KINESITHERAPY AND MIGRAINES. ILLUSION OR REALITY, OBSERVATIONS ON 30 Migraine, a real illness Migraine is not in any way a pathology specific to our own times. It was first mentioned in 1,500 BC, and it was precisely described at Aretaeus in Cappadocia in the first century AC: «. it differs from other forms of headache in its location and intermittent character. It returns after intervals
Doi:10.1016/j.coph.2005.01.006Adipose tissue as an active endocrine organ: recent advancesRuth E Gimeno and Lori D Klaman Adipose tissue secretes a variety of factors in a manner physiology and pharmacology of adipose-derived factors dependent upon its metabolic state. These factors are derived with particular emphasis on their therapeutic potential.
from adipocyte or non-adipocyte fractions, and includeproteins, metabolites and hormones. Obesity is a major risk factor for type 2 diabetes and cardiovascular disease, and Leptin, the 16 kDa product of the ob gene, signals adipocyte-derived factors might contribute to or ameliorate through central pathways to control satiety, energy obesity-associated pathologies such as insulin resistance, expenditure and neuroendocrine function. The mechan- dyslipidemia, vascular dysfunction and a chronic inflammatory ism of leptin action in the hypothalamus and its effects on satiety have been discussed elsewhere [Leptin hasprofound effects on lipid metabolism, which are mediatedthrough both central and peripheral pathways . In AddressesDepartment of Cardiovascular and Metabolic Diseases, Wyeth muscle, leptin stimulates fatty acid oxidation by activat- Research, 200 Cambridge Park Drive, Cambridge, MA 02140, USA ing 50-activated AMP kinase (AMPK) both directly andthrough a central mechanism Leptin also partitions Corresponding author: Gimeno, RE (firstname.lastname@example.org) lipids away from non-adipose tissue, thus averting lipo-toxicity; this effect might be mediated by its ability torepress stearoyl CoA desaturase through a central path- Current Opinion in Pharmacology 2005, 5:122–128 way ]. In addition, leptin has been shown recently to inhibit hepatic triglyceride accumulation directly by acti- vating phosphatidylinositol-3-kinase [Interestingly, Edited by Robert Scarborough and George Vlasuk leptin has both deleterious and protective effects oncardiovascular function ]. Leptin-deficient mice, whileobese, are resistant to hypertension, thrombosis and impaired fibrinolysis; leptin administration in these mice # 2005 Elsevier Ltd. All rights reserved.
promotes neointimal growth and stenosis ], whereas inhibition of leptin using neutralizing antibodies protectswild-type mice from thrombosis [together suggestinga prothrombotic function for leptin. Conversely, leptindeficiency is associated with cardiac hypertrophy, and leptin supplementation reverses that phenotype, suggest- Starting with the discovery of leptin as an adipocyte- ing an antihypertrophic function ]. The use of leptin as derived satiety factor, adipose tissue is increasingly being a therapeutic agent is limited by the severe leptin resis- recognized as an endocrine organ. A growing number of tance present in most obese individuals and, to date, adipocyte-derived factors have been described and their leptin therapy has been used successfully only in patients contribution to the pathophysiology of the metabolic with genetic leptin deficiency or lipodystrophy [ syndrome, characterized by central adiposity, insulinresistance, dyslipidemia, hypertension, chronic inflamma- tion and a prothrombotic state, is being investigated.
Adiponectin (ACRP30/AdipoQ) is a 30 kDa protein speci- Apart from fully differentiated adipocytes, adipose tissue fically expressed in adipocytes, plasma levels of which contains numerous other cell types, including fibroblasts, negatively correlate with adiposity, insulin resistance, cor- onary artery disease and dyslipidemia in both mice and smooth muscle cells. It is becoming increasingly clear humans [In mice, deletion of adiponectin results in that several adipose-derived factors are not, or at least not insulin resistance, dyslipidemia and increased neointimal exclusively, produced by adipocytes; in addition, some proliferation, whereas overexpression or pharmacological factors might primarily act by inducing secretion of other administration of adiponectin improves insulin sensitivity factors within adipose tissue in an autocrine or paracrine and protects against atherosclerosis Recently, fashion. Different adipose depots are functionally dis- a protective role for adiponectin in cardiomyopathy was tinct; visceral adipose tissue is of particular interest, as its demonstrated: adiponectin deletion enhances cardiac mass is most closely associated with the metabolic syn- hypertrophy, whereas overexpression attenuates it ]; drome. Several excellent reviews on adipose-derived furthermore, in vitro, adiponectin modulates hypertrophic factors have been published recently and will be referred signals in cardiomyocytes. Adiponectin also stimulates to [This review focuses on recent advances in the angiogenesis and is important for recovery from ischaemic Current Opinion in Pharmacology 2005, 5:122–128 Adipose tissue as an active endocrine organ: recent advances Gimeno and Klaman injury ]. Under different conditions, however, adipo- part of a family of resistin-like-molecules (RELMs), which nectin can also be antiangiogenic Adiponectin is contains four members in the mouse, but only two in thought to directly affect a wide variety of target cells, humans. Importantly, resistin can heterodimerize with including hepatocytes, myocytes, endothelial cells, macro- some RELM family members , and at least one resistin phages and smooth muscle cells; AMPK has been identi- homologue, RELMb, has been shown to have effects on fied as a key intracellular mediator of adiponectin function insulin resistance indistinguishable from those of resistin ]. Recently, the notion of a primarily peripheral action . Although recent studies clearly establish a role for of adiponectin has been challenged by the finding that murine resistin in glucose metabolism, and possibly dysli- central injection of adiponectin modulates energy expen- pidemia , translation of these results into diture, resulting in decreased body weight . It will be humans has been questioned given the differences important to determine whether central effects of adipo- between mouse and human tissue distribution. Human nectin also contribute to its effects on glucose metabolism resistin serum levels are associated with adiposity and insulin resistance in many, but not all, studies [Inter-estingly, human resistin is induced by inflammatory med- The study of adiponectin is complicated by the hetero- iators such as lipopolysaccharide and tumour necrosis geneity of protein preparations. Adiponectin assembles factor (TNF)a , raising the possibility that upregula- into trimers, hexamers and larger high molecular weight tion of human resistin in obesity is secondary to upregula- (HMW) structures, and is modified by hydroxylation and tion of inflammatory mediators. Human resistin promotes glycosylation ; the isoform composition of smooth muscle cell proliferation ] and endothelial cell different preparations varies depending upon the source activation supporting a possible proatherogenic role of protein. Full-length trimeric adiponectin can also be for resistin. The crystal structure of resistin has recently processed proteolytically to a 26 kDa form in mammalian been determined ; similar to adiponectin, resistin cells , and a 16 kDa tryptic digestion fragment forms multimeric complexes, and is present in mouse (globular adiponectin) has been used in numerous studies serum as two distinct isoforms, most likely trimers and An area of significant interest is the physiological hexamers. A mutant that is unable to form hexamers is effects of different adiponectin isoforms. The ratio of more potent in inducing insulin resistance than is the wild- HMW to total adiponectin is significantly decreased in type protein, suggesting processing-mediated activation patients with coronary artery disease [and increases . Although no receptors for resistin have been iden- upon treatment with thiazoledinediones . The tified, AMPK has been suggested as an important intra- HMW form mediates adiponectin effects in liver and cellular mediator . An emerging theme is a functional antagonism between resistin and adiponectin; it will be appear to be the primary mediators in heart, skeletal interesting to see whether different isoforms of resistin have distinct receptors and signaling activities as has been a preparation containing the 26 kDa processed fragment is more potent in the liver than is HMW adiponectin,possibly indicating an important role for proteolytic pro- cessing . Two adiponectin receptors, AdipoR1 and Angiopoietin-like protein 4 (ANGPTL4; FIAF/PGAR), a AdipoR2, have been identified . These receptors 50 kDa secreted protein highly expressed in adipose show a different affinity for globular and full-length tissue, is an angiopoietin family member most closely adiponectin, and differ in their tissue distribution, which related to ANGPTL3 . Expression of ANGPTL4 might explain the varying effects of different isoforms.
is directly regulated by members of the PPAR family of However, the affinity of these receptors for individual transcription factors ]; however, regulation by mammalian-derived adiponectin isoforms remains to be adipose mass or nutritional status is not consistently found determined. T-cadherin was recently suggested as an . Similar to ANGPTL3, overexpression of additional adiponectin receptor, on the basis of its ability ANPTL4 dramatically increases plasma triglyceride to bind HMW, but not trimeric, adiponectin [how- levels, possibly owing to direct inhibition of lipoprotein ever, its signaling abilities have not yet been examined. In lipase [It remains unclear, however, whether the addition to utilizing different receptors, different isoforms levels achieved by overexpression are physiologically of adiponectin can also activate distinct signal transduc- relevant. ANGPTL4 also has antiangiogenic activities tion pathways: in muscle, HMW adiponectin activates the . Structural studies and comparison to ANGPTL3 nuclear factor-kB pathway, whereas trimeric forms acti- suggests that the N-terminal coiled-coil domain is respon- sible for the triglyceride increase, whereas the C-terminalfibrinogen-like domain mediates the antiangiogenic effect . Interestingly, ANGPTL4 is processed in a Resistin is a 10 kDa protein that is secreted exclusively tissue- and species-specific manner , and this proces- by adipocytes in the mouse, but is expressed primarily in sing might enhance in vivo activity . The physiolo- macrophages and monocytes in humans [Resistin is gical role of ANGPTL4 remains to be elucidated.
Current Opinion in Pharmacology 2005, 5:122–128 enters the systemic circulation and mediates obesity- Visfatin (pre-B cell colony-enhancing factor), a 52 kDa associated metabolic and cardiovascular disorders. TNFa secreted protein, was recently added to the list of adipo- is an important mediator of inflammation and can induce cyte-derived factors . Although visfatin is widely several other inflammatory cytokines However, expressed, adipose visfatin is specific to the visceral depot, although circulating TNFa clearly is important for the and visfatin serum levels are positively correlated with development of insulin resistance in rodents, several visceral adiposity. Visfatin has effects similar to insulin, human studies did not show any beneficial effects on and can bind to and activate the insulin receptor at a site insulin sensitivity when circulating TNFa was neutralized distinct from insulin. Because the circulating levels of ], leading to the suggestion that TNFa acts in a para- visfatin are significantly lower than its affinity for the crine fashion. A recent report proposed that prolonged insulin receptor, visfatin might act in an auto- or paracrine treatment might be required to detect an effect of anti- manner, rather than in an endocrine fashion. Visfatin TNFa treatment on insulin sensitivity IL-6 is also expression is regulated in inflammation and sepsis, and secreted by adipose tissue at high levels  and is present visfatin can inhibit apoptosis in neutrophils, implying in the systemic circulation at higher levels than TNFa.
functions other than its insulin-mimetic effects .
IL-6 has been implicated in the regulation of insulinsensitivity and possibly body weight in rodents, and both peripheral and central actions of IL-6 might be involved Free fatty acids (FFAs) released from adipose tissue are a Although neutralizing anti-IL-6 antibodies have major source of plasma FFAs, and adipose tissue FFA been developed, their effect on obesity-associated disor- release as well as plasma FFA levels are elevated in obese ders has not yet been evaluated. The effects of inflamma- individuals Elevated plasma FFA levels can cause tory mediators on cells of interest to cardiovascular disease insulin resistance in muscle and liver; this is mediated have recently been reviewed . Adipose tissue-derived by intracellular fatty acid metabolites such as acyl-CoA complement components, most notably Factor D/Adipsin, and possibly ceramide [In addition, FFA infusion and the complement-derived factor acylation-stimulating decreases mitochondrial gene expression in muscle , suggesting that FFAs may modulate the metaboliccapacity of target tissues. FFAs have also been implicated in the pathogenesis of cardiomyopathy, and genetic mod- Plasminogen-activator inhibitor 1 (PAI-1) is a serine els that increase fatty acid delivery to heart recapitulate protease inhibitor that prevents plasmin generation and many of the features of diabetic cardiomyopathy .
plasmin-mediated events such as fibrinolysis and extra- Circulating FFAs are almost exclusively derived from cellular matrix degradation; elevated plasma PAI-1 levels subcutaneous adipose tissue [thus FFA lipolysis is are a known risk factor for thrombosis ]. PAI-1 might unlikely to account for the association between visceral also regulate fibrin deposition and vascular smooth mus- adiposity and metabolic syndrome disorders.
cle cell function through direct interactions with vitro-nectin ]. Although PAI-1 is synthesized by many cell types, adipose tissue is thought to be a major source of PAI-1 in the obese, and circulating PAI-1 levels correlate Obesity is well recognized as a state of low-grade inflamma- with visceral adiposity [Within obese adipose tissue, tion. Adipose tissue expresses a large variety of cytokines both adipocyte and non-adipocyte fractions produce PAI- and chemokines (e.g. TNFa, interleukin [IL]-1b, IL-6, IL- 1 , and TNFa is a key mediator of obesity-linked 8, IL-10, IL-1 receptor antagonist, monocyte chemotactic elevation of PAI-1 . Recent attention has focused on protein-1, macrophage migration inhibitory factor, macro- the possible role of PAI-1 in adipose tissue development.
phage inflammatory protein 1a, and macrophage inflam- In response to a high-fat diet, PAI-1-deficient mice show matory protein-related protein-2), as well as acute phase less weight gain, smaller adipocyte size and lower tissue reactants (e.g. serum amyloid A3, haptoglobin), and many of triglyceride levels compared with wild-type mice, these are known to be upregulated in both adipose tissue whereas energy expenditure and insulin sensitivity are and the systemic circulation in obesity Recent studies increased [Small molecule inhibitors of PAI-1 demonstrate that obesity is associated with macrophage have been developed and shown to be efficacious in infiltration into adipose tissue in both mice and humans animal models of thrombosis ]. It will be interesting [Many, but not all, of the factors cited above are to see whether these inhibitors also ameliorate obesity.
produced primarily by adipose tissue macrophages ratherthan adipocytes . Macrophages appear to Glucocorticoids and the renin-angiotensin be recruited from the circulation and adipocyte-derived factors might be involved in this process [ Localized glucocorticoid production by adipose tissue,mediated by the enzyme 11-b-hydroxysteroid dehydro- An important unanswered question is the degree to which genase 1 (11b-HSD1), is an important regulator of meta- any particular adipose-derived inflammatory mediator bolic syndrome components in rodents, and possibly Current Opinion in Pharmacology 2005, 5:122–128 Adipose tissue as an active endocrine organ: recent advances Gimeno and Klaman humans ]. Importantly, systemic glucocorticoid Havel PJ: Update on adipocyte hormones. Regulation ofenergy balance and carbohydrate/lipid metabolism.
levels are not elevated in rodent or human obesity, suggesting that glucocorticoids act within adipose tissue Ahima RS, Osei SY: Leptin Signaling. Physiol Behav 2004, or through the portal circulation on the liver. Mice over- expressing 11b-HSD1 in adipose tissue recapitulate all Minokoshi Y, Kim YB, Peroni OD, Fryer LG, Muller C, Carling D, components of the metabolic syndrome ], whereas mice Kahn BB: Leptin stimulates fatty-acid oxidation by activatingAMP-activated protein kinase. Nature 2002, 415:339-343.
with liver-specific overexpression of 11b-HSD1 displayhypertension, dyslipidemia and mild insulin resistance, Azilmaz E, Cohen P, Miyazaki M, Dobrzyn P, Ueki K, Fayzikhodjaeva G, Soukas AA, Kahn CR, Ntambi JM, but not adiposity ], demonstrating adipose-specific Socci ND, Friedman JM: Site and mechanism of leptin effects of glucocorticoids. Hypertension in mice over- action in a rodent form of congenital lipodystrophy.
J Clin Invest 2004, 113:414-424.
expressing 11b-HSD1 in either liver or adipose tissue Most recent in a series of papers that show that leptin improves hepatic involves activation of the local renin-angiotensin system steatosis through inhibition of stearoyl-CoA-desaturase via a central (RAS) . RAS is a hormonal cascade that governs vascular tone, fluid-electrolyte balance and blood pres- Huang W, Dedousis N, Bhatt BA, O’Doherty RM: Impaired sure [Adipose tissue expresses all of the components activation of phosphatidylinositol 3-kinase by leptin is a novelmechanism of hepatic leptin resistance in diet-induced of the RAS, and expression of several of these compo- obesity. J Biol Chem 2004, 279:21695-21700.
nents is positively correlated with adiposity ]. The Peelman F, Waelput W, Iserentant H, Lavens D, Eyckerman S, elevated expression of RAS components in adipose tissue Zabeau L, Tavernier J: Leptin: linking adipocyte metabolism might therefore be a reflection of increased local gluco- with cardiovascular and autoimmune diseases. Prog Lipid Res2004, 43:283-301.
corticoid action, particularly in visceral adipose tissue.
Schafer K, Halle M, Goeschen C, Dellas C, Pynn M, Loskutoff DJ, The role of the adipose tissue RAS on body weight Konstantinides S: Leptin promotes vascular remodeling and neointimal growth in mice. Arterioscler Thromb Vasc Biol 2004,24:112-117.
10. Konstantinides S, Schafer K, Neels JG, Dellas C, Loskutoff DJ: Inhibition of endogenous leptin protects mice from arterial Over the past few years, both the number of factors and venous thrombosis. Arterioscler Thromb Vasc Biol 2004, secreted by adipose tissue as well as the functions asso- ciated with known factors have expanded significantly. A 11. Barouch LA, Berkowitz DE, Harrison RW, O’Donnell CP, growing challenge is to determine which of the multitude Hare JM: Disruption of leptin signaling contributes tocardiac hypertrophy independently of body weight in mice.
of described effects for each factor are most important physiologically, and which factor(s) lend themselves to 12. Gorden P, Gavrilova O: The clinical uses of leptin.
Curr Opin Pharmacol 2003, 3:655-659.
human and mouse physiology (e.g. resistin) have been 13. Shimada K, Miyazaki T, Daida H: Adiponectin and described. Increased use of tissue-specific overexpression atherosclerotic disease. Clin Chim Acta 2004, 344:1-12.
and knockdown models in mice should help elucidate 14. Maeda N, Shimomura I, Kishida K, Nishizawa H, Matsuda M, direct versus indirect effects of individual factors on Nagaretani H, Furuyama N, Kondo H, Takahashi M, Arita Y et al.:Diet-induced insulin resistance in mice lacking adiponectin/ particular tissues; transcriptional profiling and proteomics technologies, particularly when applied to different adi- 15. Kubota N, Terauchi Y, Yamauchi T, Kubota T, Moroi M, Matsui J, pose depots, might help identify mechanisms of action. It Eto K, Yamashita T, Kamon J, Satoh H et al.: Disruption of is likely that additional adipose-derived factors will be adiponectin causes insulin resistance and neointimalformation. J Biol Chem 2002, 277:25863-25866.
identified; indeed, a mineralocorticoid-releasing factor] as well as a vascular-relaxing factor derived from 16. Combs TP, Pajvani UB, Berg AH, Lin Y, Jelicks LA, Laplante M, Nawrocki AR, Rajala MW, Parlow AF, periadventitial adipose tissue have been described [ Cheeseboro L et al.: A transgenic mouse with a deletion in the collagenous domain of adiponectin displayselevated circulating adiponectin and improved insulinsensitivity. Endocrinology 2004, 145:367-383.
17. Shibata R, Ouchi N, Ito M, Kihara S, Shiojima I, We would like to thank Vipin Suri and Mylene Perreault for critical Pimentel DR, Kumada M, Sato K, Schiekofer S, Ohashi K et al.: Adiponectin-mediated modulation ofhypertrophic signals in the heart. Nat Med 2004, Demonstrates enhanced pressure-overload-induced cardiac hypertro- Papers of particular interest, published within the annual period of phy in adiponectin-deficient mice, and shows that adiponectin over- expression can ameliorate several experimental models of cardiachypertrophy. Demonstrates activation of AMPK by trimeric adiponectin 18. Shibata R, Ouchi N, Kihara S, Sato K, Funahashi T, Walsh K: Kershaw EE, Flier JS: Adipose tissue as an endocrine organ.
Adiponectin stimulates angiogenesis in response to tissue J Clin Endocrinol Metab 2004, 89:2548-2556.
ischemia through stimulation of AMP-activated protein kinasesignaling. J Biol Chem 2004, 279:28670-28674.
Nawrocki AR, Scherer PE: The delicate balance between fat and Demonstrates that adiponectin-deficient mice have impaired angiogenic muscle: adipokines in metabolic disease and musculoskeletal repair of ischaemic hindlimbs; this phenotype could be reversed by inflammation. Curr Opin Pharmacol 2004, 4:281-289.
adiponectin overexpression in an AMPK-dependent manner.
Current Opinion in Pharmacology 2005, 5:122–128 19. Brakenhielm E, Veitonmaki N, Cao R, Kihara S, Matsuzawa Y, 33. Banerjee RR, Rangwala SM, Shapiro JS, Rich AS, Rhoades B, Zhivotovsky B, Funahashi T, Cao Y: Adiponectin-induced Qi Y, Wang J, Rajala MW, Pocai A, Scherer PE et al.: antiangiogenesis and antitumor activity involve caspase- Regulation of fasted blood glucose by resistin.
mediated endothelial cell apoptosis. Proc Natl Acad Sci USA Reports that mice deleted for resistin have lower fasting glucose andimproved glucose tolerance on a high-fat diet owing to decreased hepatic 20. Qi Y, Takahashi N, Hileman SM, Patel HR, Berg AH, Pajvani UB, glucose output. Demonstrates increased AMPK activity in livers of knock- Scherer PE, Ahima RS: Adiponectin acts in the brain to decrease body weight. Nat Med 2004, 10:524-529.
Demonstrates direct action of adiponectin on the hypothalamus, and 34. Satoh H, Nguyen MT, Miles PD, Imamura T, Usui I, Olefsky JM: suggests a role in hypothalamic regulation of energy homeostasis, pos- Adenovirus-mediated chronic ‘hyperresistinemia’ leads to in sibly involving the melanocortin pathway.
vivo insulin resistance in normal rats. J Clin Invest 2004,114:224-231.
21. Wang Y, Xu A, Knight C, Xu LY, Cooper GJ: Hydroxylation and glycosylation of the four conserved lysine residues in the 35. Sato N, Kobayashi K, Inoguchi T, Sonoda N, Imamura M, collagenous domain of adiponectin. J Biol Chem 2002, Sekiguchi N, Nakashima N, Nawata H: Adenovirus-mediated high expression of resistin causes dyslipidemia in mice.
Endocrinology 2005, 146:273-279.
22. Pajvani UB, Du X, Combs TP, Barg AH, Rajala MW, Schulthess T, Engel J, Brownlee M, Scherer PE: Structure-function studies 36. Rangwala SM, Rich AS, Rhoades B, Shapiro JS, Obici S, of the adipocyte-secreted hormone ACRP30/adiponectin.
Rossetti L, Lazar MA: Abnormal glucose homeostasis due to chronic hyperresistinemia. Diabetes 2004, Careful analysis of adiponectin isoform distribution and regulation in mouse serum. Demonstrates that a preparation containing a trimerand a 26 kDa fragment is more potent at lowering blood glucose in vivo 37. Rajala MW, Qi Y, Patel HR, Takahashi N, Banerjee R, and suppressing hepatic glucose output in vitro.
Pajvani UB, Sinha MK, Gingerich RL, Scherer PE,Ahima RS: Regulation of resistin expression and 23. Kobayashi H, Ouchi N, Kihara S, Walsh K, Kumada M, Abe Y, circulating levels in obesity, diabetes and fasting.
Funahashi T, Matsuzawa Y: Selective suppression of endothelial cell apoptosis by the high molecular weight form 38. Lehrke M, Reilly MP, Millington SC, Iqbal N, Rader DJ, of adiponectin. Circ Res 2004, 94:e27-e31.
Lazar MA: An inflammatory cascade leading to 24. Pajvani UB, Hawkins M, Combs TP, Rajala MW, Doebber T, hyperresistinemia in humans. PloS Med 2004, 1:e45.
Berger JP, Wagner JA, Wu M, Knopps A, Xiang AH et al.: Complex Demonstrates that resistin expression and secretion is induced by lipo- distribution, not absolute amount of adiponectin, correlates polysaccharide and TNFa in human macrophages. Lipopolysaccharide with thiazoledinedione-mediated improvement in insulin injection into humans increases plasma resistin levels approximately sensitivity. J Biol Chem 2004, 279:12152-12162.
Demonstrates that the ratio of HMW adiponectin to total adiponectin,rather than absolute amount of adiponectin, is decreased in diabetic mice 39. Calabro P, Samudio I, Willerson JT, Yeh ET: Resistin and humans; treatment with thialozidinediones increases the ratio in promotes smooth muscle cell proliferation through activation of extracellular signal-regulated kinase1/2 and phosphatidylinositol 3-kinase pathways.
25. Waki H, Yamauchi T, Kamon J, Ito Y, Uchida S, Kita S, Hara K, Hada Y, Vasseur F, Froguel P et al.: Impaired multimerization of 40. Verma S, Li SH, Wang CH, Fedak PW, Li RK, Weisel RD, human adiponectin mutants associated with diabetes. J Biol Mickle DA: Resistin promotes endothelial cell activation.
Further evidence of adipokine-endothelial interaction.
26. Tsao T-S, Tomas E, Murrey HE, Hug C, Lee DH, Ruderman NB, Heuser JE, Lodish HF: Role of disulfide bonds in ACRP30/ 41. Patel SD, Rajala MW, Rossetti L, Scherer PE, Shapiro L: adiponectin structure and signaling specificity. J Biol Chem Disulfide-dependent multimeric assembly of resistin family hormones. Science 2004, 304:1154-1158.
27. Yamauchi T, Kamon J, Ito Y, Tsuchida A, Yokomizo T, Kita S, Reports the crystal structures of mouse resistin and RELMb, and demon- Sugiyama T, Miyagishi M, Hara K, Tsunoda M et al.: Cloning of strates that mouse resistin circulates in serum as trimers and hexamers; a adiponectin receptors that mediate antidiabetic metabolic mutant that cannot assemble into hexamers has more potent effects on Reports the identification and characterization of two related receptors 42. Yoon JC, Chickering TW, Rosen ED, Dussault B, Qin Y, for adiponectin, AdipoR1 and AdipoR2, with distinct affinities and tissue Soukas A, Friedman JM, Holmes WE, Spiegelman BM: distribution. Demonstrates that both receptors activate AMPK.
Peroxisome proliferator-activated receptor g target 28. Hug C, Wang J, Ahmad NS, Bogan JS, Tsao T-S, Lodish HF: gene encoding a novel angiopoietin-related protein T-cadherin is a receptor for hexameric and high-molecular- associated with adipose differentiation. Mol Cell Biol 2000, weight forms of ACRP30/adiponectin. Proc Natl Acad Sci USA 43. Kersten S, Mandard S, Tan NS, Escher P, Metzger D, 29. Tsao T-S, Murrey HE, Hug C, Lee DH, Lodish HF: Oligomerization Chambon P, Gonzalez FJ, Desvergne B, Wahli W: state-dependent activation of NF-kB signaling pathway by Characterization of the fasting-induced adipose adipocyte complement-related protein of 30 kDa (ACRP30).
factor FIAF, a novel peroxisome proliferator-activated receptor target gene. J Biol Chem 2000,275:28488-28493.
30. Steppan CM, Lazar MA: The current biology of resistin.
44. Mandard S, Zandbergen F, Tan NS, Escher P, Patsouris D, Koenig W, Kleemann R, Bakker A, Veenman F, Wahli W et al.: 31. Blagoev B, Kratchmarova I, Nielsen MM, Fernandez MM, Voldby J, The direct peroxisome proliferator-activated receptor target Andersen JS, Kristiansen K, Pandey A, Mann M: Inhibition of fasting-induced adipose factor (FIAF/PGAR/ANGPTL4) is adipocyte differentiation by resistin-like molecule a. J Biol present in blood plasma as a truncated protein that is increased by fenofibrate treatment. J Biol Chem 2004,279:34411-34420.
32. Rajala MW, Obici S, Scherer PE, Rossetti L: Adipose-derived Demonstrates tissue- and species-specific processing of ANGPTL4.
resistin and gut-derived resistin-like molecule-b selectively Shows that an ANGPTL4 processed fragment is upregulated by fenofi- impair insulin action on glucose production. J Clin Invest 2003, Demonstrates that resistin or RELMb administration induces severe 45. Ge H, Yang G, Yu X, Pourbahrami T, Li C: Oligomerization hepatic, but not peripheral, insulin resistance in mice. Resistin levels state-dependent hyperlipidemic effect of angiopoietin-like required to see an effect were twice the normal serum levels.
protein 4. J Lipid Res 2004, 45:2071-2079.
Current Opinion in Pharmacology 2005, 5:122–128 Adipose tissue as an active endocrine organ: recent advances Gimeno and Klaman 46. Yoshida K, Shimizugawa T, Ono M, Furukawa H: Angiopoietin- 59. Clement K, Viguerie N, Poitou C, Carette C, Pelloux V, like protein 4 is a potent hyperlipidemia-inducing factor in Curat CA, Sicard A, Rome S, Benis A, Zucker JD et al.: mice and inhibitor of lipoprotein lipase. J Lipid Res 2002, Weight loss regulates inflammation-related genes in white adipose tissue of obese subjects. FASEB J 2004,18:1657-1669.
47. Ito Y, Oike Y, Yasunaga K, Hamada K, Miyata K, Matsumoto S-I, Sugano S, Tanihara H, Masuho Y, Suda T: Inhibition of 60. Fain JN, Madan AK, Hiler ML, Cheema P, Bahouth SW: angiogenesis and vascular leakiness by angiopoietin-related Comparison of the release of adipokines by adipose protein 4. Cancer Res 2003, 63:6651-6657.
tissue, adipose tissue matrix, and adipocytes from visceraland subcutaneous abdominal adipose tissues of obese 48. Ge H, Yang G, Huang L, Motola DL, Pourbahrami T, humans. Endocrinology 2004, 145:2273-2282.
Li C: Oligomerization and regulated proteolytic Careful assessment of the release of several factors, including leptin, processing of angiopoietin-like protein 4.
adiponectin, resistin, PAI-1, TNFa, IL-1, IL-6, IL-8, IL-10 and IL-1b, from different fractions of human adipose tissue. Moderately versus morbidly Demonstrates that adenoviral overexpression of ANGPTL4 increases plasma triglycerides through inhibition of very-low-density lipoproteinclearance. An N-terminal processed fragment is present in serum and 61. Ruan H, Lodish HF: Insulin resistance in adipose tissue: direct and indirect effects of tumor necrosis factor-alpha.
Cytokine Growth Factor Rev 2003, 14:447-455.
49. Fukuhara A, Matsuda M, Nishizawa M, Segawa K, Tanaka M, Kishimoto K, Matsuki Y, Murakami M, Ichisaka T, 62. Yazdani-Biuki B, Stelzl H, Brezinschek HP, Hermann J, Mueller T, Murakami H et al.: Visfatin: a protein secreted by visceral Krippl P, Graninger W, Wascher TC: Improvement of insulin fat that mimics the effects of insulin. Science 2005, sensitivity in insulin resistant subjects during prolonged treatment with the anti-TNF-alpha antibody infliximab.
Demonstrates that visfatin is preferentially expressed in visceral adipose tissue and that visfatin plasma levels correlate with visceral adipose massin humans. Visfatin injection or overexpression in mice lowers plasma 63. Wallenius V, Wallenius K, Ahren B, Rudling M, Carlsten H, glucose, whereas mice carrying one allele in which visfatin has been Dickson SL, Ohlsson C, Jansson J-O: Interleukin-6-deficient disrupted show increased plasma glucose levels. Visfatin activates the mice develop mature-onset obesity. Nat Med 2002, 8:75-79.
insulin receptor by binding to it at a site distinct from insulin.
64. Di Gregorio GB, Hensley L, Lu T, Ranganathan G, Kern PA: 50. Jia SH, Li Y, Parodo J, Kapus A, Fan L, Rotstein OD, Marshall JC: Lipid and carbohydrate metabolism in mice with targeted Pre-B cell colony-enhancing factor inhibits neutrophil mutation in the IL-6 gene: absence of development of apoptosis in experimental inflammation and clinical sepsis.
age-related obesity. Am J Physiol Endocrinol Metab 2004, 51. Lewis GF, Carpentier A, Adeli K, Giacca A: Disordered fat storage 65. Fernandez-Real JM, Ricart W: Insulin resistance and chronic and mobilization in the pathogenesis of insulin resistance and cardiovascular inflammatory syndrome. Endocr Rev 2003, type 2 diabetes. Endocr Rev 2002, 23:201-229.
52. Nielsen S, Guo Z, Johnson CM, Hensrud DD, Jensen MD: 66. Fay WP: Plasminogen activator inhibitor 1, fibrin, and the Splanchnic lipolysis in human obesity. J Clin Invest 2004, vascular response to injury. Trends Cardiovasc Med 2004, 53. Perseghin G, Petersen K, Shulman GI: Cellular mechanism of 67. Ma LJ, Mao SL, Taylor KL, Kanjanabuch T, Guan Y, insulin resistance: potential links with inflammation. Int J Obes Zhang Y, Brown NJ, Swift LL, McGuinness OP, Wasserman DH et al.: Prevention of obesity and insulinresistance in mice lacking plasminogen activator inhibitor 1.
54. Richardson DK, Kashyap S, Bajaj M, Cusi K, Mandarino SJ, Finlayson J, DeFronzo RA, Jenkinson CP, Mandarino LJ: Demonstrates that PAI-1-deficient mice are resistant to diet-induced Lipid infusion decreases the expression of nuclear encoded obesity and insulin resistance owing to an increase in energy expenditure.
mitochondrial genes and increases expression of extracellularmatrix genes in human skeletal muscle. J Biol Chem 2004 68. Schafer K, Fujisawa K, Konstantinides S, Loskutoff DJ: Disruption of the plasminogen activator inhibitor 1 gene reduces the Provides a link between increased plasma FFAs and downregulation of adiposity and improves the metabolic profile of genetically PGC-1 and OXPHOS gene expression in human muscle obese and diabetic ob/ob mice. FASEB J 2001, 15:1840-1842.
55. Chiu H-C, Kovacs A, Blanton RM, Han X, Courtois M, 69. Elokdah H, Abou-Gharbia M, Hennan JK, McFarlane G, Weinheimer CJ, Yamada KA, Brunet S, Xu H, Nerbonne JM et al.: Mugford CP, Krishnamurthy G, Crandall DL: Tiplaxtinin, Transgenic expression of FATP1 in the heart causes lipotoxic a novel, orally efficacious inhibitor of plasminogen cardiomyopathy. Circ Res 2004 [Epub ahead of print].
activator inhibitor-1: design, synthesis, and preclinical Most recent in a series of papers demonstrating that increased FFA characterization. J Med Chem 2004, 47:3491-3494.
supply can cause cardiac hypertrophy and heart failure.
70. Morton NM, Paterson JM, Masuzaki H, Holmes MC, Staels B, 56. Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Fievet C, Walker BR, Flier JS, Mullins JJ, Seckl JR: Novel adipose Nichols A, Ross JS, Tartaglia LA, Chen H: Chronic inflammation tissue-mediated resistance to diet-induced visceral obesity in in fat plays a crucial role in the development of obesity-related 11b-hydroxysteroid dehydrogenase type 1-deficient mice.
insulin resistance. J Clin Invest 2003, 112:1821-1830.
Demonstrates macrophage infiltration in adipose tissue in several mouse Careful analysis of the phenotype of 11b-HSD1-deficient mice in two models of obesity; macrophage infiltration can be reversed by treatment different genetic backgrounds shows decreased adiposity owing to increased energy expenditure, improved insulin sensitivity, improved lipidprofile, and beneficial changes in adipose expression of adiponectin, 57. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, resistin, leptin, peroxisome proliferator-activated receptor-g and TNFa.
Ferrante AW Jr: Obesity is associated with macrophageaccumulation in adipose tissue. J Clin Invest 2003, 71. Paterson JM, Morton NM, Fievet C, Kenyon CJ, Holmes MC, Staels B, Seckl JR, Mullins JJ: Metabolic syndrome without Demonstrates macrophage infiltration in adipose tissue in several mouse obesity: hepatic overexpression of 11b-hydroxysteroid models of obesity as well as in human obese patients. Demonstrates that dehydrogenase type 1 in transgenic mice. Proc Natl Acad Sci macrophages are derived from bone marrow precursors.
Demonstrates that liver-specific overexpression of 11b-HSD1 causes 58. Curat CA, Miranville A, Sengenes C, Diehl M, Tonus C, hypertension, dyslipidemia and moderate insulin resistance, but not Busse R, Bouloumie A: From blood monocytes to adipose tissue-resident macrophages: induction of diapedesisby human mature adipocytes. Diabetes 2004, 72. Masuzaki H, Yamamoto H, Kenyon CJ, Elmquist JK, Morton NM, Paterson JM, Shinyama H, Sharp MG, Fleming S, Mullins JJ et al.: Current Opinion in Pharmacology 2005, 5:122–128 Transgenic amplification of glucocorticoid action in adipose 74. Ehrhart-Bornstein M, Lamounier-Zepter V, Schraven A, tissue causes high blood pressure in mice. J Clin Invest 2003, Langenbach J, Willenberg HS, Barthel A, Hauner H, McCann SM, Scherbaum WA, Bornstein SR: Human adipocytes secrete Demonstrates that adipose-specific overexpression of 11b-HSD1 causes mineralocorticoid releasing factors. Proc Natl Acad Sci USA hypertension that is mediated through the RAS system.
73. Goossens GH, Blaak EE, van Baak MA: Possible involvement of 75. Gollasch M, Dubrovska G: Paracrine role for periadventitial the adipose tissue renin-angiotensin system in the adipose tissue in the regulation of arterial tone. Trends pathophysiology of obesity and obesity-related disorders.
Current Opinion in Pharmacology 2005, 5:122–128
3. Crosslauf der Breisgauer CITYSPORT Crosslaufserie 2012 am 1. Dezember 2012 in Wyhl am Kaiserstuhl ----------------------------------------------------------------------- Ergebnisliste WK U10 Schülerinnen W8 - 1000 m 1. Kapp, Milena 04 TV Endingen 4:18 2. Derigs, Valerie 04 TV Endingen 4:19 3. Rinklin, Yasmin 04 TV Endingen 4:40 4. Wellige, Mia 04 SV Gottenheim 4:41 5. Steigmann,