Leptin Activates the Anandamide Hydrolase Promoter in Human T Lymphocytes through STAT3

Physiological concentrations of leptin stimulate the activity of the endocannabinoid-degrading enzyme anandamide hydrolase (fatty acid amide hydrolase, FAAH) in human T lymphocytes up to ∼300% over the untreated controls. Stimulation of FAAH occurred through up-regulation of gene expression at transcriptional and translational levels and involved binding of leptin to its receptor with an apparent dissociation constant (Kd) of 1.95 ± 0.14 nm and maximum binding (Bmax) of 392 ± 8 fmol·mg protein−1. Leptin binding to the receptor triggered activation of STAT3 but not STAT1 or STAT5 or the mitogen-activated protein kinases p38, p42, and p44. Peripheral lymphocytes of leptin knock-out (ob/ob) mice showed decreased FAAH activity and expression (∼25% of the wild-type littermates), which were reversed to control levels by exogenous leptin. Analysis of the FAAH promoter showed a cAMP-response element-like site, which is a transcriptional target of STAT3. Consistently, mutation of this site prevented FAAH activation by leptin in transient expression assays. Electrophoretic mobility shift and supershift assays further corroborated the promoter activity data. Taken together, these results suggest that leptin, by up-regulating the FAAH promoter through STAT3, enhances FAAH expression, thus tuning the immunomodulatory effects of anandamide. These findings might also have critical implications for human fertility. Physiological concentrations of leptin stimulate the activity of the endocannabinoid-degrading enzyme anandamide hydrolase (fatty acid amide hydrolase, FAAH) in human T lymphocytes up to ∼300% over the untreated controls. Stimulation of FAAH occurred through up-regulation of gene expression at transcriptional and translational levels and involved binding of leptin to its receptor with an apparent dissociation constant (Kd) of 1.95 ± 0.14 nm and maximum binding (Bmax) of 392 ± 8 fmol·mg protein−1. Leptin binding to the receptor triggered activation of STAT3 but not STAT1 or STAT5 or the mitogen-activated protein kinases p38, p42, and p44. Peripheral lymphocytes of leptin knock-out (ob/ob) mice showed decreased FAAH activity and expression (∼25% of the wild-type littermates), which were reversed to control levels by exogenous leptin. Analysis of the FAAH promoter showed a cAMP-response element-like site, which is a transcriptional target of STAT3. Consistently, mutation of this site prevented FAAH activation by leptin in transient expression assays. Electrophoretic mobility shift and supershift assays further corroborated the promoter activity data. Taken together, these results suggest that leptin, by up-regulating the FAAH promoter through STAT3, enhances FAAH expression, thus tuning the immunomodulatory effects of anandamide. These findings might also have critical implications for human fertility. leptin leptin receptor anandamide (arachidonoylethanolamide) AEA membrane transporter chloramphenicol acetyltransferase cannabinoid receptors 5-(1,1′-dimethylheptyl)-2-[1R,5R-hydroxy-2R-(3-hydroxypropyl) cyclohexyl]-phenol cAMP-response element enzyme-linked immunosorbent assay electrophoretic mobility shift assay fatty acid amide hydrolase goat anti-rabbit/mouse antibodies conjugated with alkaline phosphatase insulin-like growth factor I receptor soluble leptin receptor mitogen-activated protein kinase rabbit anti-goat antibodies conjugated with alkaline phosphatase reverse transcriptase signal transducer and activator of transcription Leptin (L)1 is the 16-kDa non-glycosylated product of the obese gene, which is secreted by adipose cells, is released into the circulation, and transported across the blood-brain barrier into the central nervous system where it regulates energy homeostasis (1Ahima R.S. Flier J.S. Annu. Rev. Physiol. 2000; 62: 413-437Crossref PubMed Scopus (1495) Google Scholar). Leptin also serves systemic functions apart from those related to food intake and energy expenditure in mammals, including regulation of fertility (2Cunningham M.J. Clifton D.K. Steiner R.A. Biol. Reprod. 1999; 60: 216-222Crossref PubMed Scopus (441) Google Scholar) and modulation of immune response (3Matarese G. La Cava A. Sanna V. Lord G.M. Lechler R.I. Fontana S. Zappacosta S. Trends Immunol. 2002; 23: 182-187Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar). These two actions might be interconnected in humans because leptin alters the production from T lymphocytes of T helper 1 and 2 cytokines (4Lord G.M. Matarese G. Howard J.K. Baker R.J. Bloom S.R. Lechler R.I. Nature. 1998; 394: 897-901Crossref PubMed Scopus (1854) Google Scholar), which are critical in regulating embryo implantation and materno-fetal exchanges (5Piccinni M.P. Giudizi M.G. Biagiotti R. Beloni L. Giannarini L. Sampognaro S. Parronchi P. Manetti R. Annunziato F. Livi C. Romagnani S. Maggi E. J. Immunol. 1995; 155: 128-133Crossref PubMed Google Scholar, 6Piccinni M.P. Beloni L. Livi C. Maggi E. Scarselli G. Romagnani S. Nature Med. 1998; 4: 1020-1024Crossref PubMed Scopus (579) Google Scholar). In this line, mice genetically defective in leptin (ob/ob knock-out) are obese, infertile, and immunodeficient, and administration of exogenous leptin can reverse these defects (1Ahima R.S. Flier J.S. Annu. Rev. Physiol. 2000; 62: 413-437Crossref PubMed Scopus (1495) Google Scholar, 2Cunningham M.J. Clifton D.K. Steiner R.A. Biol. Reprod. 1999; 60: 216-222Crossref PubMed Scopus (441) Google Scholar, 3Matarese G. La Cava A. Sanna V. Lord G.M. Lechler R.I. Fontana S. Zappacosta S. Trends Immunol. 2002; 23: 182-187Abstract Full Text Full Text PDF PubMed Scopus (178) Google Scholar, 4Lord G.M. Matarese G. Howard J.K. Baker R.J. Bloom S.R. Lechler R.I. Nature. 1998; 394: 897-901Crossref PubMed Scopus (1854) Google Scholar). Leptin signaling is mediated by the leptin receptor (LR), which exists in at least six different isoforms (1Ahima R.S. Flier J.S. Annu. Rev. Physiol. 2000; 62: 413-437Crossref PubMed Scopus (1495) Google Scholar). Yet, only the long LR isoform has all intracellular motifs necessary for signaling via the signal transducer, activator of transcription (STAT), and/or the mitogen-activated protein kinase (MAPK) pathways (7Wang Y. Kuropatwinski K.K. White D.W. Hawley T.S. Hawley R.G. Tartaglia L.A. Baumann H. J. Biol. Chem. 1997; 272: 16216-16223Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar, 8Banks A.S. Davis S.M. Bates S.H. Myers Jr., M.G. J. Biol. Chem. 2000; 275: 14563-14572Abstract Full Text Full Text PDF PubMed Scopus (655) Google Scholar, 9Bjorbaek C. Buchholz R.M. Davis S.M. Bates S.H. Pierroz D.D. Gu H. Neel B.G. Myers Jr., M.G. Flier J.S. J. Biol. Chem. 2001; 276: 4747-4755Abstract Full Text Full Text PDF PubMed Scopus (305) Google Scholar, 10Wong M. Uddin S. Majchrzak B. Huynh T. Proudfoot A.E. Platanias L.C. Fish E.N. J. Biol. Chem. 2001; 276: 11427-11431Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar, 11Schrager J.A. Der Minassian V. Marsh J.W. J. Biol. Chem. 2002; 277: 6137-6142Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar). The relative importance of these divergent signaling events in leptin action is still unknown. Recently, leptin has been shown to reduce the levels of anandamide (arachidonoylethanolamide, AEA) in the hypothalamus ofob/ob mice, suggesting that this compound partakes of the neural circuitry regulated by leptin (12Di Marzo V. Goparaju S.K. Wang L. Liu J. Batkai S. Jarai Z. Fezza F. Miura G.I. Palmiter R.D. Sugiura T. Kunos G. Nature. 2001; PubMed Scopus Google Scholar). AEA to a of which and of long fatty R. 2002; Full Text PDF PubMed Scopus Google Scholar). to cannabinoid receptors in the central nervous system and in immune cells, thus central actions E. 2002; Full Text PDF PubMed Scopus Google Scholar). with the (12Di Marzo V. Goparaju S.K. Wang L. Liu J. Batkai S. Jarai Z. Fezza F. Miura G.I. Palmiter R.D. Sugiura T. Kunos G. Nature. 2001; PubMed Scopus Google Scholar, Fezza F. Marzo V. J. 2002; PubMed Scopus Google Scholar) and F. M. R. L. F. J. E. A. J. S. S. C. Nature. 2001; PubMed Scopus Google Scholar), AEA has been in the regulation of the of the regulation of fertility H. Wang R.J. A. S.K. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar) and immune P. T. E. 2002; Full Text PDF PubMed Scopus Google Scholar) has These actions of AEA are by through an AEA membrane transporter 2002; Full Text PDF PubMed Scopus Google Scholar), by to and acid by the enzyme AEA hydrolase (fatty acid amide hydrolase, FAAH) S. 2002; Full Text PDF PubMed Scopus Google Scholar). lymphocytes have and and the enzyme has been shown to a critical in regulating human M. H. M. C. A. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). the expression of FAAH is control of and to the of cytokines critical for the factor M. H. M. C. A. J. Immunol. 2001; PubMed Scopus Google Scholar). FAAH has been shown to control the levels of AEA in where FAAH activity AEA to M. H. M. C. A. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, M. H. M. C. A. J. Immunol. 2001; PubMed Scopus Google Scholar, M. T. H. Fezza F. C. Marzo V. A. Reprod. 2002; PubMed Scopus Google Scholar). Taken together, these have a and the system in which is in regulating and fertility in humans M. M. A. 2002; Full Text PDF PubMed Scopus Google Scholar). to leptin might AEA in human thus that the actions of this fertility and be of the events for the effects of leptin. In an of FAAH activity and expression by leptin, triggered through binding to LR and up-regulation of promoter were of the Leptin for mice and anandamide were from and were from leptin and were from antibodies were in the FAAH D.K. S. A. 1997; PubMed Scopus Google Scholar) conjugated to and were by antibodies STAT3, and antibodies and rabbit antibodies and or goat antibodies and rabbit anti-goat antibodies conjugated to alkaline phosphatase were from leptin and insulin-like growth factor I receptor and human leptin leptin were from to the of antibodies or of are to the effects of 1 nm leptin, and in this a of and goat antibodies conjugated to alkaline phosphatase and were from were from the of to the and were into of the to the human Peripheral lymphocytes were by the and were from the by of the M. H. M. C. A. J. Immunol. 2001; PubMed Scopus Google Scholar). T lymphocytes were in with and at a of in M. H. M. C. A. J. 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Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). membrane were from T lymphocytes M. T. M. G. A. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar), were in and at for 1 These membrane were in assays with the cannabinoid M. T. M. G. A. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). The assays were to the binding leptin to C. Buchholz R.M. Davis S.M. Bates S.H. Pierroz D.D. Gu H. Neel B.G. Myers Jr., M.G. Flier J.S. J. Biol. Chem. 2001; 276: 4747-4755Abstract Full Text Full Text PDF PubMed Scopus (305) Google Scholar, L.A. M. J. R. L.A. J. C. S. A. J.S. R.I. 1995; Full Text PDF PubMed Scopus Google Scholar). In this apparent dissociation constant (Kd) and maximum binding (Bmax) were from in the the binding through with the for M. T. M. G. A. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). binding in the of nm leptin C. Buchholz R.M. Davis S.M. Bates S.H. Pierroz D.D. 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Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). from the and the at in at in this are the ± of at least in by the by of the for In of human with for FAAH activity in a FAAH activation at 1 nm and a maximum at the to further the of FAAH activation by nm to prevented by antibodies or by at concentrations of antibodies were at the showed that activation of FAAH T lymphocytes and a maximum at of T showed that antibodies a of the for the of which in in control of the shown in of that FAAH protein to and of the control ± in for with or nm the the levels of at all concentrations of leptin that the different levels of FAAH in these might be to of The antibodies were to further FAAH by which showed that FAAH protein in human T lymphocytes in to the of activity and of of human T lymphocytes showed a of the for FAAH gene, which in of the shown in of that FAAH to and of the control ± in for with or nm the the expression of the gene of showed that FAAH in human T lymphocytes in a to that of activity and protein of human lymphocytes with nm leptin for the levels of AEA in these from to J. G. and A. the the concentrations of leptin, which FAAH and expression were binding and activity in FAAH activity and protein in lymphocytes from leptin knock-out (ob/ob) mice were of the levels in wild-type of a of leptin mice to FAAH activity and in lymphocytes to control it FAAH of wild-type mice of leptin FAAH of human with different of leptin and with or and the of FAAH and are to the of of the in A. The of the for FAAH and for are to the These are of activity and expression in lymphocytes from wild-type and leptin knock-out (ob/ob) of ± ± ± ± ± for ± for activity and expression of FAAH in lymphocytes of of leptin in the and of the untreated ± for the activity and ± for the protein for in a The activity and expression of FAAH in lymphocytes of of leptin in the and of the untreated ± for the activity and ± for the protein were to leptin to a which an apparent dissociation constant (Kd) of 1.95 ± 0.14 nm and maximum binding (Bmax) of 392 ± 8 fmol·mg protein−1. These are in with LR of human (7Wang Y. Kuropatwinski K.K. White D.W. Hawley T.S. Hawley R.G. Tartaglia L.A. Baumann H. J. Biol. Chem. 1997; 272: 16216-16223Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar, B. M. PubMed Scopus (655) Google Scholar) and LR into different (7Wang Y. Kuropatwinski K.K. White D.W. Hawley T.S. Hawley R.G. Tartaglia L.A. Baumann H. J. Biol. Chem. 1997; 272: 16216-16223Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar, L.A. M. J. R. L.A. J. C. S. A. J.S. R.I. 1995; Full Text PDF PubMed Scopus Google Scholar). leptin leptin from its binding site at AEA at concentrations up to The binding of leptin to the long of its receptor is to different signaling pathways by or or A.S. Davis S.M. Bates S.H. Myers Jr., M.G. J. Biol. Chem. 2000; 275: 14563-14572Abstract Full Text Full Text PDF PubMed Scopus (655) Google Scholar, 9Bjorbaek C. Buchholz R.M. Davis S.M. Bates S.H. Pierroz D.D. Gu H. Neel B.G. Myers Jr., M.G. Flier J.S. J. 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B. 2002; PubMed Scopus Google Scholar) were the activation of FAAH in by nm at concentrations to the target The of of or not to further the to these The human FAAH gene has been 1 M. 1998; PubMed Scopus Google Scholar), which has been this to the FAAH promoter FAAH promoter to this it a site site in the reverse a that the of the promoter A. A. T.S. 2002; PubMed Scopus Google Scholar). of the promoter not binding site for a of transcriptional regulation STAT3 to a site in the promoter has been M. T. M.P. F. C. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). a site in the FAAH promoter and transient only the site to or the and the to the gene in T lymphocytes showed that the an promoter the by leptin The two in the human FAAH promoter a that a site to that in the promoter M. T. M.P. F. C. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). of this site by mutation the leptin up-regulation and that leptin through this were from T lymphocytes untreated or for with nm leptin. shown in only with the site of the FAAH not the the mutation for the transient supershift assays showed the of the STAT3 protein in the of FAAH promoter by transient The of the human were in the of to only the to the two a site but with the and are in and T lymphocytes were with the and untreated or with leptin. by the of kinase The of activity were to activity and to the protein and are with to the activity of the which to and In this that leptin FAAH activity and expression in human T lymphocytes through a leptin activation of STAT3 which to up-regulation of a site in FAAH by (ob/ob) mice also that leptin FAAH activity in which for the of immune and fertility defects leptin control in Leptin FAAH activity and expression in at the levels shown to production from these (4Lord G.M. Matarese G. Howard J.K. Baker R.J. Bloom S.R. Lechler R.I. Nature. 1998; 394: 897-901Crossref PubMed Scopus (1854) Google Scholar). These concentrations of were to the binding in T lymphocytes with binding and to those of the leptin receptor (7Wang Y. Kuropatwinski K.K. White D.W. Hawley T.S. Hawley R.G. Tartaglia L.A. Baumann H. J. Biol. Chem. 1997; 272: 16216-16223Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar, B. M. PubMed Scopus (655) Google Scholar). with the of to suggest that have an thus a that that the the for the long isoform of LR (4Lord G.M. Matarese G. Howard J.K. Baker R.J. Bloom S.R. Lechler R.I. Nature. 1998; 394: 897-901Crossref PubMed Scopus (1854) Google Scholar). These findings with the that the effects of FAAH activity and expression were by antibodies and by soluble LR suggest that FAAH activation by occurred through activation of the binding and activity in T lymphocytes suggesting that FAAH the only for the of L. These the of but not receptors or AEA in in in humans M. H. M. C. A. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, M. H. M. C. A. J. Immunol. 2001; PubMed Scopus Google Scholar). are also in with the that FAAH is the of AEA levels in FAAH knock-out mice levels of AEA wild-type M.P. D.K. S. A. 2001; PubMed Scopus Google Scholar), and AEA levels in human with FAAH activity in lymphocytes M. T. H. Fezza F. C. Marzo V. A. Reprod. 2002; PubMed Scopus Google Scholar). In the line, that nm which FAAH in T lymphocytes up to ∼300% over AEA levels in these to FAAH has been shown to be to and in humans E. S. A. 2002; PubMed Scopus Google Scholar), suggesting that this enzyme is for the activity of AEA and that of and (12Di Marzo V. Goparaju S.K. Wang L. Liu J. Batkai S. Jarai Z. Fezza F. Miura G.I. Palmiter R.D. Sugiura T. Kunos G. Nature. 2001; PubMed Scopus Google Scholar, F. M. R. L. F. J. E. A. J. S. S. C. Nature. 2001; PubMed Scopus Google Scholar). In the of FAAH activity and in (ob/ob) with wild-type mice and the of exogenous leptin to reverse this in of a control of FAAH by is by the of of exogenous in wild-type mice which have to LR binding (1Ahima R.S. Flier J.S. Annu. Rev. Physiol. 2000; 62: 413-437Crossref PubMed Scopus (1495) Google Scholar, 2Cunningham M.J. Clifton D.K. Steiner R.A. Biol. Reprod. 1999; 60: 216-222Crossref PubMed Scopus (441) Google Scholar). In this it that AEA not binding to LR suggesting that AEA not to the regulation of its by the up-regulation of FAAH expression by is a of this and is with FAAH activity in The of FAAH activation by further of to the long isoform of LR is to different signaling which and/or signal (7Wang Y. Kuropatwinski K.K. White D.W. Hawley T.S. Hawley R.G. Tartaglia L.A. Baumann H. J. Biol. Chem. 1997; 272: 16216-16223Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar, 8Banks A.S. Davis S.M. Bates S.H. Myers Jr., M.G. J. Biol. Chem. 2000; 275: 14563-14572Abstract Full Text Full Text PDF PubMed Scopus (655) Google Scholar, 9Bjorbaek C. Buchholz R.M. Davis S.M. Bates S.H. Pierroz D.D. Gu H. Neel B.G. Myers Jr., M.G. Flier J.S. J. Biol. Chem. 2001; 276: 4747-4755Abstract Full Text Full Text PDF PubMed Scopus (305) Google Scholar, 10Wong M. Uddin S. Majchrzak B. Huynh T. Proudfoot A.E. Platanias L.C. Fish E.N. J. Biol. Chem. 2001; 276: 11427-11431Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar, 11Schrager J.A. Der Minassian V. Marsh J.W. J. Biol. Chem. 2002; 277: 6137-6142Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar). In human T of only STAT3 which is also in (7Wang Y. Kuropatwinski K.K. White D.W. Hawley T.S. Hawley R.G. Tartaglia L.A. Baumann H. J. Biol. Chem. 1997; 272: 16216-16223Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar, 8Banks A.S. Davis S.M. Bates S.H. Myers Jr., M.G. J. Biol. Chem. 2000; 275: 14563-14572Abstract Full Text Full Text PDF PubMed Scopus (655) Google Scholar, M. T. M.P. F. C. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar) and R.S. Flier J.S. Annu. Rev. Physiol. 2000; 62: 413-437Crossref PubMed Scopus (1495) Google and STAT3 FAAH activity and expression, the FAAH a it a site, which in the human and by site in reverse The FAAH promoter not STAT3 binding motifs it a element the two have been shown to be by STAT3, thus to a of up-regulation of gene transcription M. T. M.P. F. C. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). FAAH promoter with that these STAT3 and supershift assays further corroborated this it can be that by binding to LR in human T STAT3, which in FAAH gene transcription by to a site in the FAAH The regulation of FAAH promoter by in human is in that this is the of the promoter and the of the transcriptional regulation of human two have the promoter R.A. 2001; PubMed Scopus Google Scholar) and the transcriptional regulation A. A. T.S. 2002; PubMed Scopus Google Scholar) of FAAH in In have shown R.A. 2001; PubMed Scopus Google Scholar) or M. 1998; PubMed Scopus Google Scholar) response in the FAAH promoter to that FAAH activity in M. M. M. F. G. A. J. 2000; PubMed Scopus Google Scholar). that the human FAAH promoter not an response element at the In this have shown that FAAH in human to a M. M. A. 2002; PubMed Scopus Google Scholar). These suggest a of FAAH the human and FAAH 1 and D.K. S. A. 1997; PubMed Scopus Google Scholar) and have a M. 1998; PubMed Scopus Google Scholar). In also a of FAAH promoter activity has been R.A. 2001; PubMed Scopus Google Scholar), which might further to divergent regulation in different or in different of the The different transcription of which have been for the FAAH regulation for further In the results the of a the in T lymphocytes by leptin and the system and suggest that but not anandamide transporter or might be the target for of human defects in and fertility. and Kunos and for the assays of anandamide for and and for in and