Lanthionine synthetase C-like protein 2 (LanCL2) is important for adipogenic differentiation

Adipogenic differentiation is a highly regulated process that is necessary for metabolic homeostasis and nutrient sensing. The expression of PPARγ and the subsequent activation of adipogenic genes is critical for the process. In this study, we identified lanthionine synthetase C-like protein 2 (LanCL2) as a positive regulator of adipogenesis in 3T3-L1 cells. Knockdown of LanCL2, but not LanCL1, inhibited adipogenic differentiation, and this effect was not mediated through cAMP or Akt signaling pathways. The expression of early adipogenic markers CCAAT enhancer binding protein β (C/EBPβ) and C/EBPδ remained intact in LanCL2 knockdown cells, but levels of late adipogenic markers PPARγ and C/EBPα were suppressed. The addition of the naturally occurring PPARγ activator 15-deoxy-Δ12,14-prostaglandin J2 or conditioned medium from differentiating cells did not restore differentiation, implying that LanCL2 may not be involved in the production of a secreted endogenous PPARγ ligand. Pulldown assays demonstrated a direct physical interaction between LanCL2 and PPARγ. Consistent with a regulatory role of LanCL2, luciferase reporter assays revealed that full transcriptional activation by PPARγ was dependent on LanCL2. Taken together, our study reveals a novel role of LanCL2 in adipogenesis, specifically involved in PPARγ-mediated transactivation of downstream adipogenic genes. Adipogenic differentiation is a highly regulated process that is necessary for metabolic homeostasis and nutrient sensing. The expression of PPARγ and the subsequent activation of adipogenic genes is critical for the process. In this study, we identified lanthionine synthetase C-like protein 2 (LanCL2) as a positive regulator of adipogenesis in 3T3-L1 cells. Knockdown of LanCL2, but not LanCL1, inhibited adipogenic differentiation, and this effect was not mediated through cAMP or Akt signaling pathways. The expression of early adipogenic markers CCAAT enhancer binding protein β (C/EBPβ) and C/EBPδ remained intact in LanCL2 knockdown cells, but levels of late adipogenic markers PPARγ and C/EBPα were suppressed. The addition of the naturally occurring PPARγ activator 15-deoxy-Δ12,14-prostaglandin J2 or conditioned medium from differentiating cells did not restore differentiation, implying that LanCL2 may not be involved in the production of a secreted endogenous PPARγ ligand. Pulldown assays demonstrated a direct physical interaction between LanCL2 and PPARγ. Consistent with a regulatory role of LanCL2, luciferase reporter assays revealed that full transcriptional activation by PPARγ was dependent on LanCL2. Taken together, our study reveals a novel role of LanCL2 in adipogenesis, specifically involved in PPARγ-mediated transactivation of downstream adipogenic genes. The adipose tissue plays a critical role in lipid metabolism and energy homeostasis. It serves as a physiological depot for the storage of lipids and as an endocrine organ mediating the secretion of a variety of cytokines such as leptin, adiponectin, and TNF-α (1.Lau D.C. Dhillon B. Yan H. Szmitko P.E. Verma S. Adipokines: molecular links between obesity and atheroslcerosis.Am. J. Physiol. Heart Circ. Physiol. 2005; 288: H2031-H2041Crossref PubMed Scopus (736) Google Scholar). Many of these cytokines, often released under conditions of excessive lipid storage, are involved in pathological events such as inflammation and diabetes (2.Fasshauer M. Bluher M. Adipokines in health and disease.Trends Pharmacol. Sci. 2015; 36: 461-470Abstract Full Text Full Text PDF PubMed Scopus (597) Google Scholar). A thorough understanding of the adipogenic process is therefore crucial for developing strategies to combat such comorbidities. For the in vitro study of adipogenesis, 3T3-L1 preadipocytes are the most widely used and best-characterized cell culture model to date (3.Green H. 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Biol. 1996; 16: 4128-4136Crossref PubMed Google Scholar). PPARγ then activates C/EBPα, and the two proteins are involved in a positive-feedback mechanism, reinforcing the expression of each other and the expression of several downstream adipogenic genes (6.Zuo Y. Qiang L. Farmer S.R. Activation of CCAAT/enhancer-binding protein (C/EBP) alpha expression by C/EBP beta during adipogenesis requires a peroxisome proliferator-activated receptor-gamma-associated repression of HDAC1 at the C/ebp alpha gene promoter.J. Biol. Chem. 2006; 281: 7960-7967Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar). Among all the proteins that have been reported to be involved in adipocyte development, PPARγ remains the most critical (7.Rosen E.D. Walkey C.J. Puigserver P. Spiegelman B.M. Transcriptional regulation of adipogenesis.Genes Dev. 2000; 14: 1293-1307Crossref PubMed Google Scholar). 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This process is followed by the transcriptional activation of PPARγ-target genes and marks the final stage of adipogenic differentiation, whereby the mRNA and protein levels for several enzymes involved in triglyceride metabolism, such as adipocyte protein 2 (aP2) and stearoyl-CoA desaturase, increase severalfold and result in the accumulation of fat (10.Nolte R.T. Wisely G.B. Westin S. Cobb J.E. Lambert M.H. Kurokawa R. Rosenfeld M.G. Willson T.M. Glass C.K. Milburn M.V. Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-gamma.Nature. 1998; 395: 137-143Crossref PubMed Scopus (1689) Google Scholar, 11.Miller C.W. Ntambi J.M. Peroxisome proliferators induce mouse liver stearoyl-CoA desaturase 1 gene expression.Proc. Natl. Acad. Sci. USA. 1996; 93: PubMed Scopus Google Scholar, S.R. A. B. Spiegelman B.M. A enhancer is the of gene expression for adipocyte in Natl. Acad. Sci. USA. PubMed Scopus Google Scholar). synthetase C-like proteins are of a involved in the of lanthionine in and of PubMed Scopus Google Scholar). have LanCL1, LanCL2, and on 2, and is involved in in the and with and of and C. M. Y. L. R. H. and expression of required for Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). LanCL2 been to be involved in the signaling downstream to in and cells L. C. L. S. S. C. M. E. G. is necessary for binding and signaling in and in Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). was to increase PPARγ reporter in and knockdown LanCL2 expression to be necessary for this J. P. M. A. R. inflammation activation of peroxisome proliferator-activated receptor Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). reported LanCL2 to be a novel regulator of specifically involved in of Akt by of complex 2 through direct physical interaction with the and the M. J. synthetase C-like protein 2 (LanCL2) is a novel regulator of Biol. Cell. PubMed Scopus Google Scholar). LanCL2 is highly in the and the with expression in all other H. M. R. and expression of a novel of the protein PubMed Scopus Google Scholar). is In this study, we a novel role of LanCL2 in the adipogenic differentiation at the stage of PPARγ-mediated transactivation of adipogenic genes. 3T3-L1 cells were from and were from and were from was from and was from was from and from cell culture were from The were from Cell mouse mouse mouse binding protein and mouse was from and was from was from was by mouse LanCL2 protein as the This mouse and LanCL2. were from for and for were from The were from PPARγ luciferase M. Spiegelman B.M. activates through the production of endogenous Natl. Acad. Sci. USA. 1998; PubMed Scopus Google a of a luciferase reporter by the from S. G. Sarraf P. E. Spiegelman B.M. of the peroxisome proliferator-activated receptor gamma is to Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, Z. E.D. R. S. G. Troy A.E. C. Spiegelman B.M. of C/EBP alpha and PPAR gamma the transcriptional of adipogenesis and Cell. 1999; 3: Full Text Full Text PDF PubMed Scopus Google and protein from For LanCL2 LanCL2 was into with the to the of LanCL2, as reported M. J. synthetase C-like protein 2 (LanCL2) is a novel regulator of Biol. Cell. PubMed Scopus Google Scholar). For expression of LanCL2 was into a and in A a was into the of LanCL2 For expression of mouse from was into a and For LanCL2 was into the and with the to the of LanCL2 A of used for all the is in The 3T3-L1 cells were in with and at in the of For adipogenic differentiation, 2 the were cells were with 1 and 1 This was 2, the medium was by with 1 and cells were 2 with the the cells were for or in and with For differentiation with cAMP the of or were to the medium during the 2 of For differentiation with PPARγ or was to the medium during the 2 of or cells were in with and For LanCL2 in 3T3-L1 cells, LanCL2 was in these cells a and cells were to with for 2 and for 3T3-L1 adipocytes were with in for and in were then with for followed by with in for were to binding of and lipid was with and was at from cells in as and LanCL2 in were from the of Their are as mouse mouse mouse mouse and was by and into cells was with and were a and through a The 3T3-L1 preadipocytes or cells at were with the in the of for followed by with for 3T3-L1 or 1 for 2 The cells were for and cells were with the adipogenic was to the medium at a final of for an 2 the cells were with and in for were with 1 and for from The cells were then with and with 1 for were with and were a and cells were of were in the of and at for at were and of protein for each were with and for at were and to were then for 1 in followed by with the were with with and with were and were cAMP in 3T3-L1 cells were by a from Cell The 3T3-L1 cells in were with 1 in the of for at were and cAMP were the The cAMP were from a cAMP in the 3T3-L1 cells were with the adipogenic for 2 which the conditioned medium was and to and LanCL2 cells in medium was to the and this medium was to the and LanCL2 cells 2 This was the of the was from 3T3-L1 cells the A of of from each was into was on a the expression was to which for a and the expression of which remained during the of differentiation not The for PPARγ and were from The for other are as C/EBPα C/EBPα The for each were of and were to a of the gene not For expression of LanCL2 was into and in 2 cells. were with at for and were in 1 and LanCL2 protein was by a and a LanCL2 protein was used for For expression of E. cells were with mouse PPARγ and with 1 for at PPARγ was as a protein with and was For of PPARγ in cells, was for and the cells were in and Cell were at and were with of protein for at For of PPARγ in 3T3-L1 cells, the cells were for and were and with of protein for at The cell from and 3T3-L1 cells that been with were with for 2 The were with and in for The were used for from cells and endogenous PPARγ from 3T3-L1 cells were by was by For of PPARγ in cells, was in cells for and the cells were in 1 Cell were at for and the were with at for The were with for each and in for The were used for was by and LanCL2 was by PPARγ and LanCL2 have a direct physical of or and were at for with was by with for The were with for each and in for The were used for The protein was by and or protein were by For LanCL2 3T3-L1 or cells were in and with were with for at and cells were a were For of 3T3-L1 cell or LanCL2 cells were in and to for 2 were with for at with and a were cells were with LanCL2 or cells were with 1 and with luciferase luciferase and or was a subsequent cells were and luciferase assays were the from For was with the other in cells The from luciferase were to that of to for in cell and LanCL2 in cells the levels of were from or LanCL2 cells for and were for were For and were was to and the are as The 3T3-L1 preadipocytes were to differentiate by the addition of of lipid was by with differentiation by the expression of LanCL2 during the differentiation process and a of expression of LanCL2 in adipogenic differentiation, we of two mouse LanCL2. An with a was used as a for all of LanCL2 was by LanCL2 differentiation of 3T3-L1 cells, as by and of triglyceride accumulation of LanCL1, on the other did not differentiation of 3T3-L1 cells, implying that the effect on adipocyte differentiation is of LanCL2 in 3T3-L1 cells did not increase the differentiation of these cells that endogenous levels of LanCL2 may be sufficient for mediating full differentiation of these cells to LanCL2 cells to have in to of the of and LanCL2 cells 2 cell for LanCL2 cells A in LanCL2 cells that LanCL2 cells may in during is critical for adipogenic differentiation of 3T3-L1 cells H. An established cell line and its differentiation in the adipose Full Text PDF PubMed Scopus Google Scholar, of cell in 3T3 Natl. Acad. Sci. USA. PubMed Scopus Google Scholar), we the that the differentiation of LanCL2 cells from in LanCL2 cells were at a such that the cells the cell did not differentiation in LanCL2 cells, a role of or in mediating the inhibited differentiation LanCL2 cells be in a necessary for differentiation mediated by the addition of in and LanCL2 cells the addition of that is in LanCL2 cells in have LanCL2 to downstream of the The of are mediated by the of cAMP L. C. L. S. S. C. M. E. G. is necessary for binding and signaling in and in Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). An increase in cAMP is during early of 3T3-L1 differentiation, through M. M. protein by is involved in the regulation of adipogenic genes during fibroblasts PubMed Scopus Google Scholar). therefore to the of differentiation in LanCL2 cells is the result of cAMP The increase in cAMP in 3T3-L1 cells is mediated by H. M. S. M. E. of protein in regulation of expression of the gene in differentiating Biol. Chem. 2006; 281: Full Text Full Text PDF PubMed Scopus Google Scholar), in the adipogenic of cAMP revealed in and LanCL2 cells the addition of a role of cAMP signaling in the adipogenic of LanCL2, we in the differentiation during the 2 of A cAMP and in Full Text PDF PubMed Scopus Google Scholar), in a increase in cAMP in and LanCL2 cells addition of did not differentiation in LanCL2 cells were in cells with a of cAMP that is to and is to as cAMP Y. J. A the of in Cell PubMed Scopus Google Scholar). LanCL2 not to of cAMP in adipogenic have that LanCL2 Akt in liver cells M. J. synthetase C-like protein 2 (LanCL2) is a novel regulator of Biol. Cell. PubMed Scopus Google Scholar). Akt activation the of in the and of in the activation of the protein S.R. P. of a protein which and activates protein Biol. Full Text Full Text PDF PubMed Google Scholar, and regulation of by the 2005; PubMed Scopus Google Scholar). activation of Akt is required for the transcriptional of PPARγ J.M. Transcriptional activation of peroxisome proliferator-activated requires activation of protein A and Akt during adipocyte PubMed Scopus Google Scholar), we Akt signaling be for differentiation in LanCL2 cells. for and during differentiation did not between and LanCL2 cells implying that this is not for the adipogenesis the at which adipogenesis is inhibited in LanCL2 cells, we the expression of early and late adipogenic of C/EBPδ, C/EBPα, and from through of differentiation expression of these proteins on as Z. R.M. expression of C/EBP during adipose conversion of Dev. PubMed Scopus Google Scholar, A. M. of adipocyte differentiation of cells by J. Physiol. Cell Physiol. PubMed Scopus Google Scholar). therefore on the expression of these proteins during from 1 of early adipogenic markers C/EBPβ and C/EBPδ did not in and LanCL2 cells at during the differentiation process the expression of late adipogenic markers C/EBPα, and on and was in cells with LanCL2 revealed that the mRNA levels C/EBPα, and were in LanCL2 cells on and of differentiation expression of PPARγ during adipogenesis requires the and binding of a we LanCL2 cells have a at this An endogenous for PPARγ been to be and secreted by differentiating cells P. M. of and the of PubMed Scopus Google Scholar), and the addition of from differentiating 3T3-L1 cells the transcriptional of resulting in differentiation M. Spiegelman B.M. activates through the production of endogenous Natl. Acad. Sci. USA. 1998; PubMed Scopus Google Scholar). LanCL2 cells are in the of an endogenous the of such a in the of differentiating cells restore differentiation in the cells. from differentiating cells to or LanCL2 cells, 2 the of the This in differentiation in cells, but of differentiation was in LanCL2 cells addition of from LanCL2 cells differentiation in cells, but not in LanCL2 cells that LanCL2 may not differentiation through the production of a secreted PPARγ ligand. then the that LanCL2 cells be in the binding of a PPARγ ligand. addition of 15-deoxy-Δ12,14-prostaglandin J2 an occurring but PPARγ B.M. P. J. Spiegelman B.M. R.M. J2 is a for the adipocyte PPAR Full Text PDF PubMed Scopus Google Scholar), to the differentiation medium in not restore differentiation in LanCL2 cells. and that the protein and mRNA expression levels of late adipogenic genes C/EBPα, and remained in LanCL2 cells in the of and Taken together, these that in the of LanCL2, occurring PPARγ such as or secreted into the medium of differentiating cells, not induce that LanCL2 is not involved in the production of a secreted and that LanCL2 may with the transactivation of adipogenic genes by PPARγ. LanCL2 is involved in the transactivation of the be a direct or physical PPARγ been widely reported to in the with its role as a transcriptional activator Y. of peroxisome proliferator-activated and 17: PubMed Scopus Google Scholar). of revealed nuclear of LanCL2 in 3T3-L1 and cells and PPARγ and LanCL2 to the we the of a physical assays with from 3T3-L1 cells, the expression of endogenous PPARγ is at this lipid accumulation remains that at this endogenous the that is important for adipogenesis (8.Tontonoz P. Hu E. Spiegelman B.M. Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor.Cell. 1994; 79: 1147-1156Abstract Full Text PDF PubMed Scopus (3120) Google Scholar, P. Hu E. A.I. Spiegelman B.M. gamma regulator of an adipocyte Dev. 1994; PubMed Scopus Google and this interaction in cells, we the in cells. PPARγ in cells with endogenous LanCL2 in these cells and in vitro assays PPARγ and LanCL2 proteins demonstrated a direct physical interaction between the two proteins that LanCL2 with we the that LanCL2 PPARγ-mediated transcriptional activation of genes. this we a luciferase reporter by C. A. B. binding of peroxisome proliferator-activated receptor on peroxisome of the Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). expression of PPARγ in cells, which a of endogenous PPARγ the of this reporter The reporter was by the addition of or a activator of PPARγ B.M. P. J. Spiegelman B.M. R.M. J2 is a for the adipocyte PPAR Full Text PDF PubMed Scopus Google Scholar, J.M. Moore Willson T.M. An is a for peroxisome proliferator-activated receptor gamma Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, J. P. C. R. a conformational change in proliferator-activated binding and activation with in 1996; PubMed Scopus Google Scholar). LanCL2 was by of the reporter was under all conditions This was not by PPARγ levels LanCL2 of LanCL2 in cells did not increase that the endogenous of LanCL2 in these cells be sufficient to induce full activation of Consistent with the of PPARγ LanCL2 in these reporter restore adipogenesis in 3T3-L1 cells in which LanCL2 was Taken with the physical interaction between LanCL2 and these an important role of LanCL2 in mediating the full transactivation of PPARγ. to LanCL2 an effect on PPARγ of differentiation, but we were to LanCL2 in 3T3-L1 cells. study LanCL2 as a positive regulator of adipocyte differentiation, as of LanCL2 in 3T3-L1 cells triglyceride The effect was for LanCL2, as of did not a role of cAMP or Akt in mediating the adipogenic in LanCL2 cells. The in differentiation did not early transcription factors C/EBPβ and the in adipogenesis to be at the stage of PPARγ-mediated transactivation of downstream adipogenic genes. we that LanCL2 with PPARγ in cell is in the as and is required for the transactivation of PPARγ. that a study on in cells reported PPARγ in reporter assays LanCL2 J. P. M. A. R. inflammation activation of peroxisome proliferator-activated receptor Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). PPARγ-mediated transcriptional activation of adipogenic genes is an Ligand binding induces a conformational change in the nuclear receptor, resulting in the dissociation of transcriptional such as and the recruitment of several such as binding protein and S.R. Transcriptional of adipocyte 2006; 4: Full Text Full Text PDF PubMed Scopus Google Scholar, P. J.E. M. as a for the peroxisome proliferator-activated receptor Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, A. H. K. 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