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The farnesoid X receptor (FXR) is a bile acid (BA)-activated nuclear receptor that plays a major role in the regulation of BA and lipid metabolism. Recently, several studies have suggested a potential role of FXR in the control of hepatic carbohydrate metabolism, but its contribution to the maintenance of peripheral glucose homeostasis remains to be established. FXR-deficient mice display decreased adipose tissue mass, lower serum leptin concentrations, and elevated plasma free fatty acid levels. Glucose and insulin tolerance tests revealed that FXR deficiency is associated with impaired glucose tolerance and insulin resistance. Moreover, whole-body glucose disposal during a hyperinsulinemic euglycemic clamp is decreased in FXR-deficient mice. In parallel, FXR deficiency alters distal insulin signaling, as reflected by decreased insulin-dependent Akt phosphorylation in both white adipose tissue and skeletal muscle. Whereas FXR is not expressed in skeletal muscle, it was detected at a low level in white adipose tissue in vivo and induced during adipocyte differentiation in vitro. Moreover, mouse embryonic fibroblasts derived from FXR-deficient mice displayed impaired adipocyte differentiation, identifying a direct role for FXR in adipocyte function. Treatment of differentiated 3T3-L1 adipocytes with the FXR-specific synthetic agonist GW4064 enhanced insulin signaling and insulin-stimulated glucose uptake. Finally, treatment with GW4064 improved insulin resistance in genetically obese ob/ob mice in vivo. Although the underlying molecular mechanisms remain to be unraveled, these results clearly identify a novel role of FXR in the regulation of peripheral insulin sensitivity and adipocyte function. This unexpected function of FXR opens new perspectives for the treatment of type 2 diabetes. The farnesoid X receptor (FXR) is a bile acid (BA)-activated nuclear receptor that plays a major role in the regulation of BA and lipid metabolism. Recently, several studies have suggested a potential role of FXR in the control of hepatic carbohydrate metabolism, but its contribution to the maintenance of peripheral glucose homeostasis remains to be established. FXR-deficient mice display decreased adipose tissue mass, lower serum leptin concentrations, and elevated plasma free fatty acid levels. Glucose and insulin tolerance tests revealed that FXR deficiency is associated with impaired glucose tolerance and insulin resistance. Moreover, whole-body glucose disposal during a hyperinsulinemic euglycemic clamp is decreased in FXR-deficient mice. In parallel, FXR deficiency alters distal insulin signaling, as reflected by decreased insulin-dependent Akt phosphorylation in both white adipose tissue and skeletal muscle. Whereas FXR is not expressed in skeletal muscle, it was detected at a low level in white adipose tissue in vivo and induced during adipocyte differentiation in vitro. Moreover, mouse embryonic fibroblasts derived from FXR-deficient mice displayed impaired adipocyte differentiation, identifying a direct role for FXR in adipocyte function. Treatment of differentiated 3T3-L1 adipocytes with the FXR-specific synthetic agonist GW4064 enhanced insulin signaling and insulin-stimulated glucose uptake. Finally, treatment with GW4064 improved insulin resistance in genetically obese ob/ob mice in vivo. Although the underlying molecular mechanisms remain to be unraveled, these results clearly identify a novel role of FXR in the regulation of peripheral insulin sensitivity and adipocyte function. This unexpected function of FXR opens new perspectives for the treatment of type 2 diabetes. The farnesoid X receptor (FXR) 4The abbreviations used are: FXR, farnesoid X receptor; BA, bile acid; FFA, free fatty acid; MEF, mouse embryonic fibroblast; ITT, insulin tolerance test; GTT, glucose tolerance test; IR, insulin receptor; IRS, insulin receptor substrate; WAT, white adipose tissue; PDK1, phosphoinositide-dependent protein kinase 1; PPARγ, peroxisome proliferator-activated receptor γ; HDL, high density lipoprotein. (NR1H4) is a nuclear receptor that is activated by bile acids (BAs) (1Kuipers F. Claudel T. Sturm E. Staels B. Rev. Endocr. Metab. Disord. 2004; 5: 319-326Crossref PubMed Scopus (55) Google Scholar). A major physiological role of FXR is to protect liver cells from the deleterious effect of BA overload by decreasing their endogenous production and by accelerating BA biotransformation and excretion (1Kuipers F. Claudel T. Sturm E. Staels B. Rev. Endocr. Metab. Disord. 2004; 5: 319-326Crossref PubMed Scopus (55) Google Scholar). In addition, the generation and characterization of FXR-deficient (FXR-/-) mice has also established a critical role of FXR in lipid metabolism, since these mice display elevated serum levels of triglycerides and high density lipoprotein cholesterol (2Sinal C.J. Tohkin M. Miyata M. Ward J.M. Lambert G. Gonzalez F.J. Cell. 2000; 102: 731-744Abstract Full Text Full Text PDF PubMed Scopus (1426) Google Scholar). Recently, several studies have suggested that FXR might also regulate hepatic carbohydrate metabolism (3Cariou B. Duran-Sandoval D. Kuipers F. Staels B. Endocrinology. 2005; 146: 981-983Crossref PubMed Scopus (36) Google Scholar). The first indication came from the observation that hepatic FXR expression is reduced in several rodent models of diabetes (4Duran-Sandoval D. Mautino G. Martin G. Percevault F. Barbier O. Fruchart J.C. Kuipers F. Staels B. Diabetes. 2004; 53: 890-898Crossref PubMed Scopus (204) Google Scholar). FXR expression also varies in mouse liver during nutritional changes, being increased during fasting and decreased upon refeeding (5Zhang Y. Castellani L.W. Sinal C.J. Gonzalez F.J. Edwards P.A. Genes Dev. 2004; 18: 157-169Crossref PubMed Scopus (296) Google Scholar, 6Duran-Sandoval D. Cariou B. Percevault F. Hennuyer N. Grefhorst A. van Dijk T.H. Gonzalez F.J. Fruchart J.C. Kuipers F. Staels B. J. Biol. Chem. 2005; 280: 29971-29979Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar). Moreover, FXR activation by BAs or the synthetic nonsteroidal specific agonist GW4064 (7Maloney P.R. Parks D.J. Haffner C.D. Fivush A.M. Chandra G. Plunket K.D. Creech K.L. Moore L.B. Wilson J.G. Lewis M.C. Jones S.A. Willson T.M. J. Med. Chem. 2000; 43: 2971-2974Crossref PubMed Scopus (458) Google Scholar) modulates the expression of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (3Cariou B. Duran-Sandoval D. Kuipers F. Staels B. Endocrinology. 2005; 146: 981-983Crossref PubMed Scopus (36) Google Scholar). However, conflicting data report either a positive (8Stayrook K.R. Bramlett K.S. Savkur R.S. Ficorilli J. Cook T. Christe M.E. Michael L.F. Burris T.P. Endocrinology. 2005; 146: 984-991Crossref PubMed Scopus (235) Google Scholar) or a negative effect (9De Fabiani E. Mitro N. Gilardi F. Caruso D. Galli G. Crestani M. J. Biol. Chem. 2003; 278: 39124-39132Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar, 10Yamagata K. Daitoku H. Shimamoto Y. Matsuzaki H. Hirota K. Ishida J. Fukamizu A. J. Biol. Chem. 2004; 279: 23158-23165Abstract Full Text Full Text PDF PubMed Scopus (259) Google Scholar) of BA and/or GW4064 on phosphoenolpyruvate carboxykinase gene expression. A recent study, using FXR-/- mice, highlighted also a role of FXR in regulating the kinetics of hepatic carbohydrate metabolism during the fasting-refeeding transition phase. Indeed, FXR appears to modulate glycolytic and lipogenic pathways by interfering directly with the transcription of glucose-regulated genes, such as liver pyruvate kinase (6Duran-Sandoval D. Cariou B. Percevault F. Hennuyer N. Grefhorst A. van Dijk T.H. Gonzalez F.J. Fruchart J.C. Kuipers F. Staels B. J. Biol. Chem. 2005; 280: 29971-29979Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar). Furthermore, FXR also controls the adaptive response to fasting, since FXR-/- mice exhibit transient hypoglycemia upon fasting (11Cariou B. van Harmelen K. Duran-Sandoval D. van Dijk T. Grefhorst A. Bouchaert E. Fruchart J.C. Gonzalez F.J. Kuipers F. Staels B. FEBS Lett. 2005; 579: 4076-4080Crossref PubMed Scopus (73) Google Scholar). In the present study, we investigated the role of FXR in whole-body glucose homeostasis and insulin sensitivity by performing glucose tolerance tests and hyperinsulinemic-euglycemic clamp studies in FXR-/- mice. Interestingly, a decreased peripheral insulin sensitivity was observed in these mice. In vitro studies indicated that FXR directly modulates adipocyte function. Furthermore, we found that treatment with the specific FXR agonist GW4064 improved insulin sensitivity in ob/ob mice. These findings provide new evidence to support an important role of FXR in the maintenance of normal glucose homeostasis. Materials—Chemicals were obtained from Sigma France, GW4064 from Genfit SA (Loos, France). Rabbit polyclonal anti-IRβ antibodies were purchased from Santa Cruz Biotechnology, Inc. (Santa Cruz, CA); mouse monoclonal anti-phosphotyrosine (4G10), rabbit polyclonal anti-phosphatidylinositol 3-kinase p85, and anti-IRS-1 antibodies were from Upstate Biotechnology, Inc. (Lake Placid, NY); anti-phospho-Akt (Ser473), anti-Akt, anti-phospho-PDK1 (Ser241), and anti-PDK1 antibodies were from Cell Signaling. Different kits were used to determine plasma concentrations of various metabolites: insulin (Mercodia AB), leptin and adiponectin (R 278: 41930-41937Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar). Animals—Homozygous FXR-/- male mice of 18-20 weeks of age and sex- and age-matched wild type mice (FXR+/+) bred on the (2Sinal C.J. Tohkin M. Miyata M. Ward J.M. Lambert G. Gonzalez F.J. Cell. 2000; 102: 731-744Abstract Full Text Full Text PDF PubMed Scopus (1426) Google Scholar) were with a with free to and a France). mice of weeks of age were with the FXR agonist GW4064 of or with its for Glucose and were for with free to the glucose tolerance glucose was and glucose was measured with the (Roche Applied at and ITT, insulin was and FXR-/- mice, ob/ob mice, 2 and glucose was measured at and insulin were in as described Dijk T.H. Havinga R. Stellaard F. Kuipers F. D.J. 2003; PubMed Scopus (55) Google Scholar). In an insulin or was the of mice. and were in and at was from white adipose tissue and using the acid and from 3T3-L1 cells and using the as previously described (4Duran-Sandoval D. Mautino G. Martin G. Percevault F. Barbier O. Fruchart J.C. Kuipers F. Staels B. Diabetes. 2004; 53: 890-898Crossref PubMed Scopus (204) Google Scholar). The of be found in the or were in as described previously (6Duran-Sandoval D. Cariou B. Percevault F. Hennuyer N. Grefhorst A. van Dijk T.H. Gonzalez F.J. Fruchart J.C. Kuipers F. Staels B. J. Biol. Chem. 2005; 280: 29971-29979Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar). were at with the indicated antibodies in the of protein The were in to and to a were revealed using an from adipose tissue were in in and with Cell was using the Cell cells were in and The cells were differentiated by the of A. PubMed Scopus Google Scholar). The differentiated adipocytes were in with or GW4064 embryonic fibroblasts were derived from and FXR-/- differentiation was 2 at were differentiated with to cells were with the with and cells were and for or in and with O. were in Glucose differentiated 3T3-L1 adipocytes were and in with or insulin for the and were The was by B. were with the was measured using a and the data were expressed in of were for the by obtained in the of B. was using the or of for clamp as of were FXR-deficient and and as as several plasma were in male (FXR+/+) and FXR-deficient (FXR-/-) mice Whereas were the FXR-/- mice a in both and liver was increased The to be to these since and not the The in adipose tissue was associated with a in adipocyte in FXR-/- with mice and content of as as were in and FXR-/- mice FXR deficiency is not associated with impaired and in and FXR-/- mice male and FXR-/- mice were of fasting, and were and plasma were to as from from from from from from from cholesterol from cholesterol from from from from mice in a new plasma glucose concentrations were lower in FXR-/- mice, associated with an impaired hepatic glucose production during fasting (11Cariou B. van Harmelen K. Duran-Sandoval D. van Dijk T. Grefhorst A. Bouchaert E. Fruchart J.C. Gonzalez F.J. Kuipers F. Staels B. FEBS Lett. 2005; 579: 4076-4080Crossref PubMed Scopus (73) Google Scholar). insulin levels were decreased in FXR-/- mice, an adaptive response to the Whereas adiponectin concentrations not both plasma leptin concentrations were decreased in FXR-/- mice, the in adipose tissue (2Sinal C.J. Tohkin M. Miyata M. Ward J.M. Lambert G. Gonzalez F.J. Cell. 2000; 102: 731-744Abstract Full Text Full Text PDF PubMed Scopus (1426) Google cholesterol and levels were increased in FXR-/- mice. Moreover, plasma levels were also increased in FXR-/- mice. A was observed in mice as as in FXR-deficient mouse on a (12Kok T. Hulzebos C.V. Wolters H. Havinga R. Agellon L.B. Stellaard F. Shan B. Schwarz M. Kuipers F. J. Biol. Chem. 2003; 278: 41930-41937Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar) not FXR to of FXR-/- mice to to a glucose was a of FXR-/- mice displayed a plasma glucose the mice, with a the The decreased of plasma glucose from either an impaired insulin a peripheral insulin resistance or an increased hepatic glucose In of studies (6Duran-Sandoval D. Cariou B. Percevault F. Hennuyer N. Grefhorst A. van Dijk T.H. Gonzalez F.J. Fruchart J.C. Kuipers F. Staels B. J. Biol. Chem. 2005; 280: 29971-29979Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar, B. van Harmelen K. Duran-Sandoval D. van Dijk T. Grefhorst A. Bouchaert E. Fruchart J.C. Gonzalez F.J. Kuipers F. Staels B. FEBS Lett. 2005; 579: 4076-4080Crossref PubMed Scopus (73) Google the be the insulin tolerance tests were The of plasma glucose was in FXR-/- in mice, as indicated by the lower the that FXR deficiency alters insulin directly the effect of FXR deficiency on whole-body insulin a hyperinsulinemic-euglycemic clamp was in male and FXR-/- mice. The glucose to was lower in FXR-/- in mice, of the of whole-body insulin resistance. glucose production hepatic glucose was to by insulin in both the of hepatic insulin resistance in FXR-/- mice. In the insulin-stimulated glucose disposal and of glucose were reduced by in FXR-/- mice These results that FXR deficiency results in peripheral insulin resistance. FXR at the of Akt in in insulin receptor signaling in peripheral in vivo insulin was in and FXR-/- mice. insulin-stimulated phosphorylation of and insulin receptor as as the of the of 3-kinase to were both in skeletal and However, FXR deficiency the level of insulin-stimulated phosphorylation of the kinase kinase on in and to a in skeletal The protein expression level of phosphoinositide-dependent protein kinase plays a role in Akt P.R. Biol. Full Text Full Text PDF PubMed Google was not by FXR Furthermore, the level of phosphorylation of that is for its not the A. J. PubMed Scopus Google Scholar) previously described A. J. PubMed Scopus Google Scholar, F.J. H. F. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google insulin not FXR deficiency not the expression of several negative of insulin signaling, such as A.M. A. J. Biol. Chem. 2005; 280: Full Text Full Text PDF PubMed Scopus Google M. J.M. Diabetes. 2003; PubMed Scopus Google and B. D. D. E. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar) these results that FXR directly at the level of Akt plays a role in the regulation of the of insulin H. Metab. Full Text Full Text PDF PubMed Scopus Google Akt activation to the whole-body insulin resistance observed in FXR-/- of in glucose and lipid metabolism in skeletal and white adipose tissue of and FXR-/- mice The indicated levels were measured in and of and FXR-/- mice of to skeletal and levels and expressed to of mice, at was using the not acid acid acid adipose acid acid in a new FXR in and studies have suggested that FXR might be expressed in J. J. Biol. Chem. 2005; 280: Full Text Full Text PDF PubMed Scopus Google Scholar, Y. Edwards P.A. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar). In with both FXR and protein levels increased during 3T3-L1 adipocyte differentiation Furthermore, FXR levels were also induced during of with a the of differentiation FXR is expressed at low levels in lower in FXR levels were in skeletal in mice FXR gene expression was reduced in of mice upon high as as in of ob/ob mice the of a role of FXR in FXR in 3T3-L1 effect of FXR activation with the synthetic agonist GW4064 on insulin signaling was measured in differentiated 3T3-L1 observed in of FXR-/- mice, of FXR not insulin signaling However, GW4064 treatment increased the level of kinase phosphorylation and enhanced glucose in 3T3-L1 adipocytes upon insulin and these results that FXR directly modulates insulin signaling in the FXR in a direct role for FXR in the the in derived from FXR-/- mice was investigated in vitro. Interestingly, FXR deficiency the kinetics of the in Indeed, the of several transcription as critical was in FXR-/- mice levels of both peroxisome proliferator-activated receptor and protein were lower the of the differentiation in derived from FXR-/- with mice. In addition, protein a of adipocyte differentiation, was induced at 2 in FXR-/- The expression of the was also lower in from FXR-/- mice. Moreover, the expression of both leptin and the glucose was decreased at in from FXR-/- mice, an impaired The effect of FXR deficiency on adipocyte differentiation was investigated using to in induced to and In with the gene expression was a in in derived from FXR-/- mice, with a reduced of lipid at In addition, was a in the of the lipid both Indeed, the of lipid was reduced in from FXR-/- mice, that FXR directly with the lipid these results that FXR plays a role in adipocyte differentiation and function. The in of FXR-deficient the of gene by in peripheral insulin studies were in and skeletal from and FXR-/- mice In WAT, the expression of the PPARγ, and were the levels of both and were increased in from FXR-/- with mice. tissue is an that regulate skeletal insulin sensitivity by and In with decreased leptin concentrations, leptin levels were reduced in from FXR-/- mice. In the expression of and in the regulation of insulin sensitivity was levels were reduced in FXR-/- mice, an effect that not the peripheral insulin resistance but the decreased of these of in fatty acid phosphoenolpyruvate were not by the of FXR in levels of a enzyme in were reduced in FXR-/- with mice. In addition, the increased expression of in the of lipoprotein fatty acid in not with the reduced adipocyte of FXR-/- mice. and fatty acid to as endogenous of both and B. Endocr. Rev. PubMed Scopus Google Scholar). In with the increased concentrations in FXR-/- mice, both and levels were increased in skeletal of FXR-/- mice. Moreover, a of in and and was in of FXR-/- mice These results that FXR in skeletal muscle. FXR Treatment in in ob/ob the effect of FXR agonist treatment on insulin resistance was in vivo in mice. were for with GW4064 FXR agonist treatment effect on glucose homeostasis in and during a mice not genetically obese male ob/ob mice were In mouse of insulin GW4064 treatment not as as Whereas fasting glucose concentrations were GW4064 insulin concentrations decreased in the an in insulin sensitivity from and indicated both an improved glucose and an enhanced insulin sensitivity in ob/ob mice with controls A and GW4064 treatment effect on plasma glucose concentrations in the and during a FXR-/- mice not Moreover, GW4064 treatment also plasma lipid in ob/ob mice. and HDL cholesterol concentrations were decreased in ob/ob mice, and levels of GW4064 of GW4064 treatment on in ob/ob mice male ob/ob mice were either with GW4064 or mice were of fasting, and plasma were to as from from from from from from mice in a new This that FXR to the control of peripheral glucose homeostasis in vivo. FXR-/- mice exhibit reduced and peripheral insulin resistance as by a decreased of peripheral glucose disposal during clamp FXR activation with a synthetic agonist insulin resistance in ob/ob mice. the molecular FXR deficiency is associated with Akt activation in adipose tissue to a in skeletal muscle. In vitro studies using identify FXR as a of adipocyte expression studies in vivo in FXR-/- mice revealed an of the to the increased plasma levels. these findings that FXR plays an important role in the of insulin resistance. data a hepatic and peripheral insulin sensitivity in FXR-/- mice that the of the FXR-/- mice. insulin resistance appears since both glucose and insulin levels decreased in FXR-/- mice at the have that FXR deficiency hepatic insulin sensitivity hepatic insulin signaling (6Duran-Sandoval D. Cariou B. Percevault F. Hennuyer N. Grefhorst A. van Dijk T.H. Gonzalez F.J. Fruchart J.C. Kuipers F. Staels B. J. Biol. Chem. 2005; 280: 29971-29979Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar). Moreover, glucose levels decreased in FXR-/- mice, to an impaired hepatic glucose production (11Cariou B. van Harmelen K. Duran-Sandoval D. van Dijk T. Grefhorst A. Bouchaert E. Fruchart J.C. Gonzalez F.J. Kuipers F. Staels B. FEBS Lett. 2005; 579: 4076-4080Crossref PubMed Scopus (73) Google Scholar). in the the of FXR-/- mice the of hepatic In in the as by the tolerance tests and the hyperinsulinemic peripheral insulin resistance in FXR-/- mice. of is the of the molecular mechanisms underlying the impaired insulin-stimulated Akt activation in peripheral of FXR-/- mice. FXR deficiency to a in FFA, was on the of fatty acid that to and impaired phosphorylation and 3-kinase upon insulin Y. D. H. Y. R. B. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, J. 2000; PubMed Scopus Google Scholar). However, we were to in the insulin signaling of Moreover, gene expression of several negative of insulin signaling, such as not the is that FXR the of such as protein that regulate Akt by both and T. H. K. T. K. T. Y. A. J.M. Cell. Biol. 2004; PubMed Scopus Google Scholar, 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). studies to results that FXR directly adipocyte function. Whereas FXR is not expressed in skeletal K. B. A. F. P.R. R. PubMed Scopus Google studies have suggested that FXR is expressed at a low level in J. J. Biol. Chem. 2005; 280: Full Text Full Text PDF PubMed Scopus Google Scholar, Y. Edwards P.A. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar). FXR levels in of both genetically and obese Moreover, FXR during adipocyte differentiation in vitro both in 3T3-L1 and in adipose FXR, expressed at low has several direct activation of FXR with a synthetic agonist in 3T3-L1 adipocytes to enhanced insulin signaling and insulin-stimulated glucose uptake. FXR deficiency to an impaired in the expression of several in of FXR-/- mice in vivo not with results obtained during the in vitro. is that FXR the kinetics of the expression of transcription the levels at the of the in vitro and in vivo models have from the not gene expression is in of these mice T. N. T. J. PubMed Scopus Google Scholar). FXR also with the lipid in the clearly that from FXR-/- mice were to during the of adipocyte In with new role of FXR in the FXR-/- mice exhibit a decreased with a reduced adipocyte The molecular of such a in in FXR-/- mice remains Indeed, the expression of in lipid in the adipocyte not in of both is the observation that is reduced the increased expression of in fatty acid acid and lipoprotein since of these to decreased in mice T. H. G. A. D.J. J. G. A. J. 2004; PubMed Scopus Google Scholar, K. H. R. R. J. PubMed Scopus Google Scholar). This that an in metabolism at a distal from fatty acid in adipocytes of FXR-/- mice. is the of expression in WAT, since is to lipid in adipocytes in vitro C.J. Genes Dev. 2000; PubMed Google Scholar). However, of a in in reduced and insulin a of Y. Genes Dev. PubMed Scopus Google Scholar). studies to the molecular of FXR function in the resistance is a in the of type 2 diabetes and be to in metabolism. tissue and a of as at both the and level J. Metab. 2004; PubMed Scopus Google Scholar). insulin resistance observed in FXR-/- mice be by in levels of In addition, gene expression of such as and is not increased in FXR-/- mice. In both and plasma levels of leptin reduced in FXR-/- mice, the reduced be that is both that leptin sensitivity is not reduced in FXR-/- mice, at in the In addition, the observation that treatment with a FXR agonist insulin resistance in ob/ob mice the that FXR modulate insulin sensitivity a FXR is not expressed in skeletal muscle, FXR deficiency on major insulin FXR-/- mice also display elevated to their peripheral insulin resistance. Indeed, PubMed Scopus Google Scholar) suggested that elevated plasma concentrations a role in the of insulin resistance a glucose and FXR deficiency a potential for the peripheral insulin resistance observed in FXR-/- mice be that the reduced or impaired of adipocytes to a of the from adipocytes to skeletal muscle. In the increased gene expression of lipoprotein in skeletal as as the increased lipoprotein G. G. Gonzalez F.J. Sinal C.J. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar) to the peripheral insulin resistance observed in FXR-/- mice. Indeed, of lipoprotein in skeletal has to insulin resistance Y. Moore M. Y. A. PubMed Scopus Google Scholar). for the FXR peripheral insulin resistance be activation of the Interestingly, a recent has suggested that activation of skeletal is directly to the of insulin resistance and diabetes in mice, phosphorylation of insulin signaling T. N. Cell Metab. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). In with a role of FXR in we have that FXR deficiency is associated with increased in associated with increased hepatic low density lipoprotein production (6Duran-Sandoval D. Cariou B. Percevault F. Hennuyer N. Grefhorst A. van Dijk T.H. Gonzalez F.J. Fruchart J.C. Kuipers F. Staels B. J. Biol. Chem. 2005; 280: 29971-29979Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar). This to the increased of to the skeletal muscle. studies to determine the contribution of insulin tissue to the of FXR-/- mice. Finally, in vivo results using a synthetic FXR agonist in a mouse of insulin resistance the potential of FXR in the control of glucose homeostasis. Indeed, treatment of ob/ob mice with a specific synthetic FXR agonist improved insulin The data obtained a of a new role for FXR in regulating adipocyte function and insulin resistance. These findings perspectives for the of such as type 2 and that of FXR provide novel and for and for and for on 3T3-L1 and with
Cariou et al. (Tue,) studied this question.