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; 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 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 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, 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 [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]. ANGPTLs in obesity and related metabolic diseases T. Kadomatsu et al. 560 FEBS Journal 278 (2011) 559–564 ª 2010 The Authors Journal compilation ª 2010 FEBS 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 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. 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. T. Kadomatsu et al. ANGPTLs in obesity and related metabolic diseases FEBS Journal 278 (2011) 559–564 ª 2010 The Authors Journal compilation ª 2010 FEBS 561 ANGPTL2 receptor activity or intracellular signaling might constitute promising treatments for obesity and metabolic diseases associated with chronic inflamma- tion (Fig. 1). Activation of ANGPTL6 ⁄ AGF 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 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 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 ANGPTLs in obesity and related metabolic diseases T. Kadomatsu et al. 562 FEBS Journal 278 (2011) 559–564 ª 2010 The Authors Journal compilation ª 2010 FEBS 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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MINIREVIEW Angiopoietin-like proteins: emerging targets for treatment of obesity and related metabolic diseases Tsuyoshi Kadomatsu, Mitsuhisa Tabata and Yuichi. 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,