The Fasting-induced Adipose Factor/Angiopoietin-like Protein 4 Is Physically Associated with Lipoproteins and Governs Plasma Lipid Levels and Adiposity

Abstract

Proteins secreted from adipose tissue are increasingly recognized to play an important role in the regulation of glucose metabolism. However, much less is known about their effect on lipid metabolism. The fasting-induced adipose factor (FIAF/angiopoietin-like protein 4/peroxisome proliferator-activated receptor γ angiopoietin-related protein) was previously identified as a target of hypolipidemic fibrate drugs and insulin-sensitizing thiazolidinediones. Using transgenic mice that mildly overexpress FIAF in peripheral tissues we show that FIAF is an extremely powerful regulator of lipid metabolism and adiposity. FIAF overexpression caused a 50% reduction in adipose tissue weight, partly by stimulating fatty acid oxidation and uncoupling in fat. In addition, FIAF overexpression increased plasma levels of triglycerides, free fatty acids, glycerol, total cholesterol, and high density lipoprotein (HDL)-cholesterol. Functional tests indicated that FIAF overexpression severely impaired plasma triglyceride clearance but had no effect on very low density lipoprotein production. The effects of FIAF overexpression were amplified by a high fat diet, resulting in markedly elevated plasma and liver triglycerides, plasma free fatty acids, and plasma glycerol levels, and impaired glucose tolerance in FIAF transgenic mice fed a high fat diet. Remarkably, in mice the full-length form of FIAF was physically associated with HDL, whereas truncated FIAF was associated with low density lipoprotein. In human both full-length and truncated FIAF were associated with HDL. The composite data suggest that via physical association with plasma lipoproteins, FIAF acts as a powerful signal from fat and other tissues to prevent fat storage and stimulate fat mobilization. Our data indicate that disturbances in FIAF signaling might be involved in dyslipidemia. Proteins secreted from adipose tissue are increasingly recognized to play an important role in the regulation of glucose metabolism. However, much less is known about their effect on lipid metabolism. The fasting-induced adipose factor (FIAF/angiopoietin-like protein 4/peroxisome proliferator-activated receptor γ angiopoietin-related protein) was previously identified as a target of hypolipidemic fibrate drugs and insulin-sensitizing thiazolidinediones. Using transgenic mice that mildly overexpress FIAF in peripheral tissues we show that FIAF is an extremely powerful regulator of lipid metabolism and adiposity. FIAF overexpression caused a 50% reduction in adipose tissue weight, partly by stimulating fatty acid oxidation and uncoupling in fat. In addition, FIAF overexpression increased plasma levels of triglycerides, free fatty acids, glycerol, total cholesterol, and high density lipoprotein (HDL)-cholesterol. Functional tests indicated that FIAF overexpression severely impaired plasma triglyceride clearance but had no effect on very low density lipoprotein production. The effects of FIAF overexpression were amplified by a high fat diet, resulting in markedly elevated plasma and liver triglycerides, plasma free fatty acids, and plasma glycerol levels, and impaired glucose tolerance in FIAF transgenic mice fed a high fat diet. Remarkably, in mice the full-length form of FIAF was physically associated with HDL, whereas truncated FIAF was associated with low density lipoprotein. In human both full-length and truncated FIAF were associated with HDL. The composite data suggest that via physical association with plasma lipoproteins, FIAF acts as a powerful signal from fat and other tissues to prevent fat storage and stimulate fat mobilization. Our data indicate that disturbances in FIAF signaling might be involved in dyslipidemia. The fasting-induced adipose factor/angiopoietin-like protein 4 is physically associated with lipoproteins and governs plasma lipid levels and adiposity. VOLUME 281 (2006) PAGES 934-944Journal of Biological ChemistryVol. 281Issue 30PreviewPAGE 937: Full-Text PDF Open Access Obesity and associated diabetes mellitus type 2 have become major health concerns throughout the world. These ailments are intimately linked as excess weight greatly increases the likelihood of developing diabetes. Obesity also increases the risk for other clinical abnormalities such as hypertension and dyslipidemia. Although the positive association between obesity and several co-morbidities has been well established at the epidemiological level, the mechanisms behind these associations are much less clear. Much attention has been given to the role of plasma free fatty acids (FFAs), 3The abbreviations used are: FFAfree fatty acidFIAFfasting-induced adipose factorPPARperoxisome proliferator-activated receptorTGtriglycerideFIAF-TgFIAF transgenicVLDLvery low density lipoproteinHDLhigh density lipoproteinFPLCfast protein liquid chromatographyLPLlipoprotein lipaseWATwhite adipose tissueBATbrown adipose tissueHSLhormone-sensitive lipaseQ-PCRquantitative real time PCRHFDhigh fat dietLFDlow fat dietASPacylation-stimulating protein. which are elevated in the obese and able to disrupt cellular metabolism in several organs. However, it also has become evident that a variety of hormonal factors produced by adipose tissue can greatly affect organ functioning, especially at the metabolic and immunological levels (1Ahima R.S. Flier J.S. Trends Endocrinol. Metab. 2000; 11: 327-332Abstract Full Text Full Text PDF PubMed Scopus (1206) Google Scholar). Indeed, these so-called adipocytokines or adipokines are now known to affect diverse biological processes, ranging from energy intake, insulin sensitivity, and hepatic glucose production, to reproductive and immunological function (2Zhang Y. Proenca R. Maffei M. Barone M. Leopold L. Friedman J.M. Nature. 1994; 372: 425-432Crossref PubMed Scopus (11807) Google Scholar, 3Berg A.H. Combs T.P. Du X. Brownlee M. Scherer P.E. Nat. Med. 2001; 7: 947-953Crossref PubMed Scopus (2218) Google Scholar, 4Steppan C.M. Bailey S.T. Bhat S. Brown E.J. Banerjee R.R. Wright C.M. Patel H.R. Ahima R.S. Lazar M.A. Nature. 2001; 409: 307-312Crossref PubMed Scopus (4004) Google Scholar, 5Hotamisligil G.S. Shargill N.S. Spiegelman B.M. Science. 1993; 259: 87-91Crossref PubMed Scopus (6193) Google Scholar). Whereas the effects of adipocytokines on glucose homeostasis are becoming increasingly transparent, much less is known about how they regulate plasma lipid metabolism. free fatty acid fasting-induced adipose factor peroxisome proliferator-activated receptor triglyceride FIAF transgenic very low density lipoprotein high density lipoprotein fast protein liquid chromatography lipoprotein lipase white adipose tissue brown adipose tissue hormone-sensitive lipase quantitative real time PCR high fat diet low fat diet acylation-stimulating protein. A relatively poorly characterized adipocytokine that may be involved in regulation of plasma lipid metabolism is the fasting-induced adipose factor (FIAF), also known as PPARγ angiopoietin-related protein, angiopoietin-like protein 4, or hepatic fibrinogen/angiopoietin-related protein (6Kersten S. Mandard S. Tan N.S. Escher P. Metzger D. Chambon P. Gonzalez F.J. Desvergne B. Wahli W. J. Biol. Chem. 2000; 275: 28488-28493Abstract Full Text Full Text PDF PubMed Scopus (467) Google Scholar, 8Yoon J.C. Chickering T.W. Rosen E.D. Dussault B. Qin Y. Soukas A. Friedman J.M. Holmes W.E. Spiegelman B.M. Mol. Cell. Biol. 2000; 20: 5343-5349Crossref PubMed Scopus (339) Google Scholar, 9Kim I. Kim H.G. Kim H. Kim H.H. Park S.K. Uhm C.S. Lee Z.H. Koh G.Y. Biochem. J. 2000; 346: 603-610Crossref PubMed Scopus (232) Google Scholar, 10Yoshida K. Shimizugawa T. Ono M. Furukawa H. J. Lipid Res. 2002; 43: 1770-1772Abstract Full Text Full Text PDF PubMed Scopus (309) Google Scholar). FIAF is a glycoprotein of ∼50 kDa that belongs to the family of fibrinogen/angiopoietin-like proteins. In mice FIAF is most highly expressed in white and brown adipose tissue, and to a much lesser extent in other tissues such as heart, skeletal muscle, and liver (6Kersten S. Mandard S. Tan N.S. Escher P. Metzger D. Chambon P. Gonzalez F.J. Desvergne B. Wahli W. J. Biol. Chem. 2000; 275: 28488-28493Abstract Full Text Full Text PDF PubMed Scopus (467) Google Scholar, 8Yoon J.C. Chickering T.W. Rosen E.D. Dussault B. Qin Y. Soukas A. Friedman J.M. Holmes W.E. Spiegelman B.M. Mol. Cell. Biol. 2000; 20: 5343-5349Crossref PubMed Scopus (339) Google Scholar). The most compelling data to date link FIAF with regulation of lipid metabolism. FIAF was first identified as a target gene of the nuclear receptors PPARα and PPARγ, which govern lipid metabolism in liver and white adipose tissue, respectively (6Kersten S. Mandard S. Tan N.S. Escher P. Metzger D. Chambon P. Gonzalez F.J. Desvergne B. Wahli W. J. Biol. Chem. 2000; 275: 28488-28493Abstract Full Text Full Text PDF PubMed Scopus (467) Google Scholar, 8Yoon J.C. Chickering T.W. Rosen E.D. Dussault B. Qin Y. Soukas A. Friedman J.M. Holmes W.E. Spiegelman B.M. Mol. Cell. Biol. 2000; 20: 5343-5349Crossref PubMed Scopus (339) Google Scholar). Subsequent studies employing adenoviral-mediated overexpression of FIAF or injection of recombinant FIAF have shown that FIAF potently elevates plasma triglyceride (TG) levels (10Yoshida K. Shimizugawa T. Ono M. Furukawa H. J. Lipid Res. 2002; 43: 1770-1772Abstract Full Text Full Text PDF PubMed Scopus (309) Google Scholar, H. X. T. J. Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar, A. Y. J. B. S. A. PubMed Scopus Google Scholar). is by of lipoprotein the that is for plasma (10Yoshida K. Shimizugawa T. Ono M. Furukawa H. J. Lipid Res. 2002; 43: 1770-1772Abstract Full Text Full Text PDF PubMed Scopus (309) Google Scholar, H. X. T. J. Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar, X. H. S. A. PubMed Scopus Google Scholar). to a FIAF may also potently plasma glucose In as well as in adenoviral-mediated overexpression of FIAF was to and glucose tolerance A. Y. J. B. S. A. PubMed Scopus Google Scholar). In to lipid FIAF has also been associated with of FIAF is in both and which via the factor H. T. G.Y. J. Mol. Cell. 2002; Full Text PDF PubMed Scopus Google Scholar, S. A. J. J. M. J.M. P. S. J. Full Text Full Text PDF PubMed Scopus Google Scholar). FIAF is expressed in especially in the and has been as a for In the FIAF is able to a S. A. J. J. M. J.M. P. S. J. Full Text Full Text PDF PubMed Scopus Google Scholar). In have a function to FIAF Y. Y. K. K. K. S. S. H. Y. T. Res. Google Scholar). the role of FIAF in the role of we the effect of FIAF overexpression in a transgenic Our data indicate that which is physically associated with plasma lipoproteins, is an important of plasma and clearance at levels of In addition, it adipose tissue In to a A. Y. J. B. S. A. PubMed Scopus Google in FIAF overexpression was associated with of glucose we that the effects of FIAF overexpression were amplified by a high fat diet. of FIAF FIAF gene was amplified by PCR from of and and the the The of the was by The gene was with and behind the fatty protein) of The the gene were with and and was on from by and which the and the and and for the mice were on a were in with and in the fed were at the of the in the were of for at the of the the time of were between 2 and 4 of the diet mice were fed with a low or high fat diet for The or energy in the form of fat or was via were and in liquid Lipid for were of by was by 2 for plasma for were via the with was by at several time for plasma a fast mice were with glucose on on low fat was by and and glucose was the a fast mice were with insulin was by and and glucose was was from by for at The plasma glucose was a from the and tissue triglycerides, plasma glycerol, and plasma total and were from the free fatty acids were a from the were fast protein liquid chromatography of plasma or human plasma was a and at a of with The was in and triglyceride and levels were and lipoprotein lipase and hepatic lipase levels were in plasma as D. J. Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar). was from tissues with of total was with was with on a were to a PCR of of the was by and of of PCR of used are on on and tissues was as previously (6Kersten S. Mandard S. Tan N.S. Escher P. Metzger D. Chambon P. Gonzalez F.J. Desvergne B. Wahli W. J. Biol. Chem. 2000; 275: 28488-28493Abstract Full Text Full Text PDF PubMed Scopus (467) Google Scholar, S. Tan N.S. Escher P. D. W. R. A. Wahli W. M. S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). FIAF were the of the and proteins. was from adipose tissue of and mice and was and the by on a of was used for and of were to data were by and the gene were to the with an target was by were by the of human were by the of the role of FIAF in metabolism we transgenic mice that FIAF the of the at adipose overexpression A. B. Spiegelman B.M. S. A. PubMed Scopus Google Scholar). transgenic were are from transgenic that of to levels to FIAF was in white and brown adipose tissue in skeletal and heart, in liver and of the in skeletal and is to the of the which the FIAF we that gene is to via a S. Tan N.S. Escher P. D. W. R. A. Wahli W. M. S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). that are FIAF overexpression in The in FIAF between and mice was at the protein level, as by on adipose tissue A in and which are the and most of in plasma S. Tan N.S. Escher P. D. W. R. A. Wahli W. M. S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google was in plasma of mice and data mice less their was to a in white adipose tissue weight, which was in mice In liver weight as well as the weight of other was in the whereas weight of brown adipose tissue was weight was to a in was the of intake, which was between the of mice These data indicate that FIAF overexpression in of fat. and a of the of the plasma lipid were in both fed and A in plasma levels was in the which was of their In addition, plasma glycerol, total cholesterol, and were elevated in the mice in the whereas glucose was FIAF overexpression has effects on plasma lipid of lipoproteins that the in plasma in the was to the whereas the in was in both and a in and protein in the in that the of in plasma is increased in these mice be that in mice for of total in we markedly increased and protein in the in a in the of plasma and are elevated in plasma of mice and mice for was used for lipoprotein by were for and of protein is of plasma lipoprotein of plasma lipoprotein and plasma levels in mice can be to increased or impaired between these a and an were greatly elevated plasma levels in no in production, by the of of plasma injection with was between and mice In an lipid between the of Whereas in mice of caused a and in plasma in mice plasma levels of plasma were also increased in mice These data show that clearance of lipoproteins is severely by FIAF clearance of plasma can be caused by of lipoprotein lipase of total was total hepatic lipase and levels were in levels of these were very between and mice and In addition, and tissue protein of in adipose tissue or skeletal were by FIAF overexpression and data that FIAF may in total is by of by recombinant FIAF (10Yoshida K. Shimizugawa T. Ono M. Furukawa H. J. Lipid Res. 2002; 43: 1770-1772Abstract Full Text Full Text PDF PubMed Scopus (309) Google Scholar). these data indicate that FIAF overexpression markedly plasma clearance and plasma levels, most via of FIAF with that are physically associated with plasma lipoproteins, and are known to FIAF overexpression increases plasma and levels, we that FIAF may be physically associated with or HDL. is the was on the plasma a well characterized (6Kersten S. Mandard S. Tan N.S. Escher P. Metzger D. Chambon P. Gonzalez F.J. Desvergne B. Wahli W. J. Biol. Chem. 2000; 275: 28488-28493Abstract Full Text Full Text PDF PubMed Scopus (467) Google Scholar). Remarkably, it was that full-length FIAF was in the but in the A to truncated S. Tan N.S. Escher P. D. W. R. A. Wahli W. M. S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google was in the first that with that truncated FIAF is in the full-length and truncated FIAF were in the and of mice Remarkably, in human plasma full-length truncated FIAF and FIAF the by from the were associated with and the data indicate that in mice the full-length form of FIAF is physically associated with HDL, whereas truncated FIAF is associated with In human both full-length and truncated FIAF are associated with HDL. The that plasma FIAF and levels may be Indeed, in a of we a positive between plasma levels of and In no was for plasma or in of and in plasma and glycerol in mice be by of plasma but is of adipose tissue is by hormone-sensitive lipase which is by insulin and of was in the that of other that affect plasma and glycerol PPARγ, and glycerol of adipose triglyceride lipase a adipose tissue lipase that in with S. Kim J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, R. R. M. A. A. R. Science. PubMed Scopus Google was 50% increased in the the elevated plasma and glycerol levels are caused by via of of plasma by the fatty acids that the can be and as or can be for of the PPARγ and the nuclear receptor both of which are involved in were in of mice of in has been shown to stimulate metabolism and of the uncoupling protein whereas PPARα is known to a of involved in the fatty acid S. M. S. Cell. Mol. PubMed Scopus Google Scholar, P. Park R. Wright M. Spiegelman B.M. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). we that of uncoupling protein was elevated in of mice in and by indicated that the of PPARα target involved in fatty acid oxidation were in of mice of was whereas which is involved in and the most highly expressed in adipose tissue, was in FIAF overexpression in gene in with oxidation of fatty acids at the of of of and mice involved in energy metabolism are by PPARα and fatty acid oxidation metabolism acid acid metabolism receptor involved in metabolism Open in a of plasma has been associated with impaired of plasma Indeed, we that glucose tolerance was mildly but in mice whereas the to insulin was be that in which is the for the glucose tolerance is glucose tolerance was to of in liver and skeletal muscle, which were in mice and and in the effect of FIAF on plasma it can be that the effects of FIAF overexpression become much of fat such as high fat is the and mice were fed a high fat diet or low fat diet for Whereas had effect on plasma in it markedly elevated plasma in mice whereas had effect on glucose tolerance in which are known to be to K. Y. Res. PubMed Scopus Google Scholar, S. J. A. I. S. P. P. I. Biochem. Res. 2001; PubMed Scopus Google it caused a of glucose tolerance in mice A effect of was for plasma and glycerol levels, elevated adipose tissue and plasma levels were elevated by in mice with mice plasma with elevated adipose is to fat to the Indeed, the of plasma lipid levels in mice was associated with in as by quantitative and and liver was to increased the and fatty acid were by in and mice these data indicate that the effects of FIAF overexpression on plasma lipid metabolism. these by plasma and stimulating adipose tissue FIAF increases the of lipid to the liver to In the it has become increasingly that adipocytokines play a very important role in excess adipose tissue to of glucose Indeed, several adipocytokines have been shown to affect peripheral and hepatic insulin However, data on the effect of adipocytokines on plasma lipid and lipoprotein metabolism. The is acylation-stimulating protein which is produced by adipose tissue and plasma metabolism. in mice the gene which is the for as well as studies with mice with recombinant have shown that and storage of plasma in fat I. K. J. PubMed Google Scholar, I. K. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). to and other data show that in mice FIAF is a powerful of plasma In addition, in adipose tissue FIAF resulting in elevated plasma and glycerol levels, and may fatty acid metabolism and major of is fat the in plasma clearance is by FIAF most increases plasma levels in mice by which is by in studies and FIAF (10Yoshida K. Shimizugawa T. Ono M. Furukawa H. J. Lipid Res. 2002; 43: 1770-1772Abstract Full Text Full Text PDF PubMed Scopus (309) Google Scholar). The effect of FIAF on is to that of and and that of and the of is also physically associated with HDL. data suggest that plasma by lipoproteins to M. B. M. A. J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). However, it is the physical association of FIAF with is for can be that of is by truncated FIAF to A to but the effect can be from as it in with and to prevent of by FIAF and effect is on to FIAF may function in as in human FIAF is associated with HDL. for the impaired in mice may be elevated plasma which have been shown to potently via mechanisms M.A. M. J. Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar). In the plasma were elevated in fed and as well as the lipid the effect of FIAF on plasma clearance is by of the or and mechanisms behind of be the of the elevated levels in is highly to hepatic lipase and and impaired of these of plasma J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar, J. H. J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, W. J.S. J.M. J. PubMed Scopus Google Scholar, K. M. C.M. L. S. A. PubMed Scopus Google it is that FIAF may target hepatic lipase and lipase as is to the mechanisms behind the elevated plasma and markedly elevated plasma and levels in The increased levels of plasma and glycerol in mice are in with the in plasma FIAF injection (10Yoshida K. Shimizugawa T. Ono M. Furukawa H. J. Lipid Res. 2002; 43: 1770-1772Abstract Full Text Full Text PDF PubMed Scopus (309) Google that FIAF adipose tissue effect of FIAF on we of via an In the of the adipose triglyceride lipase was elevated by 50% in mice S. Kim J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, R. R. M. A. A. R. Science. PubMed Scopus Google Scholar). FIAF may stimulate via of studies have shown that adenoviral-mediated overexpression of FIAF or injection of recombinant FIAF potently elevates plasma triglyceride levels (10Yoshida K. Shimizugawa T. Ono M. Furukawa H. J. Lipid Res. 2002; 43: 1770-1772Abstract Full Text Full Text PDF PubMed Scopus (309) Google Scholar, H. X. T. J. Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar). Although these studies established FIAF as a of plasma levels in they of the of in FIAF is about the is that a in FIAF in peripheral tissues is to plasma to to to on the of with the severely impaired plasma clearance lipid that FIAF is an extremely powerful regulator of plasma levels in In the mice impaired plasma clearance can be to adipose K. H. R. S. R. J. PubMed Scopus Google Scholar). However, the of the excess they to be in at of low fat diet. on gene which show increased of a variety of involved in fatty acid metabolism and and uncoupling protein we that these were studies be to The that the effects of FIAF overexpression are much in mice fed a high fat diet. In which are known to be to high fat high fat had effect on plasma and glycerol as well as on glucose but markedly these in mice we that high fat plasma FIAF levels in mice (6Kersten S. Mandard S. Tan N.S. Escher P. Metzger D. Chambon P. Gonzalez F.J. Desvergne B. Wahli W. J. Biol. Chem. 2000; 275: 28488-28493Abstract Full Text Full Text PDF PubMed Scopus (467) Google which in of the may to the clearance of plasma peripheral and their hepatic and plasma FIAF overexpression the resulting in markedly elevated plasma levels and a fatty A. Y. J. B. S. A. PubMed Scopus Google that adenoviral-mediated overexpression of FIAF a in plasma glucose and glucose In we show that FIAF overexpression has no effect on plasma glucose levels and glucose a high fat diet. The for is but may be to the of which was in as well as the of overexpression peripheral previously that human liver the truncated form of whereas human adipose tissue the full-length form S. Tan N.S. Escher P. D. W. R. A. Wahli W. M. S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). can be that these may have glucose and lipid to has been for and full-length Scherer P.E. J. Med. PubMed Scopus Google Scholar). be was in A. M. A. D. Y. P. PubMed Scopus Google no effect of overexpression or FIAF on plasma glucose In with we of hepatic by FIAF is a high fat diet. The hepatic with the markedly elevated plasma levels may to the impaired glucose tolerance in mice on a high fat diet. important that is is FIAF acts in the tissue it is an or or it also organs. is the effects of FIAF on lipid and glucose metabolism are by of or an is to in a plasma level, an as and in (10Yoshida K. Shimizugawa T. Ono M. Furukawa H. J. Lipid Res. 2002; 43: 1770-1772Abstract Full Text Full Text PDF PubMed Scopus (309) Google that FIAF acts in can be that in to other adipocytokines FIAF is able to a to be Although FIAF is most highly expressed in adipose tissue, it may important effects in other tissues as it was that of FIAF in the is for the in adipose by H. T. Koh G.Y. A. S. A. PubMed Scopus Google Scholar). The data that FIAF is an important of the effects of the a that link with in it has become that angiopoietin-like are a of that play an important role in the regulation of lipid and glucose metabolism. studies indicate that overexpression or of and angiopoietin-related factor which are produced by the in major disturbances at the of lipid metabolism and energy homeostasis Y. M. K. T. T. Y. T. Y. Y. H. T. K. S. J. M. H. Y. T. T. Nat. Med. 11: PubMed Scopus Google Scholar, R. Y. Ono M. M. H. T. H. Furukawa H. Nat. 2002; PubMed Scopus Google Scholar, T. M. M. Y. H. R. M. I. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). angiopoietin-like have become very for the of and In FIAF a powerful signaling from fat and other tissues that plasma clearance and adipose mobilization. of the between human plasma FIAF and are to the role of FIAF in lipid metabolism in it can be that FIAF may be involved in adipose tissue to regulation of plasma lipid levels, and that in FIAF signaling may to of dyslipidemia. and for