TY  - JOUR
A1  - Griebsch, Nora-Isabell
A1  - Kern, Johanna
A1  - Hansen, Jonas
A1  - Rullmann, Michael
A1  - Luthardt, Julia
A1  - Helfmeyer, Stephanie
A1  - Dekorsy, Franziska J.
A1  - Soeder, Marvin
A1  - Hankir, Mohammed K.
A1  - Zientek, Franziska
A1  - Becker, Georg-Alexander
A1  - Patt, Marianne
A1  - Meyer, Philipp M.
A1  - Dietrich, Arne
A1  - Blüher, Matthias
A1  - Ding, Yu-Shin
A1  - Hilbert, Anja
A1  - Sabri, Osama
A1  - Hesse, Swen
T1  - Central serotonin/noradrenaline transporter availability and treatment success in patients with obesity
JF  - Brain Sciences
N2  - Serotonin (5-hydroxytryptamine, 5-HT) as well as noradrenaline (NA) are key modulators of various fundamental brain functions including the control of appetite. While manipulations that alter brain serotoninergic signaling clearly affect body weight, studies implicating 5-HT transporters and NA transporters (5-HTT and NAT, respectively) as a main drug treatment target for human obesity have not been conclusive. The aim of this positron emission tomography (PET) study was to investigate how these central transporters are associated with changes of body weight after 6 months of dietary intervention or Roux-en-Y gastric bypass (RYGB) surgery in order to assess whether 5-HTT as well as NAT availability can predict weight loss and consequently treatment success. The study population consisted of two study cohorts using either the 5-HTT-selective radiotracer [\(^{11}\)C]DASB to measure 5-HTT availability or the NAT-selective radiotracer [\(^{11}\)C]MRB to assess NAT availability. Each group included non-obesity healthy participants, patients with severe obesity (body mass index, BMI, >35 kg/m\(^2\)) following a conservative dietary program (diet) and patients undergoing RYGB surgery within a 6-month follow-up. Overall, changes in BMI were not associated with changes of both 5-HTT and NAT availability, while 5-HTT availability in the dorsal raphe nucleus (DRN) prior to intervention was associated with substantial BMI reduction after RYGB surgery and inversely related with modest BMI reduction after diet. Taken together, the data of our study indicate that 5-HTT and NAT are involved in the pathomechanism of obesity and have the potential to serve as predictors of treatment outcomes.
KW  - obesity
KW  - serotonin
KW  - noradrenaline
KW  - serotonin transporter
KW  - noradrenaline transporter
KW  - Roux-en-Y gastric bypass surgery
KW  - body mass index (BMI; kg/m\(^2\))
KW  - radiotracer
KW  - PET
KW  - PET imaging
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-290294
SN  - 2076-3425
VL  - 12
IS  - 11
ER  - 
TY  - THES
A1  - Jonas, Franziska
T1  - CNS1-dependency of \(in\) \(vivo\) peptide-induced CD4\(^+\)Foxp3\(^+\) regulatory T cells
T1  - CNS1-Abhängigkeit von \(in\) \(vivo\) Peptid-induzierten CD4\(^+\)Foxp3\(^+\) regulatorischen T-Zellen
N2  - CD4+Foxp3+ Tregs can be induced in vitro by TGF-b stimulation. Here, CNS1 deficient CD4+ T cells were found to show compromised Foxp3 upregulation in vitro compared to CNS1 WT CD4+ T cells. Moreover, we could demonstrate that antigen-specific CD4+Foxp3+ Tregs can be induced in vivo by tolerogenic antigen stimulation. Parenteral application of agonist BDC2.5 mimetope induced Foxp3 expression in CD4+ BDC2.5 tg cells. We could show that induction of Foxp3 expression by tolerogenic peptide stimulation is impaired in CNS1 deficient CD4+ BDC2.5 tg cells compared to CNS1 WT CD4+ BDC2.5 tg controls. These results indeed indicate that in vivo induced Tregs share mechanistic characteristics with naturally occurring pTregs.
Additional in vivo experiments with blocking monoclonal anti-TGF-b demonstrated that high dosage TGF-b blockade abrogated peptide-induced Foxp3 expression in CNS1 WT BDC2.5 tg CD4+ cells, akin to what is seen for impaired Foxp3 upregulation in peptide-stimulated CNS1 KO BDC2.5 tg CD4+ cells without anti-TGF-b-treatment.
Adoptive transfer of CD4+CD25- T cells in T cell deficient recipients dramatically increased CD4+Foxp3+ Treg frequencies in both CNS1 WT CD4+ and CNS1 KO CD4+ donor cells. Despite an initially lower increase in Foxp3 expression in CNS1 KO donor cells compared to CNS1 WT donor cells early after transfer, in this setting impaired Treg induction in CNS1 deficient cells was not preserved over time. Consequently, diabetes onset and progression were indistinguishable between mice that received CNS1 WT or CNS1 KO donor cells. Additional Foxp3 induction by peptide stimulation of immunodeficient recipients after transfer of CNS1 WT BDC2.5. tg or CNS1 KO BDC2.5 tg donor cells was not detectable.
N2  - CD4+Foxp3+ Tregs können in vitro mittels TGF-b-Stimulation induziert werden. Im Rahmen dieses Projekts konnte bestätigt werden, dass CNS1-defiziente CD4+ T-Zellen im Vergleich zu CD4+ CNS1 WT-Zellen in vitro eine eingeschränkte Foxp3-Hochregulation zeigen. Des Weiteren konnten wir Antigen-spezifische CD4+Foxp3+ Tregs mittels tolerogener Antigenstimulation in vivo induzieren. Parenteral appliziertes BDC2.5-Mimetop induzierte die Foxp3 Expression in CD4+ BDC2.5 transgenen T-Zellen. Hierbei zeigten CNS1 KO BDC2.5 transgene CD4+ T-Zellen im Vergleich zu CNS1 WT BDC2.5 transgenen CD4+ T-Zell-Kontrollen eine eingeschränkte Hochregulation der Foxp3 Expression nach Mimetop-Stimulation. Peptid-induzierte CD4+Foxp3+ Tregs verhalten sich somit ähnlich wie natürlich vorkommende pTregs.
Unter Verwendung höherer Dosen von anti-TGF-b zeigte sich bei Mimetop-Stimulation im in vivo Experiment eine eingeschränkte Foxp3-Hochregulation der CNS1 WT CD4+ BDC2.5 transgenen T-Zellen, ähnlich wie es bei CNS1 KO CD4+ BDC2.5 transgenen T-Zellen ohne anti-TGF-b-Behandlung zu beobachten war. ...
KW  - Treg
KW  - Regulatorischer T-Lymphozyt
KW  - Diabetes mellitus
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-243887
ER  -