Dual actions of fibroblast growth factor 19 on lipid metabolism

Abstract

Elevated triglyceride (TG) and cholesterol levels are risk factors for cardiovascular disease and are often associated with diabetes and metabolic syndrome. Recent reports suggest that fibroblast growth factor (FGF)19 and FGF21 can dramatically improve metabolic dysfunction, including hyperglycemia, hypertriglyceridemia, and hypercholesterolemia. Due to their similar receptor specificities and co-receptor requirements, FGF19 and FGF21 share many common properties and have been thought to be interchangeable in metabolic regulation. Here we directly compared how pharmacological administration of recombinant FGF19 or FGF21 proteins affect metabolism in B6.V-Lepob/J leptin-deficient mice. FGF19 and FGF21 equally improved glucose parameters; however, we observed increased serum TG and cholesterol levels after treatment with FGF19 but not with FGF21. Increases in serum TGs were also observed after a 4-day treatment with FGF19 in C57BL6/J mice on a high-fat diet. This is in contrast to many literature reports that showed significant improvements in hyperlipidemia after chronic treatment with FGF19 or FGF21 in high-fat diet models. We propose that FGF19 has lipid-raising and lipid-lowering actions mediated through different FGF receptors and target tissues, and the results described here provide a potential mechanism that may explain the inconsistency in the reported effects of FGF19 on lipid metabolism. Elevated triglyceride (TG) and cholesterol levels are risk factors for cardiovascular disease and are often associated with diabetes and metabolic syndrome. Recent reports suggest that fibroblast growth factor (FGF)19 and FGF21 can dramatically improve metabolic dysfunction, including hyperglycemia, hypertriglyceridemia, and hypercholesterolemia. Due to their similar receptor specificities and co-receptor requirements, FGF19 and FGF21 share many common properties and have been thought to be interchangeable in metabolic regulation. Here we directly compared how pharmacological administration of recombinant FGF19 or FGF21 proteins affect metabolism in B6.V-Lepob/J leptin-deficient mice. FGF19 and FGF21 equally improved glucose parameters; however, we observed increased serum TG and cholesterol levels after treatment with FGF19 but not with FGF21. Increases in serum TGs were also observed after a 4-day treatment with FGF19 in C57BL6/J mice on a high-fat diet. This is in contrast to many literature reports that showed significant improvements in hyperlipidemia after chronic treatment with FGF19 or FGF21 in high-fat diet models. We propose that FGF19 has lipid-raising and lipid-lowering actions mediated through different FGF receptors and target tissues, and the results described here provide a potential mechanism that may explain the inconsistency in the reported effects of FGF19 on lipid metabolism. Fibroblast growth factor (FGF)19 belongs to a distinct subfamily of FGFs that play important roles in metabolic regulation (1Wu X. Li Y. Role of FGF19 induced FGFR4 activation in the regulation of glucose homeostasis.Aging (Albany NY). 2009; 1: 1023-1027Crossref PubMed Scopus (23) Google Scholar, 2Wu X. Li Y. Therapeutic utilities of fibroblast growth factor 19.Expert Opin. Ther. Targets. 2011; 15: 1307-1316Crossref PubMed Scopus (23) Google Scholar). A diminished affinity toward heparan sulfate allows FGF19 to circulate and function as an endocrine hormone (3Asada M. Shinomiya M. Suzuki M. Honda E. Sugimoto R. Ikekita M. Imamura T. Glycosaminoglycan affinity of the complete fibroblast growth factor family.Biochim. Biophys. Acta. 2009; 1790: 40-48Crossref PubMed Scopus (97) Google Scholar). In lieu of heparan sulfate binding, FGF19 requires a protein cofactor, βKlotho, to effectively interact with and activate FGF receptors (4Kurosu H. Choi M. Ogawa Y. Dickson A.S. Goetz R. Eliseenkova A.V. Mohammadi M. Rosenblatt K.P. Kliewer S.A. Kuro-o M. Tissue-specific expression of betaKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21.J. Biol. Chem. 2007; 282: 26687-26695Abstract Full Text Full Text PDF PubMed Scopus (593) Google Scholar, 5Lin B.C. Wang M. Blackmore C. Desnoyers L.R. Liver-specific activities of FGF19 require Klotho beta.J. Biol. Chem. 2007; 282: 27277-27284Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar, 6Wu X. Ge H. Gupte J. Weiszmann J. Shimamoto G. Stevens J. Hawkins N. Lemon B. Shen W. Xu J. et al.Co-receptor requirements for fibroblast growth factor-19 signaling.J. Biol. Chem. 2007; 282: 29069-29072Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar). The requirement for a co-receptor is a unique feature common to the FGF19 subfamily and is further exemplified by another subfamily member, FGF21, which also lacks heparan sulfate affinity and uses βKlotho as its co-receptor (4Kurosu H. Choi M. Ogawa Y. Dickson A.S. Goetz R. Eliseenkova A.V. Mohammadi M. Rosenblatt K.P. Kliewer S.A. Kuro-o M. Tissue-specific expression of betaKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21.J. Biol. Chem. 2007; 282: 26687-26695Abstract Full Text Full Text PDF PubMed Scopus (593) Google Scholar). Consistent with their shared ability to use the same co-receptor for signaling, there is extensive overlap in the reported pharmacological effects of FGF19 and FGF21. FGF19 and FGF21 transgenic mice, as well as chronic administration of recombinant FGF19 or FGF21 proteins, similarly lowered serum glucose, triglyceride (TG), and cholesterol levels and improved insulin sensitivity and reduced body weight in high-fat diet-induced obesity models (7Dutchak P.A. Katafuchi T. Bookout A.L. Choi J.H. Yu R.T. Mangelsdorf D.J. Kliewer S.A. Fibroblast growth factor-21 regulates PPARgamma activity and the antidiabetic actions of thiazolidinediones.Cell. 2012; 148: 556-567Abstract Full Text Full Text PDF PubMed Scopus (428) Google Scholar, 8Fu L. John L.M. Adams S.H. Yu X.X. Tomlinson E. Renz M. Williams P.M. Soriano R. Corpuz R. Moffat B. et al.Fibroblast growth factor 19 increases metabolic rate and reverses dietary and leptin-deficient diabetes.Endocrinology. 2004; 145: 2594-2603Crossref PubMed Scopus (436) Google Scholar, 9Kharitonenkov A. Shiyanova T.L. Koester A. Ford A.M. Micanovic R. Galbreath E.J. Sandusky G.E. Hammond L.J. Moyers J.S. Owens R.A. et al.FGF-21 as a novel metabolic regulator.J. Clin. Invest. 2005; 115: 1627-1635Crossref PubMed Scopus (1618) Google Scholar). Chronic treatment with FGF19 or FGF21 similarly reduced blood glucose levels and improved glucose disposal in ob/ob (B6.V-Lepob/J) leptin-deficient mice; however, plasma TG and cholesterol levels after treatment with FGF19 have not been reported in this model (8Fu L. John L.M. Adams S.H. Yu X.X. Tomlinson E. Renz M. Williams P.M. Soriano R. Corpuz R. Moffat B. et al.Fibroblast growth factor 19 increases metabolic rate and reverses dietary and leptin-deficient diabetes.Endocrinology. 2004; 145: 2594-2603Crossref PubMed Scopus (436) Google Scholar, 9Kharitonenkov A. Shiyanova T.L. Koester A. Ford A.M. Micanovic R. Galbreath E.J. Sandusky G.E. Hammond L.J. Moyers J.S. Owens R.A. et al.FGF-21 as a novel metabolic regulator.J. Clin. Invest. 2005; 115: 1627-1635Crossref PubMed Scopus (1618) Google Scholar). The common co-receptor for FGF19 and FGF21, βKlotho, is a single-pass transmembrane protein with two homologous extracellular domains that share sequence homology to β-glucosidases in bacteria and plants (10Ito S. Kinoshita S. Shiraishi N. Nakagawa S. Sekine S. Fujimori T. Nabeshima Y.I. Molecular cloning and expression analyses of mouse betaklotho, which encodes a novel Klotho family protein.Mech. Dev. 2000; 98: 115-119Crossref PubMed Scopus (260) Google Scholar). βKlotho has a short intracellular domain and is unlikely to signal by itself. Its primary role is believed to mediate interactions between these two FGF molecules and FGF receptors (FGFR) to activate FGFR tyrosine kinase activity (11Ogawa Y. Kurosu H. Yamamoto M. Nandi A. Rosenblatt K.P. Goetz R. Eliseenkova A.V. Mohammadi M. Kuro-o M. BetaKlotho is required for metabolic activity of fibroblast growth factor 21.Proc. Natl. Acad. Sci. USA. 2007; 104: 7432-7437Crossref PubMed Scopus (479) Google Scholar). βKlotho interacts with only four of the seven major FGFRs, the “c” isoforms of FGFR1, -2, -3. and -4 (11Ogawa Y. Kurosu H. Yamamoto M. Nandi A. Rosenblatt K.P. Goetz R. Eliseenkova A.V. Mohammadi M. Kuro-o M. BetaKlotho is required for metabolic activity of fibroblast growth factor 21.Proc. Natl. Acad. Sci. USA. 2007; 104: 7432-7437Crossref PubMed Scopus (479) Google Scholar). FGF19 and FGF21 can activate FGFR1c, -2c, and -3c complexed with βKlotho in vitro (4Kurosu H. Choi M. Ogawa Y. Dickson A.S. Goetz R. Eliseenkova A.V. Mohammadi M. Rosenblatt K.P. Kliewer S.A. Kuro-o M. Tissue-specific expression of betaKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21.J. Biol. Chem. 2007; 282: 26687-26695Abstract Full Text Full Text PDF PubMed Scopus (593) Google Scholar, 6Wu X. Ge H. Gupte J. Weiszmann J. Shimamoto G. Stevens J. Hawkins N. Lemon B. Shen W. Xu J. et al.Co-receptor requirements for fibroblast growth factor-19 signaling.J. Biol. Chem. 2007; 282: 29069-29072Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar, 11Ogawa Y. Kurosu H. Yamamoto M. Nandi A. Rosenblatt K.P. Goetz R. Eliseenkova A.V. Mohammadi M. Kuro-o M. BetaKlotho is required for metabolic activity of fibroblast growth factor 21.Proc. Natl. Acad. Sci. USA. 2007; 104: 7432-7437Crossref PubMed Scopus (479) Google Scholar, 12Suzuki M. Uehara Y. Motomura-Matsuzaka K. Oki J. Koyama Y. Kimura M. Asada M. Komi-Kuramochi A. Oka S. Imamura T. betaKlotho is required for fibroblast growth factor (FGF) 21 signaling through FGF receptor (FGFR) 1c and FGFR3c.Mol. Endocrinol. 2008; 22: 1006-1014Crossref PubMed Scopus (280) Google Scholar, 13Wu X. Ge H. Lemon B. Vonderfecht S. Baribault H. Weiszmann J. Gupte J. Gardner J. Lindberg R. Wang Z. et al.Separating mitogenic and metabolic activities of fibroblast growth factor 19 (FGF19).Proc. Natl. Acad. Sci. USA. 2010; 107: 14158-14163Crossref PubMed Scopus (77) Google Scholar). Recent results using an engineered FGF19 variant with altered receptor specificity biased toward FGFR1c/βKlotho and with novel mimetic proteins that specifically activate only the FGFR1c/βKlotho receptor complex demonstrate the essential role this receptor complex plays in mediating the effects of FGF19 and FGF21 on regulating the glucose and lipid metabolism as well as energy expenditure (14Ge H. Baribault H. Vonderfecht S. Lemon B. Weiszmann J. Gardner J. Lee K.J. Gupte J. Mookherjee P. Wang M. et al.Characterization of a FGF19 variant with altered receptor specificity revealed a central role for FGFR1c in the regulation of glucose metabolism.PLoS ONE. 2012; 7: e33603Crossref PubMed Scopus (31) Google Scholar). Despite extensive similarities in their in vivo and in vitro pharmacology, differences exist between FGF19 and FGF21. FGF19 can also signal through FGFR4, but FGF21 cannot (4, 15). The ability of FGF19 to activate FGFR4, the predominant receptor expressed in the liver, has been linked to its regulation of has been that FGF19 is an target G. J. M. Wang Kliewer S.A. et of a novel growth signal for the of Dev. PubMed Scopus Google Scholar). increases in levels activate in which in expression and of FGF19 as the signal to expression of cholesterol the for the of This in the activation of FGFR4, a on G. J. M. Wang Kliewer S.A. et of a novel growth signal for the of Dev. PubMed Scopus Google Scholar). In FGF19 has been to affect expression of that may to in A.L. S. C. A. J. A.S. J. FGF19 regulates glucose and metabolism and ONE. 2011; PubMed Scopus Google Scholar). that the of cholesterol is through to and FGF19 treatment be not only to levels but also to cholesterol In are to affect TG A in levels to or treatment with in to TG levels B. K. K. B. of and on the metabolism of triglyceride in Full Text PDF PubMed Google Scholar, K. of of the of on the of Full Text PDF PubMed Scopus Google Scholar, a to the use of J. Full Text PDF PubMed Scopus Google Scholar, C. G. S. A. et cholesterol has a Clin. Invest. PubMed Scopus Google Scholar). the effects of increased cholesterol and TG levels to or in and by treatment with FGF19 may to be with the observed of these in FGF19 transgenic mice and in mice with recombinant FGF19 protein (8Fu L. John L.M. Adams S.H. Yu X.X. Tomlinson E. Renz M. Williams P.M. Soriano R. Corpuz R. Moffat B. et al.Fibroblast growth factor 19 increases metabolic rate and reverses dietary and leptin-deficient diabetes.Endocrinology. 2004; 145: 2594-2603Crossref PubMed Scopus (436) Google Scholar, E. L. John L. B. X. Renz M. L. et mice fibroblast growth factor-19 increased metabolic rate and PubMed Scopus Google Scholar). In the we compared the effects of FGF21, and a variant of FGF19 that only FGFR4 on metabolism in models. results revealed a of FGF19 and suggest that FGF19 has a function in lipid metabolism. FGF21, and proteins in this were expressed and as described X. Ge H. Lemon B. Vonderfecht S. Baribault H. Weiszmann J. Gupte J. Gardner J. Lindberg R. Wang Z. et al.Separating mitogenic and metabolic activities of fibroblast growth factor 19 (FGF19).Proc. Natl. Acad. Sci. USA. 2010; 107: 14158-14163Crossref PubMed Scopus (77) Google Scholar, X. Ge H. Lemon B. Weiszmann J. Gupte J. Hawkins N. Li X. J. Lindberg R. Li Y. activation of FGFR4 by an FGF19 variant not improve glucose metabolism in ob/ob Natl. Acad. Sci. USA. 2009; PubMed Scopus Google Scholar). were in with and were with FGF receptors using the to the and with FGF molecules as described X. Ge H. Lemon B. Weiszmann J. Gupte J. Hawkins N. Li X. J. Lindberg R. Li Y. activation of FGFR4 by an FGF19 variant not improve glucose metabolism in ob/ob Natl. Acad. Sci. USA. 2009; PubMed Scopus Google Scholar). were after in and in and the and were using an to the were in and were by the and were in a in and are and on a B6.V-Lepob/J mice The were and were in of and to four on their body weight and glucose after a mice a high-fat diet for of were and a diet. were using and recombinant proteins or were the for the as the mice were for of and proteins glucose mice were the blood by and were The as of the liver, the and the and its In the of in FGF19 or FGF21 were in the were after were by using an were a and in and a rate of were for lipid were in with by or were for and using a by to were in to well in a the of triglyceride or cholesterol or and were for and and cholesterol were the were using the to the The the of liver, and the and its and expressed as of of body reports described a in plasma TG and cholesterol with chronic FGF19 in transgenic or treatment with recombinant protein in high-fat diet mouse models. in of the effects of FGF19 on metabolism in leptin-deficient ob/ob mice, we observed increases in plasma TG and cholesterol levels mice were by body weight and serum glucose levels and with a or FGF21 for to the short significant differences in body weight were observed the with results serum glucose levels were reduced in mice with FGF19 or FGF21 as compared with the the of the treatment that showed that FGF19 and FGF21 were interchangeable in of glucose metabolism and that activation of FGFR4 by FGF19 not to toward glucose regulation. This is also with that activation of FGFR4 not improve glucose X. Ge H. Lemon B. Weiszmann J. Gupte J. Hawkins N. Li X. J. Lindberg R. Li Y. activation of FGFR4 by an FGF19 variant not improve glucose metabolism in ob/ob Natl. Acad. Sci. USA. 2009; PubMed Scopus Google Scholar). and cholesterol were also the of the the FGF19 treatment increased serum triglyceride and cholesterol levels after the the and FGF21 in in of these FGF19 is to expression in the through activation of Consistent with mice with FGF19 reduced significant were observed with FGF21 treatment FGF21 not activate FGFR4 and were by and triglyceride and cholesterol of In serum mice, levels of triglyceride were in the of the triglyceride in cholesterol increased in including and in the FGF19 treatment the in plasma TG observed in the ob/ob model be in a a with of FGF19 protein in ob/ob mice. to results in FGF19 induced significant in plasma glucose levels and after of the and there is also a significant in the ability of mice to glucose in an glucose similar to the treatment in FGF19 treatment also increased plasma TG and cholesterol levels the of the treatment the in plasma TG levels we observed after FGF19 treatment in contrast to the reported effects of FGF19 on plasma TG in diet-induced obesity mouse models (8Fu L. John L.M. Adams S.H. Yu X.X. Tomlinson E. Renz M. Williams P.M. Soriano R. Corpuz R. Moffat B. et al.Fibroblast growth factor 19 increases metabolic rate and reverses dietary and leptin-deficient diabetes.Endocrinology. 2004; 145: 2594-2603Crossref PubMed Scopus (436) Google Scholar, A.L. S. C. A. J. A.S. J. FGF19 regulates glucose and metabolism and ONE. 2011; PubMed Scopus Google we in ob/ob mice were model In in mice, we also reported a in plasma TG levels after of FGF19 for (14Ge H. Baribault H. Vonderfecht S. Lemon B. Weiszmann J. Gardner J. Lee K.J. Gupte J. Mookherjee P. Wang M. et al.Characterization of a FGF19 variant with altered receptor specificity revealed a central role for FGFR1c in the regulation of glucose metabolism.PLoS ONE. 2012; 7: e33603Crossref PubMed Scopus (31) Google Scholar). we there be a different of FGF19 on plasma TG levels in the mice. mice were on a high-fat diet of on the high-fat the were on body glucose, and were with or FGF19 for weight and glucose were were by for triglyceride and cholesterol In this FGF19 treatment not significant body weight and induced a significant in plasma glucose levels the treatment levels were reduced with the improvements in insulin sensitivity to ob/ob mice, the FGF19 treatment induced a significant in plasma TG but only The after FGF19 and to by levels were not these results suggest that the observed in plasma TG levels by FGF19 treatment is not model metabolism can affect triglyceride and cholesterol we to the observed in TG and cholesterol with FGF19 treatment be in to its ability to activation of We an FGF19 that FGFR4 but not FGFR1c, -2c, or -3c X. Ge H. Lemon B. Weiszmann J. Gupte J. Hawkins N. Li X. J. Lindberg R. Li Y. activation of FGFR4 by an FGF19 variant not improve glucose metabolism in ob/ob Natl. Acad. Sci. USA. 2009; PubMed Scopus Google Scholar). This to FGFR4 activation and its regulation of and cholesterol metabolism activation of to the described in significant differences in body weight were observed in ob/ob mice with FGF19 or for as compared with the in contrast to treatment with FGF19 or FGF21, not reduced plasma glucose levels This is with X. Ge H. Lemon B. Weiszmann J. Gupte J. Hawkins N. Li X. J. Lindberg R. Li Y. activation of FGFR4 by an FGF19 variant not improve glucose metabolism in ob/ob Natl. Acad. Sci. USA. 2009; PubMed Scopus Google and that activation of FGFR4 is not to improve glucose metabolism. Consistent with its ability to activate FGFR4, treatment expression and reduced similar to FGF19 treatment with increased plasma TG and cholesterol levels activation of FGFR4 by effects on lipid metabolism its regulation of glucose that FGFR4 is for the of and increased TG and cholesterol levels associated with FGF19 treatment the metabolism can affect triglyceride and cholesterol has been that treatment serum triglyceride through activation of M. Wang L. A. Mangelsdorf D.J. R.A. J. triglyceride levels a and Clin. Invest. 2004; PubMed Scopus Google and that triglyceride a to the use of J. Full Text PDF PubMed Scopus Google Scholar). the of to and Y. R. H. the of by in primary PubMed Google a between the and triglyceride is also the of cholesterol A of cholesterol is in by in to cholesterol C. G. S. A. et cholesterol has a Clin. Invest. PubMed Scopus Google Scholar). of be to an in plasma TG and cholesterol FGF19 is a unique endocrine FGF and its effects on metabolism have been well FGF19 FGFR4, which is expressed in the liver, and activation of this receptor by FGF19 has been to the G. J. M. Wang Kliewer S.A. et of a novel growth signal for the of Dev. PubMed Scopus Google Scholar, T. Choi M. A. L. G. S.A. B. et al.Fibroblast growth factor as an signal to 2005; Full Text Full Text PDF PubMed Scopus Google and affect A.L. S. C. A. J. A.S. J. FGF19 regulates glucose and metabolism and ONE. 2011; PubMed Scopus Google Scholar). This has been as the signal that of G. J. M. Wang Kliewer S.A. et of a novel growth signal for the of Dev. PubMed Scopus Google Scholar, T. Choi M. A. L. G. S.A. B. et al.Fibroblast growth factor as an signal to 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). the between and cholesterol as FGF19 treatment also be to plasma TG and cholesterol This is we observed in with FGF19 for in the ob/ob mouse model a in and plasma glucose levels and an in TG and cholesterol levels and and A variant of which specifically only FGFR4, effects on and cholesterol levels distinct on glucose This that the in lipid is to activation of FGFR4, glucose regulation is mediated through a different that FGF19 an in plasma TG and cholesterol has been reported in the the improvements in and hyperlipidemia have been reported in mice chronic treatment with FGF19 protein and in FGF19 transgenic mice high-fat diet (8Fu L. John L.M. Adams S.H. Yu X.X. Tomlinson E. Renz M. Williams P.M. Soriano R. Corpuz R. Moffat B. et al.Fibroblast growth factor 19 increases metabolic rate and reverses dietary and leptin-deficient diabetes.Endocrinology. 2004; 145: 2594-2603Crossref PubMed Scopus (436) Google Scholar, E. L. John L. B. X. Renz M. L. et mice fibroblast growth factor-19 increased metabolic rate and PubMed Scopus Google Scholar). FGF21 is a unique FGF that belongs to the same subfamily as FGF19 A. FGFs and Opin. 2009; PubMed Scopus Google Scholar). Chronic to FGF21 in transgenic mice or with of recombinant protein to to that of similar chronic of improved glucose metabolism and reduced plasma and body weight A. Shiyanova T.L. Koester A. Ford A.M. Micanovic R. Galbreath E.J. Sandusky G.E. Hammond L.J. Moyers J.S. Owens R.A. et al.FGF-21 as a novel metabolic regulator.J. Clin. Invest. 2005; 115: 1627-1635Crossref PubMed Scopus (1618) Google Scholar, J. D.J. C. S. M. G. Vonderfecht S. R. Li Lindberg R.A. et al.Fibroblast growth factor 21 reverses increases energy and insulin sensitivity in diet-induced 2009; PubMed Scopus Google Scholar). Recent that these effects observed with FGF21 or FGF19 treatment are not mediated through FGFR4 but through the FGFR1c/βKlotho treatment of mice with an FGF biased toward the FGFR1c/βKlotho receptor complex or can metabolic induced by FGF19 and FGF21, including of and hyperlipidemia (14Ge H. Baribault H. Vonderfecht S. Lemon B. Weiszmann J. Gardner J. Lee K.J. Gupte J. Mookherjee P. Wang M. et al.Characterization of a FGF19 variant with altered receptor specificity revealed a central role for FGFR1c in the regulation of glucose metabolism.PLoS ONE. 2012; 7: e33603Crossref PubMed Scopus (31) Google Scholar, A.L. G. S. Y. Li J. J. K. B. Li L. S. L. N. M. A. H. E. A.S. E. Y. J. of diabetes by activation of fibroblast growth factor receptor 2011; PubMed Scopus Google Scholar). effects were in A.L. G. S. Y. Li J. J. K. B. Li L. S. L. N. M. A. H. E. A.S. E. Y. J. of diabetes by activation of fibroblast growth factor receptor 2011; PubMed Scopus Google in is the target of FGF21 of in increases in metabolic rate and energy to activation A.L. G. S. Y. Li J. J. K. B. Li L. S. L. N. M. A. H. E. A.S. E. Y. J. of diabetes by activation of fibroblast growth factor receptor 2011; PubMed Scopus Google Scholar). The observed in hyperlipidemia may a of directly increased receptor expression in J. B.C. L. N. Fibroblast growth factor-21 regulates receptor levels in the and the protein Biol. Chem. 2012; Full Text Full Text PDF PubMed Scopus Google and through increased energy The increased of through metabolism E. L. John L. B. X. Renz M. L. et mice fibroblast growth factor-19 increased metabolic rate and PubMed Scopus Google Scholar, A.L. G. S. Y. Li J. J. K. B. Li L. S. L. N. M. A. H. E. A.S. E. Y. J. of diabetes by activation of fibroblast growth factor receptor 2011; PubMed Scopus Google may to lipid in and The metabolic effects of FGF19 and FGF21 are often thought to be that FGF19 can serum triglyceride and cholesterol in pharmacological but not FGF21. In this is not the receptor specificities of these two molecules are not only FGF19 can activate FGFR4 in the and to increased plasma TG and cholesterol levels we observed after FGF19 treatment with the effects we FGF19 has two actions on lipid lipid mediated through the activation of FGFR4 and of in the liver, and a lipid-lowering through FGFR1c in and results the of these two The of these two actions may be can be observed after FGF19 treatment X. Ge H. Lemon B. Weiszmann J. Gupte J. Hawkins N. Li X. J. Lindberg R. Li Y. activation of FGFR4 by an FGF19 variant not improve glucose metabolism in ob/ob Natl. Acad. Sci. USA. 2009; PubMed Scopus Google increased metabolic rate may to in mice may have this of serum were only after chronic this body lipid may have to increased energy expenditure with increased and metabolism through the lipid-lowering of FGF19 predominant the lipid-raising in these In with the short of treatment with the lipid-raising a role to its This is in in mice the TG only on and to a on and to the mechanism for the TG is is that is mediated through or receptors by the in or to the inconsistency between the observed effects FGF19 treatment as well as the effects FGF19 on metabolism. ob/ob mice to the effects of FGF19 the plasma TG and cholesterol levels after FGF19 treatment Recent results suggest that is not required for antidiabetic may or effects to FGF21 on glucose and body weight and FGF21 sensitivity in mice C. J. S. J. Vonderfecht S. Xu J. D.J. FGF21 metabolic and in ONE. 2012; 7: PubMed Scopus Google Scholar). there is also a between FGF19 and and the effects of FGF19 is an to in the In to its ability to specifically activate FGF FGF19 can have two and effects on lipid metabolism. that that FGF19 be for treatment of another of FGF19 on lipid metabolism. an ability to signal through FGFR4, FGF21 is a glucose and lipid metabolism. is to that FGFR4 may provide for The and for and of the and for this with cholesterol diet-induced obesity fibroblast growth factor triglyceride