TY - JOUR A1 - Dischinger, Ulrich A1 - Heckel, Tobias A1 - Bischler, Thorsten A1 - Hasinger, Julia A1 - Königsrainer, Malina A1 - Schmitt-Böhrer, Angelika A1 - Otto, Christoph A1 - Fassnacht, Martin A1 - Seyfried, Florian A1 - Hankir, Mohammed Khair T1 - Roux-en-Y gastric bypass and caloric restriction but not gut hormone-based treatments profoundly impact the hypothalamic transcriptome in obese rats JF - Nutrients N2 - Background: The hypothalamus is an important brain region for the regulation of energy balance. Roux-en-Y gastric bypass (RYGB) surgery and gut hormone-based treatments are known to reduce body weight, but their effects on hypothalamic gene expression and signaling pathways are poorly studied. Methods: Diet-induced obese male Wistar rats were randomized into the following groups: RYGB, sham operation, sham + body weight-matched (BWM) to the RYGB group, osmotic minipump delivering PYY3-36 (0.1 mg/kg/day), liraglutide s.c. (0.4 mg/kg/day), PYY3-36 + liraglutide, and saline. All groups (except BWM) were kept on a free choice of high- and low-fat diets. Four weeks after interventions, hypothalami were collected for RNA sequencing. Results: While rats in the RYGB, BWM, and PYY3-36 + liraglutide groups had comparable reductions in body weight, only RYGB and BWM treatment had a major impact on hypothalamic gene expression. In these groups, hypothalamic leptin receptor expression as well as the JAK–STAT, PI3K-Akt, and AMPK signaling pathways were upregulated. No significant changes could be detected in PYY3-36 + liraglutide-, liraglutide-, and PYY-treated groups. Conclusions: Despite causing similar body weight changes compared to RYGB and BWM, PYY3-36 + liraglutide treatment does not impact hypothalamic gene expression. Whether this striking difference is favorable or unfavorable to metabolic health in the long term requires further investigation. KW - obesity KW - Roux-en-Y gastric bypass surgery KW - liraglutide KW - PYY3-36 KW - hypothalamic gene expression Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-252392 SN - 2072-6643 VL - 14 IS - 1 ER - TY - JOUR A1 - Delgobo, Murilo A1 - Heinrichs, Margarete A1 - Hapke, Nils A1 - Ashour, DiyaaElDin A1 - Appel, Marc A1 - Srivastava, Mugdha A1 - Heckel, Tobias A1 - Spyridopoulos, Ioakim A1 - Hofmann, Ulrich A1 - Frantz, Stefan A1 - Ramos, Gustavo Campos T1 - Terminally Differentiated CD4\(^+\) T Cells Promote Myocardial Inflammaging JF - Frontiers in Immunology N2 - The cardiovascular and immune systems undergo profound and intertwined alterations with aging. Recent studies have reported that an accumulation of memory and terminally differentiated T cells in elderly subjects can fuel myocardial aging and boost the progression of heart diseases. Nevertheless, it remains unclear whether the immunological senescence profile is sufficient to cause age-related cardiac deterioration or merely acts as an amplifier of previous tissue-intrinsic damage. Herein, we sought to decompose the causality in this cardio-immune crosstalk by studying young mice harboring a senescent-like expanded CD4\(^+\) T cell compartment. Thus, immunodeficient NSG-DR1 mice expressing HLA-DRB1*01:01 were transplanted with human CD4\(^+\) T cells purified from matching donors that rapidly engrafted and expanded in the recipients without causing xenograft reactions. In the donor subjects, the CD4\(^+\) T cell compartment was primarily composed of naïve cells defined as CCR7\(^+\)CD45RO\(^-\). However, when transplanted into young lymphocyte-deficient mice, CD4\(^+\) T cells underwent homeostatic expansion, upregulated expression of PD-1 receptor and strongly shifted towards effector/memory (CCR7\(^-\) CD45RO\(^+\)) and terminally-differentiated phenotypes (CCR7\(^-\)CD45RO\(^-\)), as typically seen in elderly. Differentiated CD4\(^+\) T cells also infiltrated the myocardium of recipient mice at comparable levels to what is observed during physiological aging. In addition, young mice harboring an expanded CD4\(^+\) T cell compartment showed increased numbers of infiltrating monocytes, macrophages and dendritic cells in the heart. Bulk mRNA sequencing analyses further confirmed that expanding T-cells promote myocardial inflammaging, marked by a distinct age-related transcriptomic signature. Altogether, these data indicate that exaggerated CD4\(^+\) T-cell expansion and differentiation, a hallmark of the aging immune system, is sufficient to promote myocardial alterations compatible with inflammaging in juvenile healthy mice. KW - CD4+ T-cells KW - myocardial aging KW - inflammaging KW - NSG animals KW - immunosenescence KW - lymphocytes Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229612 SN - 1664-3224 VL - 12 ER - TY - JOUR A1 - Metzner, Valentin A1 - Herzog, Gloria A1 - Heckel, Tobias A1 - Bischler, Thorsten A1 - Hasinger, Julia A1 - Otto, Christoph A1 - Fassnacht, Martin A1 - Geier, Andreas A1 - Seyfried, Florian A1 - Dischinger, Ulrich T1 - Liraglutide + PYY\(_{3-36}\) combination therapy mimics effects of Roux-en-Y bypass on early NAFLD whilst lacking-behind in metabolic improvements JF - Journal of Clinical Medicine N2 - Background: Treatment options for NAFLD are still limited. Bariatric surgery, such as Roux-en-Y gastric bypass (RYGB), has been shown to improve metabolic and histologic markers of NAFLD. Glucagon-like-peptide-1 (GLP-1) analogues lead to improvements in phase 2 clinical trials. We directly compared the effects of RYGB with a treatment using liraglutide and/or peptide tyrosine tyrosine 3-36 (PYY\(_{3-36}\)) in a rat model for early NAFLD. Methods: Obese male Wistar rats (high-fat diet (HFD)-induced) were randomized into the following treatment groups: RYGB, sham-operation (sham), liraglutide (0.4 mg/kg/day), PYY\(_{3-36}\) (0.1 mg/kg/day), liraglutide+PYY\(_{3-36}\), and saline. After an observation period of 4 weeks, liver samples were histologically evaluated, ELISAs and RNA sequencing + RT-qPCRs were performed. Results: RYGB and liraglutide+PYY\(_{3-36}\) induced a similar body weight loss and, compared to sham/saline, marked histological improvements with significantly less steatosis. However, only RYGB induced significant metabolic improvements (e.g., adiponectin/leptin ratio 18.8 ± 11.8 vs. 2.4 ± 1.2 in liraglutide+PYY\(_{3-36}\)- or 1.4 ± 0.9 in sham-treated rats). Furthermore, RNA sequencing revealed a high number of differentially regulated genes in RYGB treated animals only. Conclusions: The combination therapy of liraglutide+PYY\(_{3-36}\) partly mimics the positive effects of RYGB on weight reduction and on hepatic steatosis, while its effects on metabolic function lack behind RYGB. KW - liraglutide KW - GLP-1 KW - peptide tyrosine tyrosine (PYY) KW - peptide tyrosine tyrosine 3-36 (PYY\(_{3-36}\)) KW - RYGB KW - gastric bypass KW - obesity KW - NASH KW - NAFLD Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-255244 SN - 2077-0383 VL - 11 IS - 3 ER - TY - JOUR A1 - Karikari, Akua A. A1 - McFleder, Rhonda L. A1 - Ribechini, Eliana A1 - Blum, Robert A1 - Bruttel, Valentin A1 - Knorr, Susanne A1 - Gehmeyr, Mona A1 - Volkmann, Jens A1 - Brotchie, Jonathan M. A1 - Ahsan, Fadhil A1 - Haack, Beatrice A1 - Monoranu, Camelia-Maria A1 - Keber, Ursula A1 - Yeghiazaryan, Rima A1 - Pagenstecher, Axel A1 - Heckel, Tobias A1 - Bischler, Thorsten A1 - Wischhusen, Jörg A1 - Koprich, James B. A1 - Lutz, Manfred B. A1 - Ip, Chi Wang T1 - Neurodegeneration by α-synuclein-specific T cells in AAV-A53T-α-synuclein Parkinson’s disease mice JF - Brain, Behavior, and Immunity N2 - Background Antigen-specific neuroinflammation and neurodegeneration are characteristic for neuroimmunological diseases. In Parkinson’s disease (PD) pathogenesis, α-synuclein is a known culprit. Evidence for α-synuclein-specific T cell responses was recently obtained in PD. Still, a causative link between these α-synuclein responses and dopaminergic neurodegeneration had been lacking. We thus addressed the functional relevance of α-synuclein-specific immune responses in PD in a mouse model. Methods We utilized a mouse model of PD in which an Adeno-associated Vector 1/2 serotype (AAV1/2) expressing human mutated A53T-α-Synuclein was stereotactically injected into the substantia nigra (SN) of either wildtype C57BL/6 or Recombination-activating gene 1 (RAG1)\(^{-/-}\) mice. Brain, spleen, and lymph node tissues from different time points following injection were then analyzed via FACS, cytokine bead assay, immunohistochemistry and RNA-sequencing to determine the role of T cells and inflammation in this model. Bone marrow transfer from either CD4\(^{+}\)/CD8\(^{-}\), CD4\(^{-}\)/CD8\(^{+}\), or CD4\(^{+}\)/CD8\(^{+}\) (JHD\(^{-/-}\)) mice into the RAG-1\(^{-/-}\) mice was also employed. In addition to the in vivo studies, a newly developed A53T-α-synuclein-expressing neuronal cell culture/immune cell assay was utilized. Results AAV-based overexpression of pathogenic human A53T-α-synuclein in dopaminergic neurons of the SN stimulated T cell infiltration. RNA-sequencing of immune cells from PD mouse brains confirmed a pro-inflammatory gene profile. T cell responses were directed against A53T-α-synuclein-peptides in the vicinity of position 53 (68–78) and surrounding the pathogenically relevant S129 (120–134). T cells were required for α-synuclein-induced neurodegeneration in vivo and in vitro, while B cell deficiency did not protect from dopaminergic neurodegeneration. Conclusions Using T cell and/or B cell deficient mice and a newly developed A53T-α-synuclein-expressing neuronal cell culture/immune cell assay, we confirmed in vivo and in vitro that pathogenic α-synuclein peptide-specific T cell responses can cause dopaminergic neurodegeneration and thereby contribute to PD-like pathology. KW - Parkinson’s disease KW - α-synuclein-specific T cells KW - neurodegeneration Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300600 VL - 101 SP - 194 EP - 210 ER -