Differential Modulation of 3T3-L1 Adipogenesis Mediated by 11β-Hydroxysteroid Dehydrogenase-1 Levels

The localized activation of circulating glucocorticoids in vivo by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) plays a critical role in the development of the metabolic syndrome. However, the precise contribution of 11β-HSD1 in the initiation of adipogenesis by inactive glucocorticoids is not fully understood. 3T3-L1 fibroblasts can be terminally differentiated to mature adipocytes in a glucocorticoid-dependent manner. Both inactive rodent dehydrocorticosterone and human cortisone were able to substitute for the synthetic glucocorticoid dexamethasone in 3T3-L1 adipogenesis, suggesting a potential role for 11β-HSD1 in these effects. Differentiation of 3T3-L1 cells caused a strong increase in 11β-HSD1 protein levels, which occurred late in the differentiation protocol. Reduction of 11β-HSD1 activity in 3T3-L1 fibroblasts, achieved by pharmacological inhibition or adenovirally mediated delivery of short hairpin RNA constructs, specifically blocked the ability of inactive glucocorticoids to drive 3T3-L1 differentiation. However, even modest increases in exogenous 11β-HSD1 expression in 3T3-L1 fibroblasts, to levels comparable with endogenous 11β-HSD1 in differentiated 3T3-L1 adipocytes, were sufficient to block adipogenesis. Luciferase reporter assays indicated that overexpressed 11β-HSD1 was catalyzing the inactivating dehydrogenase reaction, because the ability of both active and inactive glucocorticoids to activate the glucocorticoid receptor were largely suppressed. These results suggest that the temporal regulation of 11β-HSD1 expression is tightly controlled in 3T3-L1 cells, so as to mediate the initiation of differentiation by inactive glucocorticoids and also to prevent the inhibitory activity of prematurely expressed 11β-HSD1 during adipogenesis. The localized activation of circulating glucocorticoids in vivo by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) plays a critical role in the development of the metabolic syndrome. However, the precise contribution of 11β-HSD1 in the initiation of adipogenesis by inactive glucocorticoids is not fully understood. 3T3-L1 fibroblasts can be terminally differentiated to mature adipocytes in a glucocorticoid-dependent manner. Both inactive rodent dehydrocorticosterone and human cortisone were able to substitute for the synthetic glucocorticoid dexamethasone in 3T3-L1 adipogenesis, suggesting a potential role for 11β-HSD1 in these effects. Differentiation of 3T3-L1 cells caused a strong increase in 11β-HSD1 protein levels, which occurred late in the differentiation protocol. Reduction of 11β-HSD1 activity in 3T3-L1 fibroblasts, achieved by pharmacological inhibition or adenovirally mediated delivery of short hairpin RNA constructs, specifically blocked the ability of inactive glucocorticoids to drive 3T3-L1 differentiation. However, even modest increases in exogenous 11β-HSD1 expression in 3T3-L1 fibroblasts, to levels comparable with endogenous 11β-HSD1 in differentiated 3T3-L1 adipocytes, were sufficient to block adipogenesis. Luciferase reporter assays indicated that overexpressed 11β-HSD1 was catalyzing the inactivating dehydrogenase reaction, because the ability of both active and inactive glucocorticoids to activate the glucocorticoid receptor were largely suppressed. These results suggest that the temporal regulation of 11β-HSD1 expression is tightly controlled in 3T3-L1 cells, so as to mediate the initiation of differentiation by inactive glucocorticoids and also to prevent the inhibitory activity of prematurely expressed 11β-HSD1 during adipogenesis. Glucocorticoids are steroid hormones that have vital physiological effects in many tissues throughout the body, including adipose tissue. They are secreted by the adrenal cortex under the hormonal regulation of the hypothalamic-pituitary-adrenal axis and circulate in both active and inactive forms in rodents and humans. In stressful situations, glucocorticoid secretion increases up to 10-fold, resulting in enhanced cardiac function, increased intravascular pressure, improved skeletal muscle work capacity, and more efficient energy mobilization (1McEwen B.S. Biron C.A. Brunson K.W. Bulloch K. Chambers W.H. Dhabhar F.S. Goldfarb R.H. Kitson R.P. Miller A.H. Spencer R.L. Weiss J.M. Brain Res. 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Med. 1997; 241: 451-461Crossref PubMed Scopus (47) Google Scholar). However, glucocorticoids circulate in both active (corticosterone in mice and cortisol in humans) and inactive (dehydrocorticosterone in mice and cortisone in humans) forms. Two enzymes have been described that mediate the localized interconversion of circulating glucocorticoids in vivo. 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1), 3The abbreviations used are: HSD, hydroxysteroid dehydrogenase; shRNA, short hairpin RNA; FBS, fetal bovine serum; MIX, isobutylmethyl xanthine; DHC, dehydrocorticosterone; Dox, doxycycline; GR, glucocorticoid receptor; GRE, glucocorticoid response element; GE, 18β-glycyrrhetinic acid; DMEM, Dulbecco's modified Eagle's medium; PPAR, peroxisome proliferator-activated receptor; C/EBP, CCAAT enhancer-binding protein. was cloned from rat liver and was subsequently detected in a wide range of other tissues, especially adipose and central nervous system (8Jamieson P.M. Chapman K.E. Seckl J.R. J. Steroid Biochem. Mol. Biol. 1999; 68: 245-250Crossref PubMed Scopus (49) Google Scholar). The type 2 isoform (11β-HSD2) was found to have only 20% amino acid homology to 11β-HSD1 (9Albiston A.L. Obeyesekere V.R. Smith R.E. Krozowski Z.S. Mol. Cell Endocrinol. 1994; 105: R11-R17Crossref PubMed Scopus (748) Google Scholar, 10Agarwal A.K. Mune T. Monder C. White P.C. J. Biol. Chem. 1994; 269: 25959-25962Abstract Full Text PDF PubMed Google Scholar) and was reported to be expressed in mineralocorticoid target tissues, such as the kidney, as well as colon, placenta, and vascular endothelium (9Albiston A.L. Obeyesekere V.R. Smith R.E. Krozowski Z.S. Mol. Cell Endocrinol. 1994; 105: R11-R17Crossref PubMed Scopus (748) Google Scholar, 11Whorwood C.B. Ricketts M.L. Stewart P.M. Endocrinology. 1994; 135: 2533-2541Crossref PubMed Scopus (73) Google Scholar, 12Hirasawa G. Sasano H. Takahashi K. Fukushima K. Suzuki T. Hiwatashi N. Toyota T. Krozowski Z.S. Nagura H. J. Clin. 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Seckl J.R. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). 11β-HSD1 was overexpressed in adipose in transgenic there was a increase in the of active H. J. H. Mullins J.J. Seckl J.R. 2001; PubMed Scopus Google Scholar). The also visceral to body which with the of insulin resistance, glucose and of 11β-HSD1 activity localized glucocorticoid and insulin in a of animal the role of 11β-HSD1 in mature adipocytes has been well is the activity of the enzyme in the because of the of the in transgenic which expression of the exogenous the of differentiation. The critical role of glucocorticoids in the initiation of adipogenesis has been in by 3T3-L1 and as well as of cells from adipose Rev. 1998; PubMed Scopus Google Scholar, I.J. S. Hewison M. Stewart P.M. Endocrinology. 1999; PubMed Google Scholar). the 11β-HSD1 pharmacological 18β-glycyrrhetinic acid blocked differentiation by the inactive human glucocorticoid cortisone in suggesting a potential role for the enzyme in the localized activation of glucocorticoids in cells I.J. S. Hewison M. Stewart P.M. Endocrinology. 1999; PubMed Google Scholar). In the 11β-HSD1 enzymes levels in 3T3-L1 fibroblasts the of adenovirally mediated protein and delivery of found that 11β-HSD1 is critical for the of differentiation by inactive However, activity be tightly in a range in fibroblasts, because of 11β-HSD1 to levels comparable with in 3T3-L1 adipocytes blocked glucocorticoid receptor activation and 3T3-L1 differentiation by both inactive and active 3T3-L1 Cell and fibroblasts were as described P.M. A.R. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). Two differentiation was by the of fetal bovine and isobutylmethyl both from in the or of the indicated glucocorticoid with the of the was and the cells were for more in and The cells were in of the differentiation protocol. In was also in the with of 3T3-L1 adipocytes was as described J. PubMed Scopus Google Scholar). of and were from the for 11β-HSD1 generate a the were were of or of and in 2 The were used to 2 of for for 1 for and a were on and the for was the to the for were and fully in both the of of from the 11β-HSD1 were amino acid and the were from 11β-HSD1 was from a the and as The from the were from more of a for 11β-HSD1 was found that with the results from and that is and is have the 11β-HSD1 to and of and 11β-HSD1 were and an from the that was between both was and The were and the with the was as described R. C.B. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) the on of of were to expression of 11β-HSD1 the from The were to in 11β-HSD1 and The a caused by an in the used to the and was not subsequently the a hairpin and the were and to their and the of the the was by cells in were with of 11β-HSD1 and of or to the the were and the 11β-HSD1 levels were by and caused a comparable reduction in exogenous 11β-HSD1 whereas was largely not 1 and and a were the and as described Mol. Biol. PubMed Scopus Google Scholar). Both a reduction in 11β-HSD1 levels in 3T3-L1 cells not so 1 was used for 11β-HSD1 was and as described J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of 3T3-L1 with was overexpressed in 3T3-L1 adipocytes adenovirally mediated as described J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). 3T3-L1 fibroblasts were on were with of the as for the 11β-HSD1 2 in the of the was and the cells were to the differentiation as described and of cells were with on the cells were and The were for and the were to the were on and to & were as described K. P. A.R. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar) with and and Cell and The were with or and were in and a reporter cloned of a in a of was with of and the cells were with and treated with and the indicated of the cells were by for with in of and 2 of was with an and an of in a modified Luciferase activity was subsequently a were by was and was 3T3-L1 3T3-L1 is a used for the of adipogenesis. The of the synthetic glucocorticoid dexamethasone in the differentiation is for the of adipogenesis. the ability of other glucocorticoids to 3T3-L1 3T3-L1 fibroblasts were to by with FBS, and of the synthetic glucocorticoid the active glucocorticoid or the inactive glucocorticoid dehydrocorticosterone was of the the cells were by The cells treated with glucocorticoids their lipid and low levels of In of of the glucocorticoids in the differentiation increased lipid the expression of several and increased insulin The dexamethasone was more which in was more the inactive results were with cortisone and the inactive and active human not these that 3T3-L1 fibroblasts an oxoreductase activity that the activation of or cortisone to drive adipogenesis. 11β-HSD1 during 3T3-L1 the expression of 11β-HSD1 during 3T3-L1 differentiation. 11β-HSD1 protein levels were by a that both and human of 11β-HSD1 3T3-L1 adipocytes were differentiated by a and on were the of the of were by and 11β-HSD1 levels were by In the expression of several to be of 3T3-L1 adipogenesis was Differentiation of 3T3-L1 adipocytes in the increased expression of and Cell Metab. Full Text Full Text PDF PubMed Scopus Google Scholar), by and In levels of protein were during differentiation A.R. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar) and used as a protein 11β-HSD1 expression also during 3T3-L1 differentiation the of the protocol. Both the increased 11β-HSD1 expression and late are in with results 11β-HSD1 expression during 3T3-L1 adipogenesis A. Edwards C.R. Seckl J.R. Chapman K.E. J. Steroid Biochem. Mol. Biol. 1998; PubMed Scopus Google Scholar). the of increased levels 11β-HSD1 that may 11β-HSD1 as has been reported in liver cells V. V. V. Seckl J.R. Chapman K.E. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). However, be to a which in the differentiation were for 11β-HSD1 3T3-L1 fibroblasts were treated for with and the of MIX, and dexamethasone or of the differentiation the were and by in with or and insulin the increase in 11β-HSD1 expression and the of 11β-HSD1 protein was lower and the of insulin to the of and or dexamethasone 11β-HSD1 expression and suggesting an role for insulin on 11β-HSD1 In the were also by In with results Mol. Biol. PubMed Google Scholar), the of expression during differentiation was found to be on the of glucocorticoid in the and whereas of the the glucocorticoid in levels of of 11β-HSD1 Differentiation of 3T3-L1 more the role of 11β-HSD1 in 3T3-L1 RNA to specifically 11β-HSD1 protein levels in 3T3-L1 under during of 11β-HSD1 from several with the for that the were not to 11β-HSD1 from a and the more of a for 11β-HSD1 that was in with the 11β-HSD1 The was for expression in cells and adenovirally mediated in 3T3-L1 potential 11β-HSD1 were identified the a a was also under the were in assays cells and exogenous The and a were as and in fully differentiated 3T3-L1 adipocytes, because endogenous 11β-HSD1 levels were more reduction in 11β-HSD1 protein expression in a was with both constructs, whereas the was not 1 was used for of 3T3-L1 fibroblasts were treated in the or of of 11β-HSD1 and to for 2 3T3-L1 adipogenesis was as dexamethasone or in the differentiation the indicated the were and by were from the of the fibroblasts with 11β-HSD1 largely blocked the of and by as well as the increases in and 11β-HSD1 expression The expression of these may be to the but in these cells Mol. Biol. PubMed Scopus Google Scholar). In the ability of dexamethasone to increase expression of these was which is not because synthetic glucocorticoid is not on the 11β-HSD1 only 11β-HSD1 levels in cells differentiated in the of from the late of 11β-HSD1 expression during 3T3-L1 differentiation with the of the cells on 2 of that levels were low 11β-HSD1 expression to In because was not on in the fibroblasts, 3T3-L1 differentiation was a the in endogenous 11β-HSD1 and other these results that the of by endogenous 11β-HSD1 in 3T3-L1 fibroblasts was an in adipogenesis by 11β-HSD1 in 3T3-L1 11β-HSD1 protein and expression increased during 3T3-L1 adipogenesis 2 and and A. Edwards C.R. Seckl J.R. Chapman K.E. J. Steroid Biochem. Mol. Biol. 1998; PubMed Scopus Google Scholar), the effects of prematurely 11β-HSD1 levels on the differentiation of 3T3-L1 a system for the of 3T3-L1 cells J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of the in the exogenous protein which as a for potential effects from the 3T3-L1 fibroblasts were with of for of in the or of 1 Dox, the were and in by and the effects of 11β-HSD1 on 3T3-L1 differentiation by of or The cells were with a of 11β-HSD1 that increased exogenous enzyme expression in the to levels comparable with endogenous 11β-HSD1 expression in the fully differentiated 3T3-L1 adipocytes Two the cells were with the differentiation of inactive or active a 1 was to of the throughout the to exogenous 11β-HSD1 of the were and by 11β-HSD1 levels were of the on exogenous 11β-HSD1 its enabling differentiation of exogenous endogenous 11β-HSD1 by In cells differentiated in the of Dox, which exogenous 11β-HSD1 both glucocorticoids increased endogenous 11β-HSD1 expression by the of the In of from the in the expression of exogenous 11β-HSD1 comparable with the levels of endogenous enzyme in fully differentiated 3T3-L1 adipocytes However, expression of 11β-HSD1 in 3T3-L1 fibroblasts differentiation by as by expression of endogenous 11β-HSD1 or not These indicated that increased 11β-HSD1 protein expression is controlled during 3T3-L1 differentiation to prevent the of glucocorticoids for initiation of the adipogenesis. The results that overexpressed 11β-HSD1 activity in 3T3-L1 fibroblasts the dehydrogenase reaction, the effects of both and of 11β-HSD1 activity in is by the of the enzyme the A.K. Monder C. White P.C. Mol. Endocrinol. PubMed Scopus Google Scholar). to the of glucocorticoid and glucocorticoid receptor a a response was 3T3-L1 fibroblasts were with the and the were for in or of DHC, or The were and activity was with a In with the differentiation glucocorticoid with a of dexamethasone that endogenous 11β-HSD1 mediated the of to and activation of GR, the cells were treated as that of the pharmacological 11β-HSD1 was to the during glucocorticoid inhibition of 11β-HSD1 activity not or However, the of by the activation of the by In the effects of on 3T3-L1 differentiation were and results were on or of or but blocked the of these by the effects of on activation of the by glucocorticoids were by effects on 3T3-L1 differentiation to the of exogenous 11β-HSD1 activity in 3T3-L1 cells were with 11β-HSD1 with or Dox, and were with the The cells were with of the and activity was in the ability of or to activate was largely of 11β-HSD1 inhibitory was because of exogenous enzyme expression with the effects of both adenovirally mediated 11β-HSD1 on activation these that in 3T3-L1 fibroblasts, endogenous 11β-HSD1 activity was to activate and drive adipogenesis but that of 11β-HSD1 expression in of the dehydrogenase activity, and of both and differentiation. The of both obesity and type 2 has obesity has been as a for the development of type 2 the visceral of obesity is a more of In humans and glucocorticoid excess glucose and/or as well as visceral The of glucose and body have not been In of glucocorticoids in have normal or low glucocorticoid may be to the enzyme which inactive glucocorticoid to active have reported levels of 11β-HSD1 expression in adipose of humans E. T. S. R. D.E. Johnson Walker B.R. J. Clin. Endocrinol. Metab. 2001; PubMed Scopus Google Scholar, E. Walker B.R. S. D.E. M. Johnson R. T. J. Clin. Endocrinol. Metab. PubMed Scopus Google Scholar, S. C. M.C. M. J. Clin. Endocrinol. Metab. PubMed Scopus Google Scholar). activation of glucocorticoids by 11β-HSD1 in adipose may a critical role in the development of visceral obesity and insulin Glucocorticoids circulate in both the active and inactive forms. The liver levels of 11β-HSD1 activity and is the of glucocorticoid activation in vivo. transgenic of 11β-HSD1 in the of mice results in insulin resistance, and J.M. C. Holmes M.C. Seckl J.R. Mullins J.J. Proc. Natl. Acad. Sci. U. S. A. 2004; PubMed Scopus Google Scholar). However, work has that the localized activation of glucocorticoids by adipose may a role in the between glucocorticoids and the development of visceral obesity and insulin of 11β-HSD1 in results in a increase in the localized of active in the H. J. H. Mullins J.J. Seckl J.R. 2001; PubMed Scopus Google Scholar). with the development of visceral obesity and the in insulin resulting in and In the transgenic of under the of the to specifically glucocorticoids in adipose in mice that were to on and increased glucose and insulin H. Seckl J.R. PubMed Scopus Google Scholar). of active glucocorticoid levels in fully differentiated adipocytes the metabolic in vivo. The role of 11β-HSD1 in differentiation is well because of the in the transgenic exogenous protein expression late during adipogenesis. have been the effects of of 11β-HSD1 protein levels in In the adenovirally mediated and delivery in 3T3-L1 cells to the effects of of 11β-HSD1 protein levels on the initiation of adipogenesis by found that 3T3-L1 fibroblasts be to by the glucocorticoids DHC, and were the because are inactive glucocorticoids and an endogenous oxoreductase activity in 3T3-L1 fibroblasts to activate to initiation of differentiation. was by the ability of the pharmacological 11β-HSD1 to block 3T3-L1 differentiation. In the inactive glucocorticoid cortisone has been reported to human differentiation in and was blocked by I.J. S. Hewison M. Stewart P.M. Endocrinology. 1999; PubMed Google Scholar). However, were able to 11β-HSD1 as the activity the of inactive glucocorticoids in 3T3-L1 fibroblasts, because RNA 11β-HSD1 also blocked adipogenesis. In the and on the ability of active dexamethasone or to drive differentiation. found that the activation of by endogenous 11β-HSD1 in 3T3-L1 cells be an in the because reduction of 11β-HSD1 levels by subsequently the expression of including the and that are during adipogenesis. RNA 11β-HSD1 on that the of adipogenesis was to reduction of 11β-HSD1 levels in fibroblasts, as to and/or effects on these the of these that endogenous 11β-HSD1 protein levels increased during 3T3-L1 during the of adipogenesis. 11β-HSD1 was the protein to be of the protein by These results to work that the late of 11β-HSD1 levels during differentiation of 3T3-L1 and A. Edwards C.R. Seckl J.R. Chapman K.E. J. Steroid Biochem. Mol. Biol. 1998; PubMed Scopus Google Scholar). 11β-HSD1 activity in 3T3-L1 fibroblasts is for the reduction and activation of for glucocorticoid to mediate 3T3-L1 adipogenesis and subsequently increase 11β-HSD1 the effects of 11β-HSD1 expression in fibroblasts on differentiation. found that of 3T3-L1 11β-HSD1 blocked adipogenesis in the of the ability of the active glucocorticoid to drive differentiation was also suppressed. These results were not to effects of because of in the exogenous 11β-HSD1 expression and the ability of these glucocorticoids to 3T3-L1 differentiation. the ability of the synthetic glucocorticoid which is not a for to 3T3-L1 adipogenesis was not by 11β-HSD1 the of and 3T3-L1 differentiation was achieved by prematurely 11β-HSD1 in 3T3-L1 fibroblasts to the levels of endogenous 11β-HSD1 found in fully differentiated 3T3-L1 The inhibition of both and action by exogenous 11β-HSD1 that the of the enzyme in 3T3-L1 fibroblasts in the of a inactivating dehydrogenase a that activation by or was largely of 11β-HSD1 In the ability of which is not a for to activate the or to drive 3T3-L1 adipogenesis was not by 11β-HSD1 differentiation of cells from 11β-HSD1 activity from an inactivating dehydrogenase activity to an oxoreductase activity I.J. Walker E.A. Hewison M. Stewart P.M. J. Clin. Endocrinol. Metab. Google Scholar). The of 11β-HSD1 activity to be by the of A.K. Monder C. White P.C. Mol. Endocrinol. PubMed Scopus Google Scholar, E.A. Hewison M. Stewart P.M. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar) and the expression of the enzyme dehydrogenase G.G. Walker E.A. Draper N. P. J. K.L. White P.C. Stewart P.M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). levels increase during adipogenesis A.K. Res. PubMed Scopus Google Scholar), the in 11β-HSD1 activity differentiation in cells, as well as in 3T3-L1 11β-HSD1 activity during differentiation to be both the of expression and these suggest that 11β-HSD1 activity was tightly controlled during 3T3-L1 differentiation. The low levels of 11β-HSD1 in fibroblasts the of inactive glucocorticoids and initiation of differentiation. 11β-HSD1 levels increased late during adipogenesis, the cells have sufficient to generate and the oxoreductase activity of 11β-HSD1 and prevent glucocorticoid and of the These also suggest that transgenic of 11β-HSD1 in under of the may in inhibition of and from obesity and insulin Recently, transgenic dehydrogenase activity were described G.G. Walker E.A. Draper N. P. J. K.L. White P.C. Stewart P.M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). levels were because of of 11β-HSD1 a dehydrogenase but the effects on adipose were not work is to these and the between 11β-HSD1 expression and of activity, localized glucocorticoid of adipogenesis, and development of insulin with

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