Head

Portrait of Prof. Pamela Fischer-Posovszky

Prof. Dr. Pamela Fischer-​Posovszky

Ulm Uni­ver­sity Medi­cal Cen­ter
Depart­ment of Ped­ia­trics and Ado­les­cent Medi­cine
Eyth­str. 24 (Rese­arch Lab, House 16)
89075 Ulm, Ger­many

phone: +49-731-500 57415
fax: +49-731-500 57412

e-​mail: pamela.fischer@uniklinik-​ulm.de

Home­page Pro­file Prof. Dr. Fischer-​Posovszky

 

 

Photo of the Fischer-Posovszky Group at the 2019 christmas party of the lab
NameFirst NameFunc­tionPhoneE-​mail
Prof. Dr. Fischer-​PosovszkyPamela Head+49-731-500 57415pamela.fischer@uniklinik-​ulm.de
Halb­ge­bauer Daniel    PhD Stu­dent +49-731-500 57261daniel.halb­ge­bauer@uniklinik-​ulm.de
Kil­lian  Alex­an­draTA  +49-731-500 57421 alex­an­dra.kil­lian@uniklinik-​ulm.de
Pula Taner  PhD Stu­dent   +49-731-500 57261  taner.pula@uniklinik-​ulm.de
Dr. rer. nat. RoosJulian Post-​Doc  +49-731-500 57255 julian.roos@uniklinik-​ulm.de
Schlich­tigFer­di­nand TA  +49-731-500 57086 fer­di­nand.schlich­tig@uniklinik-​ulm.de
Dr. rer. nat. Tews  Daniel  Post-​Doc  +49-731-500 57418daniel.tews@uniklinik-​ulm.de
Wu  Hang  MD Stu­dent  +49-731-500 57282hang.wu@uniklinik-​ulm.de
Dr. med. Zinn­grebe  Julia  Post-​Doc  +49-731-500 57086julia.zinn­grebe@uniklinik-​ulm.de

Rese­arch Pro­file

Obesity is a world­wide epi­de­mic. The exces­sive accu­mu­la­tion of adi­pose tis­sue leads to the deve­lo­p­ment of severe comor­bi­di­ties such as insu­lin resis­tance, type 2 dia­be­tes mel­li­tus, hepa­tic stea­to­sis, car­dio­va­s­cu­lar disea­ses inclu­ding hyper­ten­sion and athe­ros­cle­ro­sis, and an incre­a­sed risk of deve­lo­ping cer­tain types of can­cer. Con­ven­tio­nal the­rapy con­cepts invol­ving e.g. diet, phy­si­cal exer­cise, or beha­vior the­rapy often fail. Thus, there is an urgent need to deve­lop inno­va­tive phar­ma­co­lo­gi­cal treat­ment stra­te­gies. In our group we aim to under­stand the phy­sio­logy and patho­phy­sio­logy of adi­pose tis­sue.

In vitro differentiated human adipocytes. Nuclei are stained in blue, lipid droplet in orange.
In vitro dif­fe­ren­tia­ted human adi­po­cy­tes. Nuclei are stained in blue, lipid dro­plet in orange.

Adi­pose tis­sue is a dyna­mic organ with ~10% of fat cells being rene­wed annu­ally. Our group inves­ti­ga­tes the role of death recep­tors in this remo­de­ling process.

We found out that prea­di­po­cy­tes and adi­po­cy­tes express death recep­tors, among them CD95, TNF recep­tors, and TRAIL recep­tors. Inte­restin­gly, both cell types are pro­tec­ted from apo­pto­sis indu­ced by their respec­tive ligands. Apo­pto­sis of adi­po­cy­tes can only be indu­ced under cer­tain con­di­ti­ons, e.g. by inhi­bi­tion of pro­tein bio­syn­the­sis (Fischer-​Posovszky et al., Endocri­no­logy 2004).

In our cur­rent pro­jects we study non-​apoptotic func­tion of death recep­tors in adi­pose tis­sue. We have elu­ci­da­ted that TRAIL sti­mu­la­tes the pro­li­fe­ra­tion of prea­di­po­cy­tes and inhi­bits their adi­po­ge­nic dif­fe­ren­tia­tion (Fun­cke et al., FASEB J 2015; Zol­ler et al., Cell Death Dis 2016).

Zol­ler V, Fun­cke JB, Roos J, Dahl­haus M, Abd El Hay M, Holz­mann K, Mari­en­feld R, Kietz­mann T, Deba­tin KM, Wabitsch M, Fischer-​Posovszky P: TRAIL (TNF-​related apoptosis-​inducing ligand) indu­ces an inflam­ma­tory response in human adi­po­cy­tes. Sci Rep. 2017 Jul 18;7(1):5691. doi: 10.1038/s41598-017-05932-7.

Zol­ler V, Fun­cke JB, Keu­per M, Abd El Hay M, Deba­tin KM, Wabitsch M, Fischer-​Posovszky P: TRAIL (TNF-​related apoptosis-​inducing ligand) inhi­bits human adi­po­cyte dif­fe­ren­tia­tion via caspase-​mediated down­re­gu­la­tion of adi­po­ge­nic tran­scrip­tion fac­tors. Cell Death Dis. 2016 Oct 13;7(10):e2412. doi: 10.1038/cddis.2016.286.

Fun­cke JB, Zol­ler V, El Hay MA, Deba­tin KM, Wabitsch M, Fischer-​Posovszky P: TNF-​related apoptosis-​inducing ligand pro­mo­tes human prea­di­po­cyte pro­li­fe­ra­tion via ERK1/2 acti­va­tion. FASEB J. 2015 Jul;29(7):3065-75. doi: 10.1096/fj.14-267278.

Keu­per M, Wern­stedt Aster­holm I, Sche­rer PE, West­hoff MA, Möl­ler P, Deba­tin KM, Strauss G, Wabitsch M, Fischer-​Posovszky P: TRAIL (TNF-​related apoptosis-​inducing ligand) regu­la­tes adi­po­cyte meta­bo­lism by caspase-​mediated cleavage of PPAR­gamma. Cell Death Dis. 2013 Jan 24;4:e474. doi: 10.1038/cddis.2012.212.

Immunofluorescent staining of perlipin. Nucleus is stained in blue, lipids in green, and perilipin in red.
Immu­n­o­fluo­res­cent staining of per­li­pin. Nucleus is stained in blue, lipids in green, and peri­li­pin in red.

MicroR­NAs (miRNAs) are small, 18-25 nucleo­tide long, non-​coding RNA mole­cu­les. They are cen­tral regu­la­tors of gene expres­sion and influ­ence a variety of bio­lo­gi­cal proces­ses inclu­ding cel­lu­lar dif­fe­ren­tia­tion and meta­bo­lism.

Obese adi­pose tis­sue is cha­rac­te­ri­zed by patho­lo­gi­cal alte­ra­ti­ons such as hyper­tro­phy of adi­po­cy­tes, inflam­ma­tion, hypo­xia, and fibro­sis. We showed that miRNAs are dif­fe­ren­ti­ally regu­la­ted by inflam­ma­tory sti­muli in adi­po­cy­tes (Roos et al., Sci Rep 2016). We now aim at iden­tify­ing the func­tion of spe­ci­fic miRNAs. miR-146a for example was iden­ti­fied as a nega­tive regu­la­tor of the inflam­ma­tory response in adi­po­cy­tes (Roos et al., Sci Rep 2016).

miRNAs can be released to the cir­cu­la­tion. We also seek to find out if these small RNA mole­cu­les might con­sti­tute novel bio­mar­kers of adi­pose tis­sue health.

Mys­ore R, Ortega FJ, Latorre J, Aho­nen M, Savolainen-​Peltonen H, Fischer-​Posovszky P, Wabitsch M, Olkko­nen VM, Fernández-​Real JM, Hari­das PAN: MicroRNA-​221-3p regu­la­tes angiopoietin-​like 8 (ANGPTL8) expres­sion in adi­po­cy­tes. J Clin Endocri­nol Metab. 2017 Nov 1;102(11):4001-4012. doi: 10.1210/jc.2017-00453.

Roos J, Enlund E, Fun­cke JB, Tews D, Holz­mann K, Deba­tin KM, Wabitsch M, Fischer-​Posovszky P: miR-146a-​mediated sup­pres­sion of the inflam­ma­tory response in human adi­po­cy­tes. Sci Rep. 2016 Dec 6;6:38339. doi: 10.1038/srep38339

Fischer-​Posovszky P, Roos J, Kot­nik P, Bat­telino T, Inzaghi E, Nobili V, Cian­fa­rani S, Wabitsch M: Func­tio­nal signi­ficance and pre­dic­tive value of microR­NAs in ped­ia­tric obesity: tiny mole­cu­les with huge impact? Horm Res Paediatr. 2016;86(1):3-10. doi: 10.1159/000444677.

Mys­ore R, Zhou Y, Säde­virta S, Savolainen-​Peltonen H, Nid­hina Hari­das PA, Soro­nen J, Lei­vo­nen M, Sarin AP, Fischer-​Posovszky P, Wabitsch M, Yki-​Järvinen H, Olkko­nen VM: MicroRNA-​192* impairs adi­po­cyte tri­gly­ce­ride sto­rage. Bio­chim Bio­phys Acta. 2016 Apr;1861(4):342-51. doi: 10.1016/j.bba­lip.2015.12.019.

Pediatric perirenal adipose tissue. Islets of UCP1-positive brown adipocytes are present within white adipose tissue.
Ped­ia­tric per­i­re­nal adi­pose tis­sue. Islets of UCP1-​positive brown adi­po­cy­tes are pre­sent within white adi­pose tis­sue.

The dis­co­very of active brown adi­pose tis­sue in adult humans and its nega­tive asso­cia­tion with fat mass and body weight gave rise to the idea, that this spe­cial tis­sue could be uti­li­zed for the treat­ment of obesity and meta­bo­lic disease.

Brown adi­po­cy­tes are cha­rac­te­ri­zed by the expres­sion of uncou­pling protein-​1 (UCP1). This mito­chon­drial pro­tein is capa­ble of uncou­pling cel­lu­lar respi­ra­tion from ATP syn­the­sis. The pro­ton gra­di­ent, which is built up by the elec­tron trans­port chain is not used for the pro­duc­tion of ATP. Ins­tead, energy is dis­si­pa­ted as heat. UCP1 is acti­va­ted by cold or β-​adrenergic agents, which sti­mu­late lipo­ly­sis and result in the meta­bo­lism of free fatty acids. The­re­fore, brown adi­po­cy­tes can con­sume stored energy. White adi­po­cy­tes do not express UCP1 and are thus not capa­ble of ther­mo­ge­ne­sis. They are respon­si­ble for the sto­rage of excess energy, which can be mobi­li­zed as nee­ded. A third, inter­me­diate phe­no­type of fat cells was named beige adi­po­cyte. Beige adi­po­cy­tes express UCP1 and are ther­mo­ge­nic. They can form within white adi­pose tis­sue depots, e.g. upon pro­lon­ged cold exposure, in a process cal­led “brow­ning”.

Our labo­ra­tory inves­ti­ga­tes white and beige/brown adi­pose tis­sue in humans. From sur­gi­cal ope­ra­ti­ons in the neck region we coll­ec­ted pai­red samp­les of sub­cuta­neous, white adi­pose tis­sue and brown adi­pose tis­sue from the deep neck region (Tews et al., Mol Cell Endocri­nol 2014). Pro­ge­ni­tor cells iso­la­ted from both depots showed a dis­tinct gene expres­sion pro­file. We currently study whe­ther the dif­fe­ren­ti­ally expres­sed genes play a role in white or brown adi­po­ge­ne­sis.

Tews D, Fromme T, Keu­per M, Hof­mann SM, Deba­tin KM, Klin­genspor M, Wabitsch M, Fischer-​Posovszky P: Teneurin-​2 (TENM2) defi­ci­ency indu­ces UCP1 expres­sion in dif­fe­ren­tia­ting human fat cells. Mol Cell Endocri­nol. 2017 Mar 5;443:106-113. doi: 10.1016/j.mce.2017.01.015.

Tews D, Schwar V, Scheit­hauer M, Weber T, Fromme T, Klin­genspor M, Barth TF, Möl­ler P, Holz­mann K, Deba­tin KM, Fischer-​Posovszky P, Wabitsch M. Com­pa­ra­tive gene array ana­ly­sis of pro­ge­ni­tor cells from human pai­red deep neck and sub­cuta­neous adi­pose tis­sue. Mol Cell Endocri­nol. 2014 Sep;395(1-2):41-50. doi: 10.1016/j.mce.2014.07.011.

Tews D, Fischer-​Posovszky P, Fromme T, Klin­genspor M, Fischer J, Rüt­her U, Mari­en­feld R, Barth TF, Möl­ler P, Deba­tin KM, Wabitsch M: FTO defi­ci­ency indu­ces UCP-1 expres­sion and mito­chon­drial uncou­pling in adi­po­cy­tes. Endocri­no­logy. 2013 Sep;154(9):3141-51. doi: 10.1210/en.2012-1873.

3D model of leptin
3D model of lep­tin (http://www.ebi.ac.uk/pdbe/entry/pdb/1ax8).

The hor­mone lep­tin is mainly pro­du­ced by adi­po­cy­tes to signal the energy state of the body and exerts its func­tions as a satiety hor­mone in the brain. Con­ge­ni­tal lep­tin defi­ci­ency is cau­sed by muta­ti­ons in the lep­tin gene resul­ting in defects in pro­tein expres­sion and/or secre­tion. Affec­ted pati­ents suf­fer from hyper­pha­gia and severe, early-​onset obesity. The disease is usually dia­gno­sed by the absence of lep­tin in the cir­cu­la­tion and con­firmed by sequen­cing the lep­tin gene.

Toge­ther with phy­si­ci­ans at the Divi­sion of Ped­ia­tric Endocri­no­logy and Dia­be­tes (Head: Prof. Dr. Mar­tin Wabitsch) and other col­la­bo­ra­tors, we recently cha­rac­te­ri­zed a new form of lep­tin defi­ci­ency – func­tio­nal lep­tin defi­ci­ency (Wabitsch et al., New Engl J Med 2015). Affec­ted pati­ents have high cir­cu­la­ting lep­tin levels, but the muta­ted hor­mone is bio­lo­gi­cally inac­tive and the­re­fore not capa­ble of deli­ver­ing a satiety signal to the brain. The disease can be trea­ted by daily injec­tions of human recom­bi­nant lep­tin lea­ding to a nor­ma­liza­tion of eating beha­vior and rapid weight loss (Wabitsch et al., New Engl J Med 2015; Wabitsch et al., J Clin Endocri­nol Metab 2015).

Our labo­ra­tory inves­ti­ga­tes the bio­lo­gi­cal func­tions of lep­tin and aims to bet­ter under­stand the cli­ni­cal pic­ture of con­ge­ni­tal lep­tin defi­ci­ency.

Nun­zi­ata A, Borck G, Fun­cke JB, Kohls­dorf K, Brandt S, Hin­ney A, Moepps B, Gier­schik P, Deba­tin KM, Fischer-​Posovszky P, Wabitsch M: Esti­ma­ted pre­va­lence of poten­ti­ally dama­ging vari­ants in the lep­tin gene. Mol Cell Pediatr. 2017 Nov 3;4(1):10. doi: 10.1186/s40348-017-0074-x.

Wabitsch M, Prid­zun L, Ranke M, von Schnur­bein J, Moss A, Brandt S, Kohls­dorf K, Moepps B, Schaab M, Fun­cke JB, Gier­schik P, Fischer-​Posovszky P, Fleh­mig B, Kratzsch J: Mea­su­re­ment of immu­n­o­func­tio­nal lep­tin to detect and moni­tor pati­ents with func­tio­nal lep­tin defi­ci­ency. Eur J Endocri­nol. 2017 Mar;176(3):315-322. doi: 10.1530/EJE-16-0821.

Wabitsch M, Fun­cke JB, von Schnur­bein J, Den­zer F, Lahr G, Mazen I, El-​Gammal M, Den­zer C, Moss A, Deba­tin KM, Gier­schik P, Mis­try V, Keogh JM, Farooqi IS, Moepps B, Fischer-​Posovszky P: Severe early-​onset obesity due to bioinac­tive lep­tin cau­sed by a p.N103K muta­tion in the lep­tin gene. J Clin Endocri­nol Metab. 2015 Sep;100(9):3227-30. doi: 10.1210/jc.2015-2263.

Fischer-​Posovszky P, Fun­cke JB, Wabitsch M: Bio­lo­gi­cally inac­tive lep­tin and early-​onset extreme obesity. N Engl J Med. 2015 Mar 26;372(13):1266-7. doi: 10.1056/NEJMc1501146.
Wabitsch M, Fun­cke JB, Len­n­erz B, Kuhnle-​Krahl U, Lahr G, Deba­tin KM, Vat­ter P, Gier­schik P, Moepps B, Fischer-​Posovszky P: Bio­lo­gi­cally inac­tive lep­tin and early-​onset extreme obesity. N Engl J Med. 2015 Jan 1;372(1):48-54. doi: 10.1056/NEJ­Moa1406653.

Fischer-​Posovszky P, von Schnur­bein J, Moepps B, Lahr G, Strauss G, Barth TF, Kas­subek J, Müh­le­der H, Möl­ler P, Deba­tin KM, Gier­schik P, Wabitsch M: A new mis­sense muta­tion in the lep­tin gene cau­ses mild obesity and hypo­go­na­diem wit­hout affec­ting T cell respon­si­veness. J Clin Endocri­nol Metab. 2010 Jun;95(6):2836-40. doi: 10.1210/jc.2009-2466.