Angiopoietin-like proteins: emerging targets for treatment of obesity and related metabolic diseases
2010; Wiley; Volume: 278; Issue: 4 Linguagem: Inglês
10.1111/j.1742-4658.2010.07979.x
ISSN1742-4658
AutoresTsuyoshi Kadomatsu, Mitsuhisa Tabata, Yuichi Oike,
Tópico(s)Diabetes, Cardiovascular Risks, and Lipoproteins
ResumoThe FEBS JournalVolume 278, Issue 4 p. 559-564 Free Access Angiopoietin-like proteins: emerging targets for treatment of obesity and related metabolic diseases Tsuyoshi Kadomatsu, Tsuyoshi Kadomatsu Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, JapanSearch for more papers by this authorMitsuhisa Tabata, Mitsuhisa Tabata Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, JapanSearch for more papers by this authorYuichi Oike, Yuichi Oike Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, JapanSearch for more papers by this author Tsuyoshi Kadomatsu, Tsuyoshi Kadomatsu Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, JapanSearch for more papers by this authorMitsuhisa Tabata, Mitsuhisa Tabata Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, JapanSearch for more papers by this authorYuichi Oike, Yuichi Oike Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, JapanSearch for more papers by this author First published: 07 December 2010 https://doi.org/10.1111/j.1742-4658.2010.07979.xCitations: 92 Y. Oike, Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, JapanFax: +81 96 373 5145Tel: +81 96 373 5140E-mail: [email protected] Note: Tsuyoshi Kadomatsu and Mitsuhisa Tabata contributed equally to this work AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Abstract Obesity and related metabolic diseases, such as type 2 diabetes, hypertension and hyperlipidemia are an increasingly prevalent medical and social problem in developed and developing countries. These conditions are associated with increased risk of cardiovascular disease, the leading cause of death. Therefore, it is important to understand the molecular basis underlying obesity and related metabolic diseases in order to develop effective preventive 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 ANGPTL6/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 mediator 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 function as molecular targets for the prevention and treatment of obesity and metabolic diseases. Abbreviations AGF angiopoietin-related growth factor ANGPTL angiopoietin-like protein PGC-1α peroxisome proliferator-activated receptor-γ (PPARγ) coactivator 1α PPAR peroxisome proliferator-activated receptor 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 disease [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 mechanisms underlying adipose tissue inflammation could provide clues for the development of effective preventive and therapeutic approaches to obesity-related insulin resistance. We and others independently identified seven angiopoietin-like proteins (ANGPTLs) [6]. ANGPTLs are structurally similar to angiopoietins, which are characterized by a coiled-coil domain in the N-terminus and a fibrinogen-like domain in the C-terminus. Angiopoietins have a signal sequence in the N-terminus for protein secretion, and secreted angiopoietin functions to maintain the vascular system and hematopoietic stem cells through the Tie2 receptor [6]. However, 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 ANGPTL1, -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 angiogenesis, 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/angiopoietin-like growth factor (AGF) reportedly counteracts obesity by increasing systemic energy expenditure and thereby antagonizing related metabolic diseases [14]. Furthermore, we recently reported that ANGPTL2 causes inflammation of adipose tissue in obesity and related insulin resistance [15]. Here, we focus on the roles of ANGPTL2 and ANGPTL6/AGF in obesity 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 diseases; 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 disease. Although peroxisome proliferator-activated receptor (PPAR)γ 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 undesirable long-term cardiovascular outcomes (Rosiglitazone). 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 angiogenesis similarly to several other ANGPTLs. However, ANGPTL2 has the unique capacity to induce an inflammatory response in blood vessels [15,16]. ANGPTL2 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-1α response element found in its promoter region (our unpublished data); thus regulation is likely independent of hypoxia-inducible factor-1α. 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 expansion [15]. Further understanding of mechanisms governing ANGPTL2 expression would be helpful in treating obesity by suggesting ways to target ANGPTL2 expression. In humans, ANGPTL2 concentration 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 pathophysiological 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 PPARγ 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 primary sources of circulating ANGPTL2. In addition, ANGPTL2 mRNA expression in cultured 3T3-L1 adipocytes was halved 24 h after addition of a PPARγ agonist to the medium, which may in part explain reduction in plasma ANGPTL2 levels following pioglitazone treatment [15]. These results are compatible with the observation that suppressing ANGPTL2 ameliorates insulin sensitivity in mice. The antidiabetic effect of pioglitazone may be due in part to ANGPTL2 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 unaltered by ANGPTL2 overexpression [15,16]. This finding 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-α, interleukin-6 and interleukin-1β) was increased in the adipose tissue of ANGPTL2 transgenic mice compared with that of wild-type mice [15]. Conversely, ANGPTL2 null mice fed a high-fat diet show fewer infiltrated macrophages and decreased tumor necrosis factor-α 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 suppresses the expression of other inflammatory cytokines. 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 therapeutic strategy is more beneficial. Because ANGPTL2 promotes vascular inflammation via the α5β1 integrin/Rac1/NF-κB pathway [15] and vascular injury accompanied by inflammation is considered an early feature of arteriosclerosis [19], circulating 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 subjects, 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 nonsmokers with similar disease [20]. Because smoking is closely associated with the development of inflammation 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). Figure 1Open in figure viewerPowerPoint 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. To date, integrins have been regarded as a functional ANGPTL2 receptor. ANGPTL2 induces an inflammatory cascade in blood endothelial cells through α5β1 integrin receptors and promotes monocyte chemotaxis through α4 and β2 integrin receptors [15]. Angiopoietin signaling is regulated by two independent 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 expression, neutralizing secreted ANGPTL2 or blocking ANGPTL2 receptor activity or intracellular signaling might constitute promising treatments for obesity and metabolic diseases associated with chronic inflammation (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 angiogenesis 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 β-actin promoter with cytomegalovirus immediate-early enhancer; CAG–ANGPTL6/AGF mice) exhibit a lean phenotype 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 transgenic mice, which persistently overexpress ANGPTL6/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 sensitivity [14]. Moreover, adenoviral overexpression of ANGPTL6/AGF in the liver of diet-induced obese mice results in elevated ANGPTL6/AGF serum levels and amelioration of diet-induced obesity and insulin resistance [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 physiological 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 adenoviral 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 PPARα, PPARδ, PPARγ and their coactivators, peroxisome proliferator-activated receptor-γ (PPARγ) coactivator (PGC)-1α and PGC-1β, in response to energy overload [28–31]. We found significant decreases in the expression of PPARδ and PGC-1α in skeletal muscle in ANGPTL6/AGF null mice, and increases in the expression of PPARα, PPARδ and PGC-1α 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-1α protein [30]. ANGPTL6/AGF was also reported to suppress 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 autocrine/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 ANGPTL2 and ANGPTL6/AGF in obesity and related metabolic diseases. We proposed that suppression of ANGPTL2 signaling or enhancement of ANGPTL6/AGF signaling could represent novel and effective 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 characterize their downstream signaling. Acknowledgements This work was supported by Grants-in-Aid for Scientific Research on Innovative Areas (No.22117514) from the Ministry of Education, Culture, Sports, Science 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 Biochemical Research Foundation. References 1 Schenk S, Saberi M & Olefsky JM (2008) Insulin sensitivity: modulation by nutrients and inflammation. J Clin Invest 118, 2992– 3002. 2 Handschin C & Spiegelman BM (2008) The role of exercise and PGC1α in inflammation and chronic disease. Nature 454, 463– 469. 3 Reaven GM (2005) The insulin resistance syndrome: definition and dietary approaches to treatment. Annu Rev Nutr 25, 391– 406. 4 Apovian CM, Bigornia S, Mott M, Meyers MR, Ulloor J, Gagua M, McDonnell M, Hess D, Joseph L & Gokce N (2008) Adipose macrophage infiltration is associated with insulin resistance and vascular endothelial dysfunction in obese subjects. Arterioscler Thromb Vasc Biol 28, 1654– 1659. 5 Guilherme A, Virbasius JV, Puri V & Czech MP (2008) Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes. Nat Rev Mol Cell Biol 9, 367– 377. 6 Hato T, Tabata M & Oike Y (2008) The role of angiopoietin-like proteins in angiogenesis and metabolism. Trends Cardiovasc Med 18, 6– 14. 7 Kim I, Moon SO, Koh KN, Kim H, Uhm CS, Kwak HJ, Kim NG & Koh GY (1999) Molecular cloning, expression, and characterization of angiopoietin-related protein. Angiopoietin-related protein induces endothelial cell sprouting. J Biol Chem 274, 26523– 26528. 8 Ito Y, Oike Y, Yasunaga K, Hamada K, Miyata K, Matsumoto S, Sugano S, Tanihara H, Masuho Y & Suda T (2003) Inhibition of angiogenesis and vascular leakiness by angiopoietin-related protein 4. Cancer Res 63, 6651– 6657. 9 Oike Y, Ito Y, Maekawa H, Morisada T, Kubota Y, Akao M, Urano T, Yasunaga K & Suda T (2004) Angiopoietin-related growth factor (AGF) promotes angiogenesis. Blood 103, 3760– 3765. 10 Kim I, Kim HG, Kim H, Kim HH, Park SK, Uhm CS, Lee ZH & Koh GY (2000) Hepatic expression, synthesis and secretion of a novel fibrinogen/angiopoietin-related protein that prevents endothelial-cell apoptosis. Biochem J 346(Pt 3), 603– 610. 11 Ono M, Shimizugawa T, Shimamura M, Yoshida K, Noji-Sakikawa C, Ando Y, Koishi R & Furukawa H (2003) Protein region important for regulation of lipid metabolism in angiopoietin-like 3 (ANGPTL3): ANGPTL3 is cleaved and activated in vivo. J Biol Chem 278, 41804– 41809. 12 Ge H, Cha JY, Gopal H, Harp C, Yu X, Repa JJ & Li C (2005) Differential regulation and properties of angiopoietin-like proteins 3 and 4. J Lipid Res 46, 1484– 1490. 13 Oike Y, Akao M, Kubota Y & Suda T (2005) Angiopoietin-like proteins: potential new targets for metabolic syndrome therapy. Trends Mol Med 11, 473– 479. 14 Oike Y, Akao M, Yasunaga K, Yamauchi T, Morisada T, Ito Y, Urano T, Kimura Y, Kubota Y, Maekawa H et al. (2005) Angiopoietin-related growth factor antagonizes obesity and insulin resistance. Nat Med 11, 400– 408. 15 Tabata M, Kadomatsu T, Fukuhara S, Miyata K, Ito Y, Endo M, Urano T, Zhu HJ, Tsukano H, Tazume H et al. (2009) Angiopoietin-like protein 2 promotes chronic adipose tissue inflammation and obesity-related systemic insulin resistance. Cell Metab 10, 178– 188. 16 Oike Y & Tabata M (2009) Angiopoietin-like proteins – potential therapeutic targets for metabolic syndrome and cardiovascular disease. Circ J 73, 2192– 2197. 17 Lebovitz HE & Banerji MA (2001) Insulin resistance and its treatment by thiazolidinediones. Recent Prog Horm Res 56, 265– 294. 18 Takano H & Komuro I (2009) Peroxisome proliferator-activated receptor γ and cardiovascular diseases. Circ J 73, 214– 220. 19 Higashi Y, Noma K, Yoshizumi M & Kihara Y (2009) Endothelial function and oxidative stress in cardiovascular diseases. Circ J 73, 411– 418. 20 Farhat N, Thorin-Trescases N, Voghel G, Villeneuve L, Mamarbachi M, Perrault LP, Carrier M & Thorin E (2008) Stress-induced senescence predominates in endothelial cells isolated from atherosclerotic chronic smokers. Can J Physiol Pharmacol 86, 761– 769. 21 Kakafika AI & Mikhailidis DP (2007) Smoking and aortic diseases. Circ J 71, 1173– 1180. 22 Carlson TR, Feng Y, Maisonpierre PC, Mrksich M & Morla AO (2001) Direct cell adhesion to the angiopoietins mediated by integrins. J Biol Chem 276, 26516– 26525. 23 Urano T, Ito Y, Akao M, Sawa T, Miyata K, Tabata M, Morisada T, Hato T, Yano M, Kadomatsu T et al. (2008) Angiopoietin-related growth factor enhances blood flow via activation of the ERK1/2–eNOS–NO pathway in a mouse hind-limb ischemia model. Arterioscler Thromb Vasc Biol 28, 827– 834. 24 Ebert T, Bachmann A, Lossner U, Kratzsch J, Bluher M, Stumvoll M & Fasshauer M (2009) Serum levels of angiopoietin-related growth factor in diabetes mellitus and chronic hemodialysis. Metabolism 58, 547– 551. 25 Auwerx J & Staels B (1998) Leptin. Lancet 351, 737– 742. 26 Friedman JM & Halaas JL (1998) Leptin and the regulation of body weight in mammals. Nature 395, 763– 770. 27 Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, Ohannesian JP, Marco CC, McKee LJ, Bauer TL et al. (1996) Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med 334, 292– 295. 28 Wu Z, Puigserver P, Andersson U, Zhang C, Adelmant G, Mootha V, Troy A, Cinti S, Lowell B, Scarpulla RC et al. (1999) Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 98, 115– 124. 29 Lowell BB & Spiegelman BM (2000) Towards a molecular understanding of adaptive thermogenesis. Nature 404, 652– 660. 30 Puigserver P & Spiegelman BM (2003) Peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α): transcriptional coactivator and metabolic regulator. Endocr Rev 24, 78– 90. 31 Evans RM, Barish GD & Wang YX (2004) PPARs and the complex journey to obesity. Nat Med 10, 355– 361. 32 Kitazawa M, Ohizumi Y, Oike Y, Hishinuma T & Hashimoto S (2007) Angiopoietin-related growth factor suppresses gluconeogenesis through the Akt/forkhead box class O1-dependent pathway in hepatocytes. J Pharmacol Exp Ther 323, 787– 793. Citing Literature Volume278, Issue4February 2011Pages 559-564 This article also appears in:Review Content 2010-2011 FiguresReferencesRelatedInformation
Referência(s)