Tài liệu Báo cáo khoa học: Angiopoietin-like proteins: emerging targets for treatment of obesity and related metabolic diseases pptx

Recently, the concept has emerged that persistent low-grade activation of proinflammatory pathways in obese adipose tissue directly promotes systemic insulin resistance [1,4,5], suggestin

Angiopoietin-like proteins: emerging targets for treatment

of obesity and related metabolic diseases

Tsuyoshi Kadomatsu, Mitsuhisa Tabata and Yuichi Oike

Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Japan

Introduction

A worldwide increase in obesity due to lifestyle

changes, such as inactivity and overnutrition, is an

increasing medical and social problem in developed

and developing countries [1] Obesity increases the risk

of related metabolic diseases, including type 2 diabetes,

hypertension, hyperlipidemia and cardiovascular

dis-ease [2], which interfere with healthy aging A major

metabolic manifestation of obesity in the early phase is

systemic insulin resistance [3] Recently, the concept

has emerged that persistent low-grade activation of

proinflammatory pathways in obese adipose tissue directly promotes systemic insulin resistance [1,4,5], suggesting that identification of the molecular mecha-nisms underlying adipose tissue inflammation could provide clues for the development of effective preven-tive and therapeutic approaches to obesity-related insu-lin resistance

We and others independently identified seven angiopoietin-like proteins (ANGPTLs) [6] ANGPTLs are structurally similar to angiopoietins, which are

Keywords

adipose tissue; ANGPTL2; ANGPTL6 ⁄ AGF;

cardiovascular disease; chronic

inflammation; energy metabolism;

insulin resistance; metabolic syndrome;

obesity; obesity-related metabolic disease

Correspondence

Y Oike, Department of Molecular Genetics,

Graduate School of Medical Sciences,

Kumamoto University, 1-1-1 Honjo,

Kumamoto 860-8556, Japan

Fax: +81 96 373 5145

Tel: +81 96 373 5140

E-mail: oike@gpo.kumamoto-u.ac.jp

Note

Tsuyoshi Kadomatsu and Mitsuhisa Tabata

contributed equally to this work

(Received 21 July 2010, revised 21

November 2010, accepted 29 November

2010)

doi:10.1111/j.1742-4658.2010.07979.x

Obesity and related metabolic diseases, such as type 2 diabetes, hyperten-sion and hyperlipidemia are an increasingly prevalent medical and social problem in developed and developing countries These conditions are asso-ciated with increased risk of cardiovascular disease, the leading cause of death Therefore, it is important to understand the molecular basis underly-ing obesity and related metabolic diseases in order to develop effective pre-ventive and therapeutic approaches against these conditions Recently, a family of proteins structurally similar to the angiogenic-regulating factors known as angiopoietins was identified and designated ‘angiopoietin-like proteins’ (ANGPTLs) Encoded by seven genes, ANGPTL1–7 all possess

an N-terminal coiled-coil domain and a C-terminal fibrinogen-like domain, both characteristic of angiopoietins ANGPTLs do not bind to either the angiopoietin receptor Tie2 or the related protein Tie1, indicating that these ligands function differently from angiopoietins Like angiopoietins, some ANGPTLs potently regulate angiogenesis, but ANGPTL3, -4 and ANG-PTL6⁄ angiopoietin-related growth factor (AGF) directly regulate lipid, glucose and energy metabolism independent of angiogenic effects Recently,

we found that ANGPTL2 is a key adipocyte-derived inflammatory media-tor that links obesity to systemic insulin resistance In this minireview, we focus on the roles of ANGPTL2 and ANGPTL6⁄ AGF in obesity and related metabolic diseases, and discuss the possibility that both could func-tion as molecular targets for the prevenfunc-tion and treatment of obesity and metabolic diseases

Abbreviations

AGF, angiopoietin-related growth factor; ANGPTL, angiopoietin-like protein; PGC-1a, peroxisome proliferator-activated receptor-c (PPARc) coactivator 1a; PPAR, peroxisome proliferator-activated receptor.

characterized by a coiled-coil domain in the

N-termi-nus and a fibrinogen-like domain in the C-termiN-termi-nus

Angiopoietins have a signal sequence in the

N-termi-nus for protein secretion, and secreted angiopoietin

functions to maintain the vascular system and

hemato-poietic stem cells through the Tie2 receptor [6]

How-ever, ANGPTLs do not bind to either Tie2 or the

related protein Tie1, suggesting that these orphan

ligands function differently from angiopoietins Cells

transfected with expression vectors encoding

ANG-PTL1, -2, -3, -4 or -6 secrete each ANGPTL protein

into culture supernatants [7–9], and ANGPTL2, -3, -4

and -6 have been detected in the systemic circulation,

suggesting that at least some ANGPTLs function in an

endocrine manner in vivo [7,10–13] Several studies

show that most ANGPTLs potently regulate

angiogen-esis, whereas a subset also functions in glucose, lipid

and energy metabolism [6] For example, ANGPTL3

and ANGPTL4 regulate lipid metabolism by inhibiting

lipoprotein lipase activity [6,11,12] ANGPTL6⁄

angio-poietin-like growth factor (AGF) reportedly

counter-acts obesity by increasing systemic energy expenditure

and thereby antagonizing related metabolic diseases

[14] Furthermore, we recently reported that

ANG-PTL2 causes inflammation of adipose tissue in obesity

and related insulin resistance [15] Here, we focus on

the roles of ANGPTL2 and ANGPTL6⁄ AGF in

obes-ity and related metabolic diseases, and discuss whether

these ANGPTLs could be targets for the prevention

and treatment of these conditions

Suppression of ANGPTL2 as an

effective strategy against

obesity-related insulin resistance

It is well known that lifestyle intervention is the best

strategy to overcome obesity and related metabolic

dis-eases; however, it is difficult for busy people to follow

recommended regimes on a daily basis An alternative

strategy might be to suppress inflammation in obese

adipose tissue, which secretes numerous inflammatory

molecules that mediate insulin resistance in skeletal

muscle and⁄ or vascular dysfunction in blood vessels,

leading to type 2 diabetes and⁄ or cardiovascular

dis-ease Although peroxisome proliferator-activated

receptor (PPAR)c agonists used in clinical practice

effectively ameliorate adipose tissue inflammation and

systemic insulin sensitivity, they have potential side

effects, such as increased body weight (adiposity

and⁄ or edema), altered bone metabolism and

undesir-able long-term cardiovascular outcomes

(Rosiglitaz-one) For these reasons, the recently identified adipose

tissue-derived inflammatory mediator, ANGPTL2,

might be an alternative and more specific therapeutic target against obesity-induced metabolic alterations ANGPTL2, a secreted protein, regulates angiogene-sis similarly to several other ANGPTLs However, ANGPTL2 has the unique capacity to induce an inflammatory response in blood vessels [15,16] ANG-PTL2 expression is induced by chronic but not acute hypoxia [15] Increased ANGPTL2 transcription following hypoxia is not altered by mutations in the hypoxia-inducible factor-1a response element found in its promoter region (our unpublished data); thus regu-lation is likely independent of hypoxia-inducible factor-1a Interestingly, ANGPTL2 is abundantly expressed in adipose tissue [15] ANGPTL2 mRNA levels in adipose tissue and circulating protein levels are both elevated in obese mice [15], consistent with the finding that in obesity ANGPTL2 expression is induced by both chronic hypoxia and endoplasmic reticulum stress resulting from adipose tissue expan-sion [15] Further understanding of mechanisms governing ANGPTL2 expression would be helpful in treating obesity by suggesting ways to target ANG-PTL2 expression In humans, ANGANG-PTL2 concentra-tion in the circulaconcentra-tion is also upregulated in obesity (particularly visceral obesity) and correlated with the levels of systemic insulin resistance and inflammation [15] Circulating ANGPTL2 levels decrease with body weight reduction, likely reflecting the pathophysiologi-cal effect (hypoxia and endoplasmic reticulum stress)

of adipose tissue These findings support the possibility that the alteration of circulating ANGPTL2 levels could serve as a marker of obesity-induced metabolic abnormalities Furthermore, circulating ANGPTL2 levels decrease in parallel with reduction of visceral fat

in obese diabetic patients treated with pioglitazone, a PPARc agonist with unique antidiabetic activity that decreases visceral fat, suppresses inflammation and ameliorates insulin sensitivity [15,17,18] These findings suggest that, in humans, visceral fat is one of the pri-mary sources of circulating ANGPTL2 In addition, ANGPTL2 mRNA expression in cultured 3T3-L1 adipocytes was halved 24 h after addition of a PPARc agonist to the medium, which may in part explain reduction in plasma ANGPTL2 levels following piog-litazone treatment [15] These results are compatible with the observation that suppressing ANGPTL2 ame-liorates insulin sensitivity in mice The antidiabetic effect of pioglitazone may be due in part to ANG-PTL2 reduction

Overexpression of ANGPTL2 in skin and adipose tissues results in local inflammation as evidenced by leukocyte attachment to the wall of post-capillary venules and increased blood vessel permeability [15]

However, the number of blood vessels remains

unal-tered by ANGPTL2 overexpression [15,16] This

find-ing suggests that ANGPTL2 promotes vascular

inflammation rather than angiogenesis in these tissues,

although it has been shown to enhance endothelial cell

migration in vitro and in avascular tissues, such as the

cornea [15] Transgenic mice expressing ANGPTL2 in

adipose tissue show vascular inflammation and

increased macrophage infiltration in adipose tissue,

although they are not obese [15] The expression of

inflammatory cytokines (tumor necrosis factor-a,

inter-leukin-6 and interleukin-1b) was increased in the

adi-pose tissue of ANGPTL2 transgenic mice compared

with that of wild-type mice [15] Conversely,

ANG-PTL2 null mice fed a high-fat diet show fewer

infil-trated macrophages and decreased tumor necrosis

factor-a and interleukin-6 expression in the adipose

tissue of ANGPTL2 null mice compared with that of

wild-type mice [15] These results raise the possibility

that blocking ANGPTL2 signaling simultaneously

sup-presses the expression of other inflammatory

cyto-kines In addition, because ANGPTL2 null mice

survive and grow normally, it is predicted that the

suppression of ANGPTL2 signaling has few side

effects Therefore, for these reasons, we consider that

the suppression of ANGPTL2 signaling as a

therapeu-tic strategy is more beneficial

Because ANGPTL2 promotes vascular inflammation

via the a5b1 integrin⁄ Rac1 ⁄ NF-jB pathway [15] and

vascular injury accompanied by inflammation is

con-sidered an early feature of arteriosclerosis [19],

circu-lating ANGPTL2 may also function in obesity-related

insulin resistance but also obesity-related or unrelated cardiovascular disease Interestingly, the circulating ANGPTL2 concentration in patients with coronary artery disease is higher than that seen in healthy sub-jects, even when there is no difference in body weight between groups [15] Moreover, endothelial cells from tissue segments of internal mammary arteries from smokers with coronary artery disease express higher levels of ANGPTL2 mRNA than tissues from non-smokers with similar disease [20] Because smoking is closely associated with the development of inflamma-tion and increased risk of atherosclerosis [21], focal ANGPTL2 secreted by vascular endothelial cells may

be a mediator linking smoking to cardiovascular disease in an autocrine or paracrine manner Blocking ANGPTL2 signaling may also be beneficial also

in preventing and treating cardiovascular disease (Fig 1)

To date, integrins have been regarded as a func-tional ANGPTL2 receptor ANGPTL2 induces an inflammatory cascade in blood endothelial cells through a5b1 integrin receptors and promotes mono-cyte chemotaxis through a4 and b2 integrin receptors [15] Angiopoietin signaling is regulated by two inde-pendent receptors; Tie2 receptor and integrins [22] Therefore, we cannot rule out the possibility that endothelial cells and⁄ or monocytes express a specific ANGPTL2 receptor Although further studies are needed to identify a specific ANGPTL2 receptor and its downstream effectors, strategies aimed at blocking ANGPTL2 signaling through suppressing its expres-sion, neutralizing secreted ANGPTL2 or blocking

Lifestyle changes (inactivity, overnutrition, etc)

Obesity-related metabolic diseases Hyperlipidemia Hypertension

Type 2 diabetes Insulin resistance Chronic adipose tissue inflammation

Cardiovascular disease

ANGPTL2

Activation of vascular inflammation and monocyte migration

Enhancement of systemic energy expenditure

ANGPTL6/AGF

Anti-obesity effect

Improvement o

f glucose intolerance

Induction Obesity

Induction

Fig 1 Schematic diagram showing the

roles of ANGPTL2 and ANGPTL6 ⁄ AGF in

obesity and related metabolic diseases.

The expression of ANGPTL2 and ANGPTL6 ⁄

AGF is induced in obese conditions.

ANGPTL2 induces chronic adipose tissue

inflammation and systemic insulin resistance

through the induction of vascular

inflammation and monocyte migration.

ANGPTL6 ⁄ AGF antagonizes obesity and

insulin resistance through the enhancement

of systemic energy expenditure The solid

lines show effects that are through to be

direct, whereas dashed lines indicate what

are likely indirect or secondary effects.

ANGPTL2 receptor activity or intracellular signaling

might constitute promising treatments for obesity and

metabolic diseases associated with chronic

inflamma-tion (Fig 1)

counteracts obesity and related

metabolic diseases

ANGPTL6⁄ AGF, the angiopoietin-like protein most

closely related to ANGPTL2, is abundantly expressed

in liver, and expressed at relatively low levels in other

tissues [6] ANGPTL6⁄ AGF exhibits a signal

sequence in the N-terminus and ANGPTL6⁄ AGF

protein is detected in the circulation, indicating that

it is secreted [9,13] ANGPTL6⁄ AGF induces

angio-genesis and arterioangio-genesis through activation of the

ERK1⁄ 2–eNOS–NO pathway in endothelial cells

[6,9,16,23]

ANGPTL6⁄ AGF null mice show marked obesity

because of decreased energy expenditure and insulin

resistance [13,14,16] By contrast, transgenic mice in

which ANGPTL6⁄ AGF expression is constitutive and

broadly driven by the CAG promoter (chicken b-actin

promoter with cytomegalovirus immediate-early

enhan-cer; CAG–ANGPTL6⁄ AGF mice) exhibit a lean

phe-notype with enhanced energy expenditure [13,14,16]

In wild-type mice, a high-fat diet causes obesity and

insulin resistance, whereas CAG–ANGPTL6⁄ AGF

mice are protected against diet-induced obesity and

insulin resistance [13] K14–ANGPTL6⁄ AGF

trans-genic mice, which persistently overexpress

ANG-PTL6⁄ AGF in the skin, also exhibit increased

ANGPTL6⁄ AGF serum levels comparable with those

seen in CAG–ANGPTL6⁄ AGF transgenic mice and

exhibit a lean phenotype and increased insulin

sensitiv-ity [14] Moreover, adenoviral overexpression of

ANG-PTL6⁄ AGF in the liver of diet-induced obese mice

results in elevated ANGPTL6⁄ AGF serum levels and

amelioration of diet-induced obesity and insulin

resis-tance [14] Taken together, these findings suggest that

ANGPTL6⁄ AGF in the circulation counteracts obesity

and related insulin resistance by increasing systemic

energy expenditure

A recent study indicates that circulating levels of

human ANGPTL6⁄ AGF are elevated in obese or

diabetic conditions [24] Similarly, we found that

ANGPTL6⁄ AGF serum levels are elevated in not only

diet-induced obese mice and ob⁄ ob mice, but also in

obese humans (unpublished data), suggesting that

increased circulating ANGPTL6⁄ AGF in obesity does

not reverse obesity at all Furthermore, ANGPTL6⁄

AGF levels have been positively correlated with fasting

serum glucose levels [24] These findings raise the possibility that ANGPTL6⁄ AGF resistance occurs in obese or diabetic conditions Leptin, which is known

to reduce body weight by decreasing appetite and increasing energy expenditure [25,26], has a positive correlation with obesity [27] Although under physio-logical conditions leptin serves to counteract weight gain, inflammation induces a state of ‘leptin resistance’

in obese animals and humans resulting in development

of hyperleptinemia Similarly, hyperleptinemia is a consequence of the development of insulin resistance

in obesity and type 2 diabetes Thus, we consider that although the normal production of ANGPTL6⁄ AGF from liver may be upregulated to counteract weight gain and promote insulin sensitivity, the effect of ANGPTL6⁄ AGF might also be attenuated in the obese state Nonetheless, an approximately twofold increase in serum ANGPTL6⁄ AGF levels by adenovi-ral overexpression of ANGPTL6⁄ AGF results in marked body weight reduction in diet-induced obese mice that have two to three times higher ANGPTL6⁄ AGF levels than lean mice already [13], so ANGPTL6⁄ AGF resistance might be milder than leptin resistance Therefore, because ANGPTL6⁄ AGF transgenic mice exhibit twofold-increased ANGPTL6⁄ AGF serum levels and enhanced energy expenditure compared with wild-type mice [13], they might be protected against diet-induced obesity As a next step to investigate this possibility, further studies are needed to elucidate how ANGPTL6⁄ AGF gene expression is regulated in the liver and to define mechanisms underlying its signaling

Recent studies indicate that skeletal muscle regulates energy expenditure, which is mediated by PPARa, PPARd, PPARc and their coactivators, peroxisome proliferator-activated receptor-c (PPARc) coactivator (PGC)-1a and PGC-1b, in response to energy overload [28–31] We found significant decreases in the expression

of PPARd and PGC-1a in skeletal muscle in ANG-PTL6⁄ AGF null mice, and increases in the expression

of PPARa, PPARd and PGC-1a in skeletal muscle of ANGPTL6⁄ AGF transgenic mice [14] Moreover, ANGPTL6⁄ AGF protein binds to C2C12 myocytes and stimulates phosphorylation of p38 MAPK [14], which directly enhances stability and activation of PGC-1a protein [30] ANGPTL6⁄ AGF was also reported to sup-press gluconeogenesis by activating the PI3K⁄ Akt ⁄ FoxO1 pathway, decreasing glucose-6-phosphatase expression in rat hepatocytes [32] Because ANGPTL6⁄ AGF is primarily expressed in hepatocytes, it may suppress gluconeogenesis in those cells in an auto-crine⁄ paracrine manner Taken together, activation of ANGPTL6⁄ AGF signaling could counteract obesity

and insulin resistance (Fig 1) Further studies are

required to clarify how transcription of ANGPTL6⁄

AGF is regulated and to identify the ANGPTL6⁄ AGF

receptor and its downstream effectors

Conclusions

In this review, we have focused on the roles of

ANG-PTL2 and ANGPTL6⁄ AGF in obesity and related

metabolic diseases We proposed that suppression of

ANGPTL2 signaling or enhancement of

ANG-PTL6⁄ AGF signaling could represent novel and

effec-tive therapeutic strategies against obesity and related

metabolic diseases (Fig 1) In advance of clinical

applications, further studies are necessary to define the

transcriptional regulatory mechanisms regulating these

factors, identify their cognate receptors and

character-ize their downstream signaling

Acknowledgements

This work was supported by Grants-in-Aid for

Scien-tific Research on Innovative Areas (No.22117514)

from the Ministry of Education, Culture, Sports,

Sci-ence and Technology of Japan, by Grants-in-Aid for

Scientific Research (B) (No 21390245) from Japan

Society for the Promotion of Science, by a grant from

the Takeda Science Foundation, by a grant from the

Sumitomo Foundation, by a grant from the Mitsubishi

Foundation, and by a grant from the Tokyo

Biochemi-cal Research Foundation

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