathway, APPL1 modulates adiponectin-

mediated p38 MAPK activation[73]. Suppression of APPL1 abolishes adiponectin-elicited phosphor-ylation of p38, whereas overexpression of APPL1 has opposite effect. This APPL1 action may be due to

its binding ability to the upstream kinases of p38 including transforming growth factor-b-activated

kinase and mitogen-activated protein kinase kinase 3[73].

APPL2, a close homolog of APPL1, sharing 52% identity and 72% similarity in amino acid sequence

with an identical domain organization with APPL1, has been shown as a negative regulator of adipo-

nectin signaling. APPL2 forms a heterodimer with APPL1 via their BAR domains [74]. Similar to APPL1,

APPL2 exhibits membrane and lipid binding ability, and resides in the early endosome and undergoes

subcellular translocation in response to various stimuli[74,75]. APPL2 is also expressed in insulin- and

adiponectin-responsive tissues including liver, skeletal muscle and adipose tissue, and interacts with

AdipoR1 and AdipoR2 via the PTB domain [76]. However, in contrast to APPL1, APPL2 negatively

regulates adiponectin signaling in skeletal muscle cells through two distinct mechanisms [76]. First,APPL2 competes with APPL1 for the binding of adiponectin receptors. Second, APPL2 forms a heter-

odimer with APPL1, which prevents the binding of APPL1 to AdipoRs. Treatment with adiponectin or

anti-diabetic drug metformin causes dissociation of APPL1 and APPL2, which allows the membrane

recruitment and binding of APPL1 to the AdipoRs [76]. The opposite actions of APPL1 and APPL2 on

adiponectin signaling are perhaps due to their distinct secondary structure and binding partners.

Structural analysis revealed that APPL2 incorporates two dimers, whereas APPL1 incorporates only one

dimer in the asymmetric unit [36,49,50]. Indeed, the electrostatic surface of APPL1 is also different

from that of APPL2, indicating that they may reside in different subcellular localization[36,49,50]. In

addition, the binding partners of APPL2 are different from those of APPL1 [36], suggesting that these

interactions may also contribute to their opposite effects on adiponectin signaling.

APPL1 as a master coordinator in regulating both action and secretion of insulin

The discovery of APPL1 as a binding partner of Akt2 and PI3K, the two major components of insulin

signaling cascades, raises the possibility that APPL1 regulates insulin signaling[40]. Indeed, suppression

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of APPL1 expression attenuates insulin-elicited phosphorylation of Akt and plasma translocation of

GLUT4 as well as glucose uptake in adipocytes and skeletal muscle cells [43,62]. In response to insulin

stimulation, APPL1 is recruited to the light microsomal fraction and plasma membrane of adipocytes and

hepatocytes[42,43]. In single tibialis cranialis muscles of rats, overexpression of APPL1 by electropo-

ration can prevent HFD-induced deleterious effect on insulin-stimulated glucose uptake and glycogen

synthesis, whereas knockdown of APPL1 produces an opposite effect [77]. This insulin-sensitizing actionof APPL1 is mainly attributed to its activation of the Akt-glycogen synthase kinase 3 beta (GSK3b)- TBC1

domain family member 4 (TBC1D4)-dependent signaling pathway.

In the liver, APPL1 also serves as a sensitizer for the inhibitory effect of insulin on glucose production

[42]. Adenovirus-mediated hepatic overexpression of APPL1 alleviates hyperglycemia, glucose intol-

erance and insulin resistance in db/db diabetic mice, whereas hepatic silencing of APPL1 causes

impairment in insulin signaling and hyperglycemia in lean mice [42]. Further analysis revealed that

APPL1 can potentiate insulin-mediated activation of Akt, which in turn inhibits the expression of key

genes involved in gluconeogenesis. At the molecular level, APPL1 interacts with Akt, and this inter-

action blocks Akt from binding to the endogenous Akt inhibitor Tribble-3 (TRB3) [78]. Under basal

conditions, TRB3 interacts with Akt and traps it within the cytoplasm, thereby preventing Akt trans-

location to plasma membrane for subsequent activation. Upon insulin stimulation, the interaction ofAPPL1 with Akt competes with TRB3 and therefore promotes Akt translocation to the plasma mem-

brane and endosomal compartment for further activation. In diabetic mouse models, the elevated

expression of TRB3 causes insulin resistance and diabetes by trapping and inactivating Akt in cytosol.

On the other hand, overexpression of APPL1 can counteract the negative effects of TRB3 on the sup-

pression of insulin-evoked Akt activation, resulting in improved insulin sensitivity and glycemic

control. Interestingly, Marinho R et al. recently found that endurance exercise training increases the

association of APPL1 with Akt, and concurrently decreases the interaction between Akt and TRB3. Such

changes are associated with improvement in hepatic insulin sensitivity[53]. Dong and her colleagues

have proposed a distinct molecular mechanism by which phosphorylation of APPL1 regulates its

insulin-sensitizing action in hepatocytes. They found that PKCa and endoplasmic reticulum stress

induce phosphorylation of APPL1 at serine 430 [52]. The insulin-sensitizing action of APPL1 isdiminished when this serine residue is mutated to a phospho-mimic amino acid, suggesting that this

phosphorylation negatively regulates APPL1 function.

We have recently explored the physiological role of APPL1 in vascular function using both APPL1

transgenic and knockout mouse models. In dietary obese mice, insulin loses its effects on NO-

dependent vasodilatation owing to impaired insulin-evoked Akt activation in vascular endothelium,

but exhibits the activity of inducing vasoconstriction via augmented production of endothelin-1 [79].

Transgenic overexpression of APPL1 reverses obesity-induced insulin resistance in vascular endothe-

lium and restores the ability of insulin on NO-dependent vasodilatation. By contrast, genetic disruption

of APPL1 leads to endothelial dysfunction by shifting the effect of insulin from vasodilation to vaso-

constriction [79]. At the molecular level, APPL1 enhances insulin-stimulated Akt activation by

competing with TRB3 and suppresses ERK1/2 signaling through altering the phosphorylation status ofits upstream kinase Raf-1 [79]. In contrast to a previous study [73], no direct association between

APPL1 and MAP kinase in endothelial cells could be detected. Whether these associations are cell-type

specic need further investigation.

Although the peripheral metabolic tissues are the main targets of insulin, mounting evidence from

animaland human studiessuggests thatbcell itself alsopossessesan insulin signalingsystem, which plays

a critical role in regulatingb cell mass, survival, insulin biosynthesis, and secretion[80].b-cell-specic

inactivationof several components involvedin insulin signaling, including IR, IRS-2, class IA PI3K, and Akt,

leadsto impaired insulin secretion and/ordecreasedbcell mass[80,81]. By contrast, transgenicexpression

of active Akt or IRS-2 inb cells increasesb cell mass and enhances insulin secretion, thereby rendering the

mice resistant to experimental diabetes[80]. However, the molecular basis by which insulin regulatesb

cell function remains poorly characterized. In this connection, we recently demonstrated that APPL1couples insulin signaling and insulin secretion inb cells [54]. Lack of APPL1 impairs the rst-phase insulin

secretionandcauses glucose intolerance, both of which areattributedto diminished insulin-mediatedAkt

activation. These phenotypic changes are aggregated in APPL1-decient mice fed with a HFD. On the

contrary, transgenic expression of APPL1 prevents HFD-induced glucose intolerance at least in part, by

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potentiating insulin secretion. The pancreatic islets lacking APPL1 exhibit a signicant reduction in the

numberof dockedinsulin granules, whichis accompanied with impaired exocytosis of insulin as a resultof

profoundly decreased expression of the exocytosis machinery soluble N-ethylmaleimide-sensitive factor

attachment protein receptor (SNARE) proteins [54]. Activation of Akt by expressing the constitutive active

form of this kinase rescues the APPL1 null phenotypes in the islets. Similar to the observations in endo-

thelial cells and hepatocytes, APPL1 enhances insulin-mediated Aktactivation by suppressing the bindingofAkttoTRB3in b cells.Ourndingsfurther support the notion that insulin signaling inb cell is important

foritssecretion, andalsosuggestthatreduced expression of APPL1 inpancreaticislets in obesitymay serve

as a mediator coupling insulin resistance to b cell dysfunction, thereby accelerating the progression of

T2DM. Since SNARE proteins are alsoexpressed in skeletal muscle and mediate glucose uptake [82],itisof

considerable interest to investigate whether APPL1 is involved in this process. Taken together, APPL1

integrates the effects of insulin in peripheral target tissues and pancreatic b cells to maintain systemic

glucose homeostasis.

Summary

Defective adiponectin and insulin signaling contribute to obesity-related metabolic and vascular

disorders including endothelial dysfunction and T2DM. It has become evident in recent yearsthat APPL1

acts as a key molecule in mediating both adiponectin and insulin signaling. APPL1 links the AdipoRs and

its downstream targets including LKB1, AMPK and p38 MAPK, and hence mediates the multiple actions

of adiponectin. In insulin signaling, APPL1 regulates Akt activity by competing with TRB3, leading to the

activation of its downstream substrates. Recent animal studies demonstrated that overexpression of

APPL1 prevents obesity-related insulin resistance, diabetes and endothelial dysfunction, whereas APPL1

deciency results in metabolic and vascular disturbances. The benecial effects of APPL1 appear to be

attributed to its insulin-sensitizing ability via modulating both Akt and AMPK activities, suggesting that

both adiponectin and insulin signaling cascades converge on APPL1, which in turn confer the synergistic

effects of these two metabolic hormones on maintenance of glucose homeostasis and vascular functions

(Fig. 1). Further investigations into the biochemical and structural basis by which APPL1 potentiatesinsulin and adiponectin signaling will shed new light on the fundamental processes of metabolic and

vascular regulation, and will also provide valuable insights for the future development of effective in-

sulin sensitizers for treatment of T2DM and its vascular complications.

Practice points

Insulin resistance is a major contributor to obesity-related cardio-metabolic disorders.

The degree of hypoadiponectinemia is closely associated with the degree of insulin resis-

tance, and is a strong indicator of metabolic and vascular disorders.

Research agenda

Continued research into the mechanism mediating the cross-talk between adiponectin and

insulin signaling cascades in more details.

Further investigation into the physiological roles of APPL1 in adiponectin and insulin

signaling using tissue-specic genetically modied animal models.

Exploration of APPL2 functions in insulin and adiponectin signaling in vitro and in animals.

Elucidation of biochemical and structural basis by which APPL1 and APPL2 exert oppositeeffects on adiponectin and insulin actions.

Development of chemical compounds that enhance adiponectin and insulin activities by

targeting the APPL1/APPL2 complex.

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Conict of interest statement

All the authors have declared that no conict of interest exists.

Acknowledgements

This work is supported by General Research Fund (783010 and 781309) and Collaborative Research

Fund (HKU4/CRF/10) from the Research Grant Council of Hong Kong.

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