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ÃCorresponding author.Institut de Ge ne tique et de Biologie Mole culaire et Cellulaire(IGBMC)INSERM/CNRS/ULP,1,rue Laurent Fries,67404ILLKIRCH,France.

E-mail address:[email protected](D.Metzger).

established in mature adipocytes.We thus generated mice in which RXR a or PPAR g are selectively ablated in adipocytes in a temporally controlled manner.The phenotypic analysis ofsuch mice is presented below.

2.RXR a ablation in adipocytes of prepubertal mice induces alteration of adipocyte differentiation and resistance to obesity

To disrupt in a temporally controlled manner the RXR a gene selectively in adipocytes,we generated

aP2-Cre-ER T2(tg/0)/RXR a L2/À

mice,named hereafter

RXR a ad À/À

pre-mutant mice,bearing one LoxP-flanked RXR a L2allele and one RXR a –null (À)allele,as well as the aP2-Cre-ER T2transgene that expresses,under the control ofthe adipocyte-selective aP2promoter,the conditional Cre-ER T2Cre recombinase whose activity is dependent on Tamoxifen administration [11].

Tamoxifen administration to 4-week-old RXR a ad À/Àpre-mutant mice efficiently converted the RXR a L2allele into RXR a L-allele selectively in adipocytes (Fig.1A ),thus generating RXR a ad À/Àmice.This disruption did not affect RXR b levels in WAT,3months after Tamoxifen administration,while RXR g levels were increased (Fig.1B ,compare lanes 1and 2),indicating a possible compensatory up-regulation of RXR g expression.Note that RXR g expression was up-regulated 2weeks after Tam treatment (Fig.1C ),indicating that RXR a must be functionally ablated in RXR a ad À/Àmice shortly after Tam-induced Cre-mediated disruption ofthe RXR a gene.

Even though the body weight ofRXR a ad À/Àmice fed with a regular diet (named RD-KO mice)was about 10%lower than that ofsimilarly f ed control

(aP2-Cre-ER T2(tg/0)/RXR a +/À

;RD-CT)mice during the first 4weeks following Tam treatment,it progressively reached that ofadult RD-CT mice (Fig.2Aa ).From the age of10weeks,the weight ofRD-KO mice was indistinguishable from that of RD-CT animals,thus

suggesting that RXR a ablation may delay the formation of fat deposits.Moreover,no differences in subcutaneous (inguinal and interscapular)and retroperitoneal WAT weight was observed between 6-month-old RD-KO and RD-CT mice (Fig.2B ),and their adipocytes exhibited a similar size distribution (Fig.2C ,panels a and b).

To investigate whether RXR a controls adipocyte differentiation and/or hypertrophy generated by a caloric intake excess,CT and KO mice were fed with a high fat/high sucrose diet (HFD).In contrast to control animals that became obese (HFD-CT in Fig.2A panel a),the body and WAT weight ofH FD-KO mice remained similar to that ofRD-CT and RD-KO animals (Fig.2Aa and B ).As expected,the adipocytes ofH FD-CT mice were much larger than those ofRD-CT mice,but those ofH FD-KO mice exhibited a size distribution similar to those ofRD-CT and RD-KO animals (Fig.2C ,panel a–d).

As monosodium glutamate (MSG)administration to newborn mice induces hypothalamic lesions that result in a marked obesity at the adult stage ([12–14],see Fig.2A ,panel b,and Fig.2E ),we administered MSG to RXR a ad À/Àpre-mutant new born mice,which were Tam-treated at the age of4weeks.As expected,MSG-treated control animals (MSG-CT)developed an obesity from the age of 10weeks onwards (Fig.2A ,panel b;Fig.2B and E ).Interestingly,the adipocyte population in WAT ofobese MSG-CT animals included not only hypertrophic adipocytes,but also a markedly increased population ofsmall adipocytes,which was not found in HFD-induced obesity [Fig.2C ,compare panel e (MSG-CT,arrows)with panels a (RD-CT)and c (HFD-CT)].These smaller adipocytes most probably represent maturing adipocytes derived from an increased population ofpreadipocytes in MSG-treated animals,as the levels oftranscripts encoding Pref-1,a protein abundant in preadipocytes,but not expressed in mature adipocytes,were strongly increased in MSG-treated mice ([15,16];see Fig.1D ,lanes 1and 3).

T am - + WAT T S P T S P RXR α L2RXR α L-

RXR α (-)RXR βRXR γ36B4

CT

RXR γ36B4

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RXR αad-/-

CT RXR αad-/-(A)

(B)

(C)Fig.1.Efficient and selective temporally controlled RXR a ablation in mouse adipocytes.(A)RXR a inactivation in adipocytes.Cre-ER T2-mediated RXR a disruption was analysed by Southern blotting on DNA extracted from WAT (T)isolated from 4-month-old aP2-Cre-ER T2(tg/0)/RXR a L À/Àmice (RXR a ad À/Àmice),3months after vehicle (À)and Tam (+)treatments,and from the supernatant (S)and pellet (P)fractions obtained by centrifugation of collagenase-treated WAT [11].The position ofRXR a L2,L-and (-)alleles are indicated.(B)Expression ofRXR b and RXR g in RXR a -deficient adipose tissue.RXR b and RXR g mRNA levels were analysed by northern blotting on RNA isolated from WAT of 6-month-old control (CT,lane 1)and RXR a ad À/À(lane 2)mice fed a regular diet [11].36B4RNA was used as an internal control.(C)Altered RXR g expression in the adipose tissue ofRXR a ad À/Àmice 2weeks after Tam injection.RXR g mRNA levels were analysed by northern blotting on RNA isolated from adipose tissue oftwo 6-week-old control (CT,lane 1and 2)and RXR a ad À/À(lane 3and 4)mice,2weeks after Tam treatment.

D.Metzger et al./Prostaglandins,Leukotrienes and Essential Fatty Acids 73(2005)51–58

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In contrast,MSG-treated RXR a adÀ/À(MSG-KO) mice did not develop obesity(Fig.2E).Their body and WAT deposits weights were similar to those ofadult RD-CT animals(Fig.2A,panel b,and Fig.2B),and most oftheir WAT adipocytes were reduced in size when compared to those ofMSG-CT mice,being only slightly larger than adipocytes present in mice fed with a regular diet(RD-CT;in Fig.2C,compare panels fwith panels e and a).Interestingly,much smaller cells,which were not or only poorly stained with Oil Red O,were present in MSG-KO WAT deposits(Fig.2C,panel f,arrows,and data not shown).It is likely that these cells correspond

Fig.2.RXR a adÀ/Àmice are resistant to dietary-and chemically induced obesity.(A)RXR a adÀ/Àmice are resistant to HFD-and MSG-induced obesity.Total body weight ofcontrol(CT)and RXR a adÀ/À(KO)mice under regular diet(RD;a and b),under HFD(a)and after MSG treatment(b) was measured weekly.Each group was composed of10–15males.Values are expressed as the mean+/ÀSEM.(B)Reduced adipose tissue weight in RXR a adÀ/Àmice under HFD-or after MSG treatment compared to control mice.Inguinal(ING),interscapular(INT)and retroperitoneal(RET) WAT weight was determined in6-month-old control(CT)and RXR a adÀ/À(KO)mice,fed with regular diet(RD),high fat diet(HFD)and after MSG treatment.Each group was composed of5–7males.Values are expressed as the mean+/ÀSEM.(C)Impaired adipogenesis in RXR a adÀ/Àmice.Cryosections ofsubcutaneous inguinal WAT f rom6-month-old control(CT;a,c and e)and RXR a adÀ/À(KO;b,d and f)mice,under RD(a and b),HFD(c and d)and after MSG-treatment(e and f)were stained with hematoxylin and eosin[11].Scale bar,160m m.Arrows point to small adipocytes,and preadipocytes or poorly differentiated adipocytes in(e)and(f),respectively.(D)Expression of Pref-1in RXR a-deficient adipose tissue.Pref-1expression was analysed by RT-PCR on RNA isolated from WAT of6-month-old control(CT,lane1,3and5)and RXR a adÀ/À(lane2, 4and6)mice,under RD(lane1and2),after MSG treatment(lane3and4)and under HFD(lane5and6)[11].HPRT was used as an internal control.(E)Gross morphology of6-month-old MSG-treated control(CT)and RXR a adÀ/À(KO)male mice.

D.Metzger et al./Prostaglandins,Leukotrienes and Essential Fatty Acids73(2005)51–5853

to preadipocytes or poorly differentiated adipocytes,as their presence was accompanied by a further increase in Pref-1transcripts,when compared with MSG-CT mice (Fig.1D,compare lanes3and4).Thus,RXR a appears to be required in MSG-treated mice for adipogenesis during both adipocytes differentiation and the forma-tion ofhypertrophic adipocytes.

3.Temporally controlled PPAR c ablation in adipocytes induces their death

To determine the function of PPAR g in mature adipocytes,mice bearing LoxP-flanked PPAR g L2 alleles were bred with aP2-Cre-ER T2transgenic mice to generate aP2-Cre-ER T2(tg/0)/PPAR g L2/L2mice (hereafter named PPAR g adÀ/Àpre-mutant mice),as well as control littermates(aP2-Cre-ER T2(tg/0)/ PPAR g L2/+,aP2-Cre-ER T2(0/0)/PPAR g L2/+,aP2-Cre-ER T2(tg/0)/PPAR g+/+,aP2-Cre-ER T2(0/0)/PPAR g+/+ and aP2-Cre-ER T2(0/0)/PPAR g L2/L2mice)[17].Eight-week-old PPAR g adÀ/Àpre-mutant mice and control mice were intraperitoneally injected with1mg Tam(D0) to produce PPAR g adÀ/Àmutant mice(MT),selectively bearing a PPAR g null mutation in adipocytes,and control mice(CT).Indeed,at day4(D4),430% and420%ofthe PPAR g L2alleles from epididymal white adipose tissue and interscapular brown adipose tissue(iBAT)ofPPAR g adÀ/Àpre-mutant mice,respec-tively,were converted into PPAR g LÀalleles,whereas no Cre-mediated recombination was observed in other cell types or tissues,such as peritoneal macrophages, muscle,kidney and liver[17].Purification ofadipocytes from epididymal WAT of MT mice revealed that PPAR g was ablated in more than90%ofD4 adipocytes,whereas no DNA excision was observed at D0(Fig.3A,and data not shown).Thus,temporally controlled PPAR g ablation in mature white and brown adipocytes was efficiently induced by Tam treatment of PPAR g adÀ/Àpre-mutant mice.

Interestingly,epididymal fat pad and iBAT weights were%lower in MT than in CT mice at D7[17], and the relative body fat content in MT animals was reduced by17–25%from D7to D21.However,at D42 and D49the relative body fat content was similar in MT and CT mice(Fig.3B).

To estimate the fraction of PPAR g-deficient adipo-cytes over time,PPAR g alleles were characterised in purified epididymal adipocytes and iBAT from Tam-treated PPAR g adÀ/Àpre-mutant(MT)and aP2-Cre-ER T2(tg/0)/PPAR g L2/+CT mice at various times after Tam administration.In CT mice,most ifnot all PPAR g L2alleles from epididymal adipocytes were converted into LÀalleles at D4,and similar amounts ofLÀalleles were found for at least6weeks(Fig.3A).In marked contrast,even though PPAR g L2alleles were efficiently converted into PPAR g LÀalleles in WAT adipocytes from MT mice at D4,only half of these PPAR g LÀalleles were left by D14,and none were present at D42 (Fig.3A).Moreover,similar disappearance ofPPAR g LÀalleles between D4and D42also occurred in BAT of MT,but not ofCT mice[17].As the aP2promoter is known to be active only at late stages ofadipocyte differentiation[6],mature white and brown adipocytes most probably died within2to3weeks after PPAR g ablation,and were progressively replaced by new adipocytes generated from PPAR g L2/L2preadipocytes. Histological analysis showed that epididymal fat pads ofPPAR g adÀ/Àpre-mutant and ofuntreated or Tam-treated CT mice contained large adipocytes with a single central large fat droplet and a peripheral nucleus, surrounded by a thin rim ofcytoplasm(Fig.4A a,and 150

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MT

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Fig.3.Temporally controlled PPAR g gene disruption in adipocytes of adult mice.(A)Tamoxifen-induced generation of PPAR g LÀalleles. PCR analysis ofDNA f rom purified epididymal adipocytes isolated from aP2-Cre-ER T2(tg/0)/PPAR g L2/L2mice at times D0,D4,D14and D42,and from control aP2-Cre-ER T2(tg/0)/PPAR g L2/+mice at D0,D4 and D42[17].PCR fragments corresponding to the PPAR g L2,LÀand+alleles are displayed.(B)Body fat content evaluated by DEXA scanning.CT and PPAR g adÀ/Àpre-mutant mice(MT)were analysed before and for7weeks after Tam treatment[17].The percent off at content in mutant mice relative to CT mice for each time point is shown.Values(black squares for CT and open circles for MT)are expressed as the mean+/ÀSEM(n¼7).The body fat content of CT mice for each time point was set to100.*,p o0:05.

D.Metzger et al./Prostaglandins,Leukotrienes and Essential Fatty Acids73(2005)51–58 54

data not shown).Interestingly,in MT mice at D1and D2,few(less than5%)epididymal adipocytes displayed irregular outlines,and supernumerary small lipid droplets were present in about halfofthem(Fig.4,compare a and b,and data not shown).Moreover,in the vicinity ofadipocytes with irregular outlines,neutrophil infiltration was occasionally seen(data not shown). With time,the number ofabnormal adipocytes in-creased,and by D4–D7%ofthe adipocytes were affected and fat droplets were laying free in the connective tissue.The adipose tissue was infiltrated by lymphocytes(B and T cells)and macrophages,forming inflammatory foci in some regions(Fig.4,c and d;and data not shown).Electron microscopy(EM)revealed the presence ofadipocytes with a disrupted cell membrane at D4and D7[17].It is unlikely that adipocyte death was due to defects in lipid droplet formation or holding,as only some of these necrotic adipocytes contained groups ofsmall lipid droplets adjacent to the large lipid droplet(Fig.4e;and data not shown).Moreover,lymphocytes,macrophages and fibroblasts were present in the vicinity ofnecrotic adipocytes and lipid droplets(Fig.4e;see below). Abundant collagen deposits were revealed in inflamma-tory regions,by trichrome staining ofhistological sections at D7,D14and D21(Fig.4f,and data not shown).Importantly,similar defects were observed in subcutaneous fat(data not shown).In marked contrast, at D42–56epididymal and subcutaneous fat pads of mutant mice were similar to those ofCT mice[17],thus suggesting that WAT had regenerated through differ-entiation ofpreadipocytes into mature adipocytes.This was further supported by the strongly increased Pref-1 transcripts at D7and D14in epididymal fat pad of MT mice,whereas their levels remained unchanged in CT mice(Fig.4B).Moreover,in agreement with the histological data,Pref-1RNA levels were similar in D42MT and CT mice(see Fig.4B,and data not shown).Interestingly,when Tam was re-administered to MT mice at D56,abnormalities similar to those described above were observed over a4week period, but had totally disappeared by D116[17].

H istological examination ofBAT sections at D1and D2did not reveal any obvious difference between CT and MT animals(data not shown).However,at D4 %ofbrown adipocytes f rom MT mice contained much larger lipid droplets than those from CT mice (Fig.5,compare a and b).Interestingly,EM analysis revealed the presence ofnumerous brown adipocytes with clumping ofnuclear chromatin in MT mice,as well as hypertrophic mitochondria,with normal or increased cristae density,and swollen mitochondria,characterised by rare or peripherically displaced cristae,in5–10%and 60–70%ofadipocytes,respectively([17]and data not shown).Impaired mitochondrial function was sup-ported by a25–50%reduction in transcripts ofnuclear genes involved in respiratory chain function,such as the ATP synthase F1a,b and d subunits,the adenine nucleotide translocator,the cytochrome C and the cytochrome c-oxidase subunit COX IV at D4[17].At

Fig.4.Abnormalities in WAT ofPPAR g adÀ/Àmutants.(A)Histolo-

gical analysis ofWAT ofPPAR g adÀ/Àmutant mice(MT).Histological

sections from paraffin-embedded epididymal WAT from CT(aP2-Cre-

ER T2(0/0)/PPAR g L2/L2)mice at D2(a)and MT mice at D2(b),D4(c,

d)and D14(f)(Tam injection at D0).(a–d)hematoxylin and eosin

staining.(f)trichrome staining.(e)Ultrastructure of adipose tissue of

MT mice at D7[17].Arrowheads:black,in(b),adipocytes with

abnormal profiles,and in(d)and(e)lymphocytes;white,in(b)and(e),

small lipid droplets in adipocytes;grey,in(c)and(d),neutrophils;in

(e)and(f)fibroblast-like cells;arrow in(d)and(e),macrophages.Lp,

lipid droplet.Scales are indicated in each panel.(B)Expression ofPref-

1in PPAR g adÀ/Àmutant mice.Pref-1expression was analysed by RT-

PCR on RNA extracted from epididymal WAT of CT(lanes2,4,6

and8)and MT(lanes3,5,7and9)mice at D0,D7,D14and D42[17].

HPRT was used as an internal control.

D.Metzger et al./Prostaglandins,Leukotrienes and Essential Fatty Acids73(2005)51–5855

D7and D14,30–40%ofthe BAT section areas contained necrotic adipocytes (Fig.5c ),and were markedly infiltrated by lymphocytes (Fig.5d ).More-over,foci of fibrosis were much larger than at D4(Fig.5e ,and data not shown).EM analysis at D14confirmed the presence ofnumerous necrotic brown adipocytes with swollen and hypertrophic mitochondria,as well as fibroblasts and collagen fibers [17].However,%of cells with high number ofmitochondria contained numerous small lipid droplets (diameter o 0.3m m),abundant ribosomes and polysomes and small clusters ofglycogen (Fig.5f ),features previously reported in newborn adipoblasts (see [18]).Taken together with the progressive loss ofPPAR g L Àalleles and the concomi-tant increase ofPPAR g L2alleles,it appears that PPAR g -null brown adipocytes were progressively re-placed by newly differentiated brown adipocytes.At

D42,all BAT abnormalities had disappeared (data not shown).

4.Conclusion

To study RXR a and PPAR g function in mature adipocytes,we ablated the corresponding genes in adipocytes ofmice in a temporally controlled manner,by using the Tamoxifen-dependent Cre-ER T2recombi-nation system.

We found that mice lacking RXR a in their adipocytes have a normal adiposity when fed a regular diet,but are resistant to dietary-and chemically induced obesity,thus demonstrating that adipocytic RXR a is essential for the formation of hypertrophic adipocytes.Further-more,the increased number ofsmall adipocytes in MSG-treated RXR a ad À/Àmice indicates that RXR a is not only involved in adipocyte hypertrophy,but might also be involved in differentiation of preadipocytes.In contrast,PPAR g -null adipocytes die within a few days,thus demonstrating that this nuclear receptor is essential for mature adipocytes survival.Surprisingly,mice in which PPAR g was ablated in adipocytes by the Cre recombinase expressed under the control ofthe aP2promoter became lipodystrophic only after several months [19].As in these mice,PPAR g is most probably ablated during adipocyte differentiation rather than in mature adipocytes,compensatory mechanisms might substitute for PPAR g functions during adipocyte differentiation.Alternatively or concomitantly,in young mutant animals,PPAR g -null adipocytes might die and be efficiently replaced by newly differentiated adipo-cytes,but progenitor cells might be exhausted with age,thus leading to lipodystrophy.The high number ofsmall adipocyte-like cells in aged mutant mice [19]might correspond to PPAR g -null pre-adipocytes that cannot further differentiate,and as PPAR g was only ablated in 90–95%ofadipocytes,the hypertrophic adipocytes might represent,at least in part,PPAR g -expressing adipocytes.

Even though adipocyte death was neither noticed in RXR b -or RXR g -null mice ([20,21];and our unpub-lished results)nor in RXR a ad À/Àmice,PPAR g most probably exerts its adipocyte vital functions as a heterodimer with RXR.Indeed,ablation ofRXR a in adipocytes ofRXR g -null mice results in similar mature adipocyte death (our published data),thus revealing a functional redundancy between RXR a and RXR g ,which most probably results from a compensatory-enhanced expression ofRXR g in adipocytes of RXR a ad À/Àmice.Interestingly,as mice selectively lacking RXR a in their adipocytes are resistant to HFD-induced obesity,there is no such redundancy between RXR a and RXR g for the function (s)exerted by PPAR g /RXR heterodimers when hypertrophic adi-

Fig.5.H istological analysis ofBAT in PPAR g ad À/Àmutant mice.Histological sections from paraffin-embedded interscapular BAT from CT (aP2-Cre-ER T2(0/0)/PPAR g L2/+)mice at D4(a)and PPAR g ad À/Àmutant (MT)mice (b–e)at D4(b),D7(c)and D14(d and e).(a–d)hematoxylin and eosin staining;(e)trichrome staining.(f)electron microscopic analysis ofMT BAT at D14[17].Arrowheads:white,fused lipid droplets (b)and small lipid droplets (f);black,necrotic area (c);grey,lymphocytes (d),fibroblast-like cells (e)and glycogen (f).Scales are indicated in each panel.m,mitochondria.

D.Metzger et al./Prostaglandins,Leukotrienes and Essential Fatty Acids 73(2005)51–58

56

pocytes are formed during a high-fat diet(HFD) treatment.It appears therefore that the lipogenic and vital functions exerted by PPAR g in mature adipocytes have different requirements for RXR heterodimeric partners:whereas the lipogenic function requires PPAR g/RXR a heterodimers,the vital function can be mediated by either PPAR g/RXR a or PPAR g/RXR g heterodimers.As the RXR a levels are higher than those ofRXR g in adipocytes,the threshold level ofPPAR g/ RXR heterodimers required to ensure the survival of adipocytes is lower than that required to trigger lipogenesis.These differential requirements might ex-plain why heterozygous PPAR g-deficient mice[22,23], as well as mice treated with low affinity PPAR g or RXR antagonists[23,24],are resistant to HFD-induced obesity,and that administration for several weeks of such low affinity RXR or PPAR g antagonists to heterozygous PPAR g-deficient mice is necessary to reach a lipoatrophic state with disappearance ofvisible WAT[24].Partial antagonists ofPPAR g/RXR activity have been proposed to be used to prevent obesity and related diseases such as type2diabetes[23,24].Our data indicate that high affinity full antagonists of PPAR g/ RXR a activity might allow to acutely reduce obesity. The newly differentiated adipocytes expressing PPAR g,which appear within a few weeks after the death ofPPAR g-ablated white and brown adipocytes, most probably derive fromfibroblast-like cells,whose number was strongly increased after ablation of PPAR g. This adipocyte regeneration is in agreement with previousfindings showing that adipose progenitor cells, the origin ofwhich remains controversial,are widely distributed in connective tissues and can proliferate and differentiate into adipocytes in adult tissues[25].The possibility offered by our present observations to massively stimulate this process in adult PPAR g adÀ/Àmice might allow to further characterise such precursor cells in vivo.

Finally,the effectiveness of the Tamoxifen-inducible Cre-ER T2chimeric recombinase expressed under the control ofthe aP2promoter to generate adipocyte-selective temporally controlled targeted mutations in transgenic mice paves the way to the elucidation ofthe function of the many pleiotropic genes that are involved in energy homeostasis,obesity and diabetes. Acknowledgments

We thank R.Lorenz,M.F.Champy(ICS),N. Messaddeq,O.Wendling,A.Dierich and the animal facility staff for excellent technical assistance,M.Mark for helpful discussions and the secretariat for typing the manuscript.R.T.was supported by a fellowship from the Fondation de la Recherche Me dicale.This work was supported by funds from the Centre National de la Recherche Scientifique,the Institut National de la Sante et de la Recherche Me dicale,the Colle ge de France,the Ho pital Universitaire de Strasbourg,the Association pour la Recherche sur le Cancer,the Fondation pour la Recherche Me dicale,the Human Frontier Science Program,the Ministe re de l’Education Nationale de la Recherche et de la Technologie,the Swiss National Science Foundation,the Etat de Vaud and the European Community.

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