MINIREVIEW
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;

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 prevention 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.
FEBS Journal 278 (2011) 559–564 ª 2010 The Authors Journal compilation ª 2010 FEBS 559
characterized by a coiled-coil domain in the N-termi-
nus and a fibrinogen-like domain in the C-terminus.
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 ⁄ 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, ANGPTL2 concentra-
tion in the circulation is also upregulated in obesity
(particularly visceral obesity) and correlated with the
levels of systemic insulin resistance and inflammation

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-

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 of
g
lucose intolerance
Induction
Obesity
Induction
Fig. 1. Schematic diagram showing the
roles of ANGPTL2 and ANGPTL6 ⁄ AGF in
obesity and related metabolic diseases.

genesis and arteriogenesis 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

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

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