Hongfei Ge

G protein-coupled receptor 43 (GPR43) has been identified as a receptor for short-chain fatty acids that include acetate and propionate. A potential involvement of GPR43 in immune and inflammatory response has been previously suggested because its expression is highly enriched in immune cells. GPR43 is also expressed in a number of other tissues including adipocytes; however, the functional consequences of GPR43 activation in these other tissues are not clear. In this report, we focus on the potential functions of GPR43 in adipocytes. We show that adipocytes treated with GPR43 natural ligands, acetate and propionate, exhibit a reduction in lipolytic activity. This inhibition of lipolysis is the result of GPR43 activation, because this effect is abolished in adipocytes isolated from GPR43 knockout animals. In a mouse in vivo model, we show that the activation of GPR43 by acetate results in the reduction in plasma free fatty acid levels without inducing the flushing side effect that has been observed by the activation of nicotinic acid receptor, GPR109A. These results suggest a potential role for GPR43 in regulating plasma lipid profiles and perhaps aspects of metabolic syndrome.

Recombinant fibroblast growth factor (FGF)21 has antihyperglycemic, antihyperlipidemic, and antiobesity effects in diabetic rodent and monkey models. Previous studies were confined to measuring steady-state effects of FGF21 following subchronic or chronic administration. The present study focuses on the kinetics of biological actions of FGF21 following a single injection and on the associated physiological and cellular mechanisms underlying FGF21 actions. We show that FGF21 resulted in rapid decline of blood glucose levels and immediate improvement of glucose tolerance and insulin sensitivity in two animal models of insulin resistance (ob/ob and DIO mice). In ob/ob mice, FGF21 led to a 40-60% decrease in blood glucose, insulin, and amylin levels within 1 h after injection, and the maximal effects were sustained for more than 6 h despite the 1- to 2-h half-life of FGF21. In DIO mice, FGF21 reduced fasting blood glucose and insulin levels and improved glucose tolerance and insulin sensitivity within 3 h of treatment. The acute improvement of glucose metabolism was associated with a 30% reduction of hepatic glucose production and an increase in peripheral glucose turnover. FGF21 appeared to have no direct effect on ex vivo pancreatic islet insulin or glucagon secretion. However, it rapidly induced typical FGF signaling in liver and adipose tissues and in several hepatoma-derived cell lines and differentiated adipocytes. FGF21 was able to inhibit glucose release from H4IIE hepatoma cells and stimulate glucose uptake in 3T3-L1 adipocytes. We conclude that the acute glucose-lowering and insulin-sensitizing effects of FGF21 are potentially associated with its metabolic actions in liver and adipose tissues.

Fibroblast growth factor 21 (FGF21) is a distinctive member of the FGF family with potent beneficial effects on lipid, body weight, and glucose metabolism and has attracted considerable interest as a potential therapeutic for treating diabetes and obesity. As an alternative to native FGF21, we have developed a monoclonal antibody, mimAb1, that binds to βKlotho with high affinity and specifically activates signaling from the βKlotho/FGFR1c (FGF receptor 1c) receptor complex. In obese cynomolgus monkeys, injection of mimAb1 led to FGF21-like metabolic effects, including decreases in body weight, plasma insulin, triglycerides, and glucose during tolerance testing. Mice with adipose-selective FGFR1 knockout were refractory to FGF21-induced improvements in glucose metabolism and body weight. These results in obese monkeys (with mimAb1) and in FGFR1 knockout mice (with FGF21) demonstrated the essential role of FGFR1c in FGF21 function and suggest fat as a critical target tissue for the cytokine and antibody. Because mimAb1 depends on βKlotho to activate FGFR1c, it is not expected to induce side effects caused by activating FGFR1c alone. The unexpected finding of an antibody that can activate FGF21-like signaling through cell surface receptors provided preclinical validation for an innovative therapeutic approach to diabetes and obesity.

Leptin is an adipocyte-derived hormone with potent effects on food intake and body weight. Genetically obese rodents with mutations of leptin or leptin receptor develop morbid obesity and diabetes. The receptor for leptin, OB-R, is alternatively spliced to at least five transcripts, encoding receptors designated OB-Ra, -b, -c, -d, and -e. OB-Re does not encode a transmembrane domain and is secreted. In humans, transcripts corresponding to OB-Re have not been discovered. However, soluble leptin receptor does circulate in human plasma and represents the major leptin-binding activity. In this report, we attempted to determine whether the soluble leptin receptor may also be derived from membrane-spanning receptor isoforms by ectodomain shedding. Using stable cell lines expressing both OB-Ra, the most abundant leptin receptor isoform, and OB-Rb, the signaling form of the leptin receptor, we demonstrate that soluble leptin receptor protein can indeed be generated by proteolytic cleavage of these two receptor isoforms in vitro. Experiments using adenoviruses expressing dually tagged OB-Ra or Ob-Rb also demonstrate that soluble leptin receptor may be derived from ectodomain shedding of both receptor isoforms in vivo. Because our earlier and other studies have shown that the soluble receptors modulate the levels as well as activity of leptin, our findings suggest that regulated shedding of the ectodomain of membrane-spanning leptin receptors may represent a novel mechanism of modulating leptin's biological activity. Leptin is an adipocyte-derived hormone with potent effects on food intake and body weight. Genetically obese rodents with mutations of leptin or leptin receptor develop morbid obesity and diabetes. The receptor for leptin, OB-R, is alternatively spliced to at least five transcripts, encoding receptors designated OB-Ra, -b, -c, -d, and -e. OB-Re does not encode a transmembrane domain and is secreted. In humans, transcripts corresponding to OB-Re have not been discovered. However, soluble leptin receptor does circulate in human plasma and represents the major leptin-binding activity. In this report, we attempted to determine whether the soluble leptin receptor may also be derived from membrane-spanning receptor isoforms by ectodomain shedding. Using stable cell lines expressing both OB-Ra, the most abundant leptin receptor isoform, and OB-Rb, the signaling form of the leptin receptor, we demonstrate that soluble leptin receptor protein can indeed be generated by proteolytic cleavage of these two receptor isoforms in vitro. Experiments using adenoviruses expressing dually tagged OB-Ra or Ob-Rb also demonstrate that soluble leptin receptor may be derived from ectodomain shedding of both receptor isoforms in vivo. Because our earlier and other studies have shown that the soluble receptors modulate the levels as well as activity of leptin, our findings suggest that regulated shedding of the ectodomain of membrane-spanning leptin receptors may represent a novel mechanism of modulating leptin's biological activity. Leptin is an adipocyte-derived hormone of 167 amino acids (1Zhang Y. Proenca P. Maffei M. Barone M. Leopold L. Friedman J.M. Nature. 1994; 372: 425-432Crossref PubMed Scopus (11631) Google Scholar). It has potent weight-reducing effects in vivo (2Campfield L.A. Smith F.J. Guisez Y. Devos R. Burn P. Science. 1995; 269: 546-549Crossref PubMed Scopus (3060) Google Scholar, 3Halaas J.L. Gajiwala K.S. Maffei M. Cohen S.L. Chait B.T. Rabinowitz D. Lallone R.L. Burley S.K. Friedman J.M. Science. 1995; 269: 543-546Crossref PubMed Scopus (4199) Google Scholar, 4Pelleymounter M.A. Cullen M.J. Baker M.B. Hecht R. Winters D. Boone T. Collins F. Science. 1995; 269: 540-543Crossref PubMed Scopus (3850) Google Scholar). Inob/ob mice, the gene encoding leptin is mutated, resulting in morbid obesity and associated abnormalities, including hyperphagia, hypothermia, diabetes, and infertility.The leptin receptor, OB-R, is a member of the cytokine receptor family (5Tartaglia L.A. Dembski M. Weng X. Deng N. Culpepper J. Devos R. Richards G.J. Campfield L.A. Clark F.T. Deeds J. Muir C. Sanker S. Moriarty A. Moore K.J. Smutko J.S. Mays G.G. Woolf E.A. Monroe C.A. Tepper R.I. Cell. 1995; 83: 1263-1271Abstract Full Text PDF PubMed Scopus (3205) Google Scholar). It is encoded by the diabetes (db) gene, mutation of which also results in phenotypes similar to that exhibited byob/ob mice. OB-R is alternatively spliced into at least five transcripts from a single gene. These transcripts encode proteins that are called the long (OB-Rb), short (OB-Ra, -c, and -d), and soluble (OB-Re) forms of the leptin receptor. With the exception of the soluble leptin receptor, other receptor isoforms differ from each other by the alternative use of a unique terminal coding exon (6Lee G.H. Proenca R. Montez J.M. Carroll K.M. Darvishzadeh J.G. Lee J.I. Friedman J.M. Nature. 1996; 379: 632-635Crossref PubMed Scopus (2095) Google Scholar). OB-Rb is essential in mediating leptin's weight-reducing effects via the hypothalamus (6Lee G.H. Proenca R. Montez J.M. Carroll K.M. Darvishzadeh J.G. Lee J.I. Friedman J.M. Nature. 1996; 379: 632-635Crossref PubMed Scopus (2095) Google Scholar, 7Chen H. Charlat O. Tartaglia L.A. Woolf E.A. Weng X. Ellis S.J. Lakey N.D. Culpepper J. Moore K.J. Breitbart R.E. Duyk G.M. Tepper R.I. Morgenstern J.P. Cell. 1996; 84: 491-495Abstract Full Text Full Text PDF PubMed Scopus (1919) Google Scholar).OB-R is expressed in both the nervous system and in peripheral tissues. The relative expression levels of different receptor isoforms vary among tissues, possibly to allow leptin's biological activity to be more precisely regulated at various leptin target sites (8Ghilardi N. Ziegler S. Wiestner A. Stoffel R. Heim M.H. Skoda R. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 6231-6235Crossref PubMed Scopus (730) Google Scholar). OB-Rb is enriched in the hypothalamus, the site of leptin's action on food intake and body weight. Leptin activation of OB-Rb within this brain region results in the inhibition of neuropeptide Y/agouti-related protein neurons and activation of pro-opiomelanocortin neurons (9Friedman J.M. Nature. 2000; 404: 632-634Crossref PubMed Scopus (626) Google Scholar). Leptin-activated pro-opiomelanocortin neurons become depolarized and release anorexigenic peptides; leptin-inhibited neuropeptide Y/agouti-related protein neurons become hyperpolarized and reduce the release of orexigenic peptides (10Cowley M.A. Smart J.L. Rubinstein M. Cerdan M.G. Diano S. Horvath T.L. Cone R.D. Low M.J. Nature. 2001; 411: 480-484Crossref PubMed Scopus (1754) Google Scholar). These neural circuits represent the main known downstream mediators of leptin's biological effect on food intake. OB-Rb can also activate signal transduction in a variety of peripheral tissues, including adipose tissue, T cells, endothelial cells, and pancreatic β-cells (11Kim Y.B. Uotani S. Pierroz D.D. Flier J.S. Kahn B.B. Endocrinology. 2000; 141: 2328-2339Crossref PubMed Scopus (196) Google Scholar, 12Lord G.M. Matarese G. Howard J.K. Baker R.J. Bloom S.R. Lechler R.I. Nature. 1998; 394: 897-901Crossref PubMed Scopus (1828) Google Scholar, 13Sierra-Honigmann M.R. Nath A.K. Murakami C. Garcia-Cardena G. Papapetropoulos A. Sessa W.C. Madge L.A. Schechner J.S. Schwabb M.B. Polverini P.J. Flores-Riveros J.R. Science. 1998; 281: 1683-1686Crossref PubMed Scopus (1266) Google Scholar, 14Unger R.H. Zhou Y.T. Orci L. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 2327-2332Crossref PubMed Scopus (372) Google Scholar, 15Huang L. Li C. Cell Res. 2000; 10: 81-92Crossref PubMed Scopus (187) Google Scholar). More recently, it is also demonstrated that leptin-induced fatty acid oxidation in muscle via 5′-AMP-activated protein kinase is mediated by both leptin acting on muscle directly and by functioning through the hypothalamic-sympathetic nervous system axis (16Minokoshi Y. Kim Y.B. Peroni O.D. Fryer L.G. Muller C. Carling D. Kahn B.B. Nature. 2002; 415: 339-343Crossref PubMed Scopus (1651) Google Scholar). Taken together, these results confirm that direct as well as indirect leptin signaling at these sites may be necessary for the many biological effects of leptin. In all cases, the presence of OB-Rb is required, asdb/db mice that are without this receptor isoform do not respond to OB-Rb is essential in mediating leptin's biological other receptor isoforms may be necessary for leptin to of in vivo the short forms of the leptin receptor, OB-Ra is most expressed H. Li C. Lee C. R. Friedman J.M. Natl. Acad. U. S. A. PubMed Scopus Google Scholar). It is enriched at the and brain sites of the and the that it may be in the of leptin these to the we have shown that the form of the leptin receptor, in plasma and is of to leptin C. N. Friedman J.M. J. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). In this report, we that soluble leptin receptor may from both OB-Re and ectodomain shedding of membrane-spanning OB-R demonstrate that stable cell lines OB-Ra or OB-Rb are of soluble leptin receptor into the by proteolytic as by we demonstrate that in of OB-Ra or OB-Rb also results in release of soluble leptin receptor into plasma in mice via the shedding of both OB-Ra and OB-Rb is by a the with the amino of receptor expressing OB-Ra and OB-Rb release the soluble leptin receptor that the cleavage of receptor may be mediated by in the Because the soluble leptin receptor leptin's effect on food intake and body mice L. Li C. J. 2001; Full Text Full Text PDF PubMed Scopus Google regulated ectodomain shedding of membrane-spanning leptin receptors may represent a novel mechanism of leptin's biological our earlier we demonstrated that the soluble leptin receptor in plasma and is of to leptin C. N. Friedman J.M. J. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). results also demonstrated that the soluble receptor in the of leptin in L. Li C. J. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). studies also suggest that expression and plasma of the soluble leptin receptor may be regulated O. M. J. Full Text Full Text PDF PubMed Scopus Google Scholar, A. R. A. G. 2000; PubMed Scopus Google Scholar). However, the of soluble leptin receptor in plasma has not been as the encoding this receptor isoform in has not been L. J. S.J. R.L. PubMed Scopus Google of leptin in vivo S.L. J.L. Friedman J.M. Chait B.T. L. D. Hecht R. Collins F. Nature. 1996; PubMed Scopus Google soluble leptin receptor may be an leptin's and is by findings that in human soluble leptin receptor represents the major leptin activity A. A. A. J. Res. 2001; PubMed Scopus Google main site of expression of the encoding the soluble leptin receptor in vivo we to a signal for OB-Re H. Li C. Lee C. R. Friedman J.M. Natl. Acad. U. S. A. PubMed Scopus Google Scholar). have demonstrated that in mice, OB-Re is expressed by the expression at of to the in mice O. M. J. Full Text Full Text PDF PubMed Scopus Google Scholar, M. Murakami T. Y. S. M. H. T. Y. Res. 1998; PubMed Scopus Google Scholar). In and humans, the of leptin and soluble receptor is a a more in mice R. D. P. G. J. 1999; 84: PubMed Scopus Google of an mechanism for the of soluble leptin receptor by ectodomain shedding of membrane-spanning receptor, both in and in vivo. is also in with an earlier on the of human soluble leptin receptor from expressed membrane-spanning receptors in M. M. R.J. Endocrinology. 2001; PubMed Scopus Google shedding by to soluble has been for many as and J.L. P. Lee N. R.J. Science. 1998; PubMed Scopus Google Scholar). The for these is a member of the and family of that are of are as for Science. 2002; PubMed Scopus Google Scholar). the the of the soluble leptin receptor on leptin is not well of the presence of and leptin in human by of plasma J.P. J. J. 1996; PubMed Scopus Google Scholar). and studies that obesity is associated with levels of the soluble leptin receptor in humans, it M. S. A. H. H. F. J.R. Res. 2002; 10: PubMed Scopus Google Scholar, C. J. 2002; PubMed Scopus Google Scholar, N. T. Y. L. M. J. 2002; PubMed Scopus Google Scholar, Ziegler O. L. J.P. A. J. 2002; PubMed Scopus Google Scholar). In obese and to have similar of soluble leptin receptor, in the obese most soluble leptin receptor is to leptin, in a of soluble leptin receptor is to leptin in the obese in the the to soluble leptin receptor be a in the of obesity J.P. J. J. 1996; PubMed Scopus Google Scholar, C. J. 2002; PubMed Scopus Google Scholar, M. C. M. K.M. J. 2002; PubMed Scopus Google Scholar). However, a of leptin in the form in the obese M. C. M. K.M. J. 2002; PubMed Scopus Google Scholar). of levels of leptin and soluble receptor also the with plasma levels of soluble leptin receptor in with or in with or are obese are P. M. A. A. M. 2002; PubMed Scopus Google Scholar). leptin receptor levels are also regulated by and J.L. S. N. M.A. J. 2002; PubMed Scopus Google Scholar). In these studies suggest that the soluble leptin receptor may have for the biological activity of leptin. results of in our using mice the soluble leptin receptor the that soluble leptin receptor in mice is associated with as well as body weight. It is that studies more on the of to the of the soluble leptin receptor for Leptin is an adipocyte-derived hormone of 167 amino acids (1Zhang Y. Proenca P. Maffei M. Barone M. Leopold L. Friedman J.M. Nature. 1994; 372: 425-432Crossref PubMed Scopus (11631) Google Scholar). It has potent weight-reducing effects in vivo (2Campfield L.A. Smith F.J. Guisez Y. Devos R. Burn P. Science. 1995; 269: 546-549Crossref PubMed Scopus (3060) Google Scholar, 3Halaas J.L. Gajiwala K.S. Maffei M. Cohen S.L. Chait B.T. Rabinowitz D. Lallone R.L. Burley S.K. Friedman J.M. Science. 1995; 269: 543-546Crossref PubMed Scopus (4199) Google Scholar, 4Pelleymounter M.A. Cullen M.J. Baker M.B. Hecht R. Winters D. Boone T. Collins F. Science. 1995; 269: 540-543Crossref PubMed Scopus (3850) Google Scholar). Inob/ob mice, the gene encoding leptin is mutated, resulting in morbid obesity and associated abnormalities, including hyperphagia, hypothermia, diabetes, and The leptin receptor, OB-R, is a member of the cytokine receptor family (5Tartaglia L.A. Dembski M. Weng X. Deng N. Culpepper J. Devos R. Richards G.J. Campfield L.A. Clark F.T. Deeds J. Muir C. Sanker S. Moriarty A. Moore K.J. Smutko J.S. Mays G.G. Woolf E.A. Monroe C.A. Tepper R.I. Cell. 1995; 83: 1263-1271Abstract Full Text PDF PubMed Scopus (3205) Google Scholar). It is encoded by the diabetes (db) gene, mutation of which also results in phenotypes similar to that exhibited byob/ob mice. OB-R is alternatively spliced into at least five transcripts from a single gene. These transcripts encode proteins that are called the long (OB-Rb), short (OB-Ra, -c, and -d), and soluble (OB-Re) forms of the leptin receptor. With the exception of the soluble leptin receptor, other receptor isoforms differ from each other by the alternative use of a unique terminal coding exon (6Lee G.H. Proenca R. Montez J.M. Carroll K.M. Darvishzadeh J.G. Lee J.I. Friedman J.M. Nature. 1996; 379: 632-635Crossref PubMed Scopus (2095) Google Scholar). OB-Rb is essential in mediating leptin's weight-reducing effects via the hypothalamus (6Lee G.H. Proenca R. Montez J.M. Carroll K.M. Darvishzadeh J.G. Lee J.I. Friedman J.M. Nature. 1996; 379: 632-635Crossref PubMed Scopus (2095) Google Scholar, 7Chen H. Charlat O. Tartaglia L.A. Woolf E.A. Weng X. Ellis S.J. Lakey N.D. Culpepper J. Moore K.J. Breitbart R.E. Duyk G.M. Tepper R.I. Morgenstern J.P. Cell. 1996; 84: 491-495Abstract Full Text Full Text PDF PubMed Scopus (1919) Google Scholar). OB-R is expressed in both the nervous system and in peripheral tissues. The relative expression levels of different receptor isoforms vary among tissues, possibly to allow leptin's biological activity to be more precisely regulated at various leptin target sites (8Ghilardi N. Ziegler S. Wiestner A. Stoffel R. Heim M.H. Skoda R. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 6231-6235Crossref PubMed Scopus (730) Google Scholar). OB-Rb is enriched in the hypothalamus, the site of leptin's action on food intake and body weight. Leptin activation of OB-Rb within this brain region results in the inhibition of neuropeptide Y/agouti-related protein neurons and activation of pro-opiomelanocortin neurons (9Friedman J.M. Nature. 2000; 404: 632-634Crossref PubMed Scopus (626) Google Scholar). Leptin-activated pro-opiomelanocortin neurons become depolarized and release anorexigenic peptides; leptin-inhibited neuropeptide Y/agouti-related protein neurons become hyperpolarized and reduce the release of orexigenic peptides (10Cowley M.A. Smart J.L. Rubinstein M. Cerdan M.G. Diano S. Horvath T.L. Cone R.D. Low M.J. Nature. 2001; 411: 480-484Crossref PubMed Scopus (1754) Google Scholar). These neural circuits represent the main known downstream mediators of leptin's biological effect on food intake. OB-Rb can also activate signal transduction in a variety of peripheral tissues, including adipose tissue, T cells, endothelial cells, and pancreatic β-cells (11Kim Y.B. Uotani S. Pierroz D.D. Flier J.S. Kahn B.B. Endocrinology. 2000; 141: 2328-2339Crossref PubMed Scopus (196) Google Scholar, 12Lord G.M. Matarese G. Howard J.K. Baker R.J. Bloom S.R. Lechler R.I. Nature. 1998; 394: 897-901Crossref PubMed Scopus (1828) Google Scholar, 13Sierra-Honigmann M.R. Nath A.K. Murakami C. Garcia-Cardena G. Papapetropoulos A. Sessa W.C. Madge L.A. Schechner J.S. Schwabb M.B. Polverini P.J. Flores-Riveros J.R. Science. 1998; 281: 1683-1686Crossref PubMed Scopus (1266) Google Scholar, 14Unger R.H. Zhou Y.T. Orci L. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 2327-2332Crossref PubMed Scopus (372) Google Scholar, 15Huang L. Li C. Cell Res. 2000; 10: 81-92Crossref PubMed Scopus (187) Google Scholar). More recently, it is also demonstrated that leptin-induced fatty acid oxidation in muscle via 5′-AMP-activated protein kinase is mediated by both leptin acting on muscle directly and by functioning through the hypothalamic-sympathetic nervous system axis (16Minokoshi Y. Kim Y.B. Peroni O.D. Fryer L.G. Muller C. Carling D. Kahn B.B. Nature. 2002; 415: 339-343Crossref PubMed Scopus (1651) Google Scholar). Taken together, these results confirm that direct as well as indirect leptin signaling at these sites may be necessary for the many biological effects of leptin. In all cases, the presence of OB-Rb is required, asdb/db mice that are without this receptor isoform do not respond to leptin. OB-Rb is essential in mediating leptin's biological other receptor isoforms may be necessary for leptin to of in vivo the short forms of the leptin receptor, OB-Ra is most expressed H. Li C. Lee C. R. Friedman J.M. Natl. Acad. U. S. A. PubMed Scopus Google Scholar). It is enriched at the and brain sites of the and the that it may be in the of leptin these to the we have shown that the form of the leptin receptor, in plasma and is of to leptin C. N. Friedman J.M. J. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). In this report, we that soluble leptin receptor may from both OB-Re and ectodomain shedding of membrane-spanning OB-R demonstrate that stable cell lines OB-Ra or OB-Rb are of soluble leptin receptor into the by proteolytic as by we demonstrate that in of OB-Ra or OB-Rb also results in release of soluble leptin receptor into plasma in mice via the shedding of both OB-Ra and OB-Rb is by a the with the amino of receptor expressing OB-Ra and OB-Rb release the soluble leptin receptor that the cleavage of receptor may be mediated by in the Because the soluble leptin receptor leptin's effect on food intake and body mice L. Li C. J. 2001; Full Text Full Text PDF PubMed Scopus Google regulated ectodomain shedding of membrane-spanning leptin receptors may represent a novel mechanism of leptin's biological activity. our earlier we demonstrated that the soluble leptin receptor in plasma and is of to leptin C. N. Friedman J.M. J. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). results also demonstrated that the soluble receptor in the of leptin in L. Li C. J. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). studies also suggest that expression and plasma of the soluble leptin receptor may be regulated O. M. J. Full Text Full Text PDF PubMed Scopus Google Scholar, A. R. A. G. 2000; PubMed Scopus Google Scholar). However, the of soluble leptin receptor in plasma has not been as the encoding this receptor isoform in has not been L. J. S.J. R.L. PubMed Scopus Google of leptin in vivo S.L. J.L. Friedman J.M. Chait B.T. L. D. Hecht R. Collins F. Nature. 1996; PubMed Scopus Google soluble leptin receptor may be an leptin's and is by findings that in human soluble leptin receptor represents the major leptin activity A. A. A. J. Res. 2001; PubMed Scopus Google main site of expression of the encoding the soluble leptin receptor in vivo we to a signal for OB-Re H. Li C. Lee C. R. Friedman J.M. Natl. Acad. U. S. A. PubMed Scopus Google Scholar). have demonstrated that in mice, OB-Re is expressed by the expression at of to the in mice O. M. J. Full Text Full Text PDF PubMed Scopus Google Scholar, M. Murakami T. Y. S. M. H. T. Y. Res. 1998; PubMed Scopus Google Scholar). In and humans, the of leptin and soluble receptor is a a more in mice R. D. P. G. J. 1999; 84: PubMed Scopus Google of an mechanism for the of soluble leptin receptor by ectodomain shedding of membrane-spanning receptor, both in and in vivo. is also in with an earlier on the of human soluble leptin receptor from expressed membrane-spanning receptors in M. M. R.J. Endocrinology. 2001; PubMed Scopus Google shedding by to soluble has been for many as and J.L. P. Lee N. R.J. Science. 1998; PubMed Scopus Google Scholar). The for these is a member of the and family of that are of are as for Science. 2002; PubMed Scopus Google Scholar). the the of the soluble leptin receptor on leptin is not well of the presence of and leptin in human by of plasma J.P. J. J. 1996; PubMed Scopus Google Scholar). and studies that obesity is associated with levels of the soluble leptin receptor in humans, it M. S. A. H. H. F. J.R. Res. 2002; 10: PubMed Scopus Google Scholar, C. J. 2002; PubMed Scopus Google Scholar, N. T. Y. L. M. J. 2002; PubMed Scopus Google Scholar, Ziegler O. L. J.P. A. J. 2002; PubMed Scopus Google Scholar). In obese and to have similar of soluble leptin receptor, in the obese most soluble leptin receptor is to leptin, in a of soluble leptin receptor is to leptin in the obese in the the to soluble leptin receptor be a in the of obesity J.P. J. J. 1996; PubMed Scopus Google Scholar, C. J. 2002; PubMed Scopus Google Scholar, M. C. M. K.M. J. 2002; PubMed Scopus Google Scholar). However, a of leptin in the form in the obese M. C. M. K.M. J. 2002; PubMed Scopus Google Scholar). of levels of leptin and soluble receptor also the with plasma levels of soluble leptin receptor in with or in with or are obese are P. M. A. A. M. 2002; PubMed Scopus Google Scholar). leptin receptor levels are also regulated by and J.L. S. N. M.A. J. 2002; PubMed Scopus Google Scholar). In these studies suggest that the soluble leptin receptor may have for the biological activity of leptin. results of in our using mice the soluble leptin receptor the that soluble leptin receptor in mice is associated with as well as body weight. It is that studies more on the of to the of the soluble leptin receptor for In our earlier we demonstrated that the soluble leptin receptor in plasma and is of to leptin C. N. Friedman J.M. J. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). results also demonstrated that the soluble receptor in the of leptin in L. Li C. J. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). studies also suggest that expression and plasma of the soluble leptin receptor may be regulated O. M. J. Full Text Full Text PDF PubMed Scopus Google Scholar, A. R. A. G. 2000; PubMed Scopus Google Scholar). However, the of soluble leptin receptor in plasma has not been as the encoding this receptor isoform in has not been L. J. S.J. R.L. PubMed Scopus Google Scholar). Because of leptin in vivo S.L. J.L. Friedman J.M. Chait B.T. L. D. Hecht R. Collins F. Nature. 1996; PubMed Scopus Google soluble leptin receptor may be an leptin's and is by findings that in human soluble leptin receptor represents the major leptin activity A. A. A. J. Res. 2001; PubMed Scopus Google Scholar). The main site of expression of the encoding the soluble leptin receptor in vivo we to a signal for OB-Re H. Li C. Lee C. R. Friedman J.M. Natl. Acad. U. S. A. PubMed Scopus Google Scholar). have demonstrated that in mice, OB-Re is expressed by the expression at of to the in mice O. M. J. Full Text Full Text PDF PubMed Scopus Google Scholar, M. Murakami T. Y. S. M. H. T. Y. Res. 1998; PubMed Scopus Google Scholar). In and humans, the of leptin and soluble receptor is a a more in mice R. D. P. G. J. 1999; 84: PubMed Scopus Google Scholar). of an mechanism for the of soluble leptin receptor by ectodomain shedding of membrane-spanning receptor, both in and in vivo. is also in with an earlier on the of human soluble leptin receptor from expressed membrane-spanning receptors in M. M. R.J. Endocrinology. 2001; PubMed Scopus Google Scholar). shedding by to soluble has been for many as and J.L. P. Lee N. R.J. Science. 1998; PubMed Scopus Google Scholar). The for these is a member of the and family of that are of are as for Science. 2002; PubMed Scopus Google Scholar). the the of the soluble leptin receptor on leptin is not well of the presence of and leptin in human by of plasma J.P. J. J. 1996; PubMed Scopus Google Scholar). and studies that obesity is associated with levels of the soluble leptin receptor in humans, it M. S. A. H. H. F. J.R. Res. 2002; 10: PubMed Scopus Google Scholar, C. J. 2002; PubMed Scopus Google Scholar, N. T. Y. L. M. J. 2002; PubMed Scopus Google Scholar, Ziegler O. L. J.P. A. J. 2002; PubMed Scopus Google Scholar). In obese and to have similar of soluble leptin receptor, in the obese most soluble leptin receptor is to leptin, in a of soluble leptin receptor is to leptin in the obese in the the to soluble leptin receptor be a in the of obesity J.P. J. J. 1996; PubMed Scopus Google Scholar, C. J. 2002; PubMed Scopus Google Scholar, M. C. M. K.M. J. 2002; PubMed Scopus Google Scholar). However, a of leptin in the form in the obese M. C. M. K.M. J. 2002; PubMed Scopus Google Scholar). of levels of leptin and soluble receptor also the with plasma levels of soluble leptin receptor in with or in with or are obese are P. M. A. A. M. 2002; PubMed Scopus Google Scholar). leptin receptor levels are also regulated by and J.L. S. N. M.A. J. 2002; PubMed Scopus Google Scholar). In these studies suggest that the soluble leptin receptor may have for the biological activity of leptin. results of in our using mice the soluble leptin receptor the that soluble leptin receptor in mice is associated with as well as body weight. It is that studies more on the of to the of the soluble leptin receptor for J. for the and for to and R. H. C. and G. for a of the

FGF19 and FGF21, unique members of the fibroblast growth factor (FGF) family, are hormones that regulate glucose, lipid, and energy homeostasis. Increased hepatocyte proliferation and liver tumor formation have also been observed in FGF19 transgenic mice. Here, we report that, in contrast to FGF19, FGF21 does not induce hepatocyte proliferation in vivo. To identify the mechanism for FGF19-induced hepatocyte proliferation, we explored similarities and differences in receptor specificity between FGF19 and FGF21. We find that although both are able to activate FGF receptors (FGFRs) 1c, 2c, and 3c, only FGF19 activates FGFR4, the predominant receptor in the liver. Using a C-terminal truncation mutant of FGF19 and a series of FGF19/FGF21 chimeric molecules, we determined that amino acids residues 38–42 of FGF19 are sufficient to confer both FGFR4 activation and increased hepatocyte proliferation in vivo to FGF21. These data suggest that activation of FGFR4 is the mechanism whereby FGF19 can increase hepatocyte proliferation and induce hepatocellular carcinoma formation. FGF19 and FGF21, unique members of the fibroblast growth factor (FGF) family, are hormones that regulate glucose, lipid, and energy homeostasis. Increased hepatocyte proliferation and liver tumor formation have also been observed in FGF19 transgenic mice. Here, we report that, in contrast to FGF19, FGF21 does not induce hepatocyte proliferation in vivo. To identify the mechanism for FGF19-induced hepatocyte proliferation, we explored similarities and differences in receptor specificity between FGF19 and FGF21. We find that although both are able to activate FGF receptors (FGFRs) 1c, 2c, and 3c, only FGF19 activates FGFR4, the predominant receptor in the liver. Using a C-terminal truncation mutant of FGF19 and a series of FGF19/FGF21 chimeric molecules, we determined that amino acids residues 38–42 of FGF19 are sufficient to confer both FGFR4 activation and increased hepatocyte proliferation in vivo to FGF21. These data suggest that activation of FGFR4 is the mechanism whereby FGF19 can increase hepatocyte proliferation and induce hepatocellular carcinoma formation.