TY - JOUR A1 - Hankir, Mohammed K. A1 - Rotzinger, Laura A1 - Nordbeck, Arno A1 - Corteville, Caroline A1 - Dischinger, Ulrich A1 - Knop, Juna-Lisa A1 - Hoffmann, Annett A1 - Otto, Christoph A1 - Seyfried, Florian T1 - Leptin receptors are not required for Roux-en-Y gastric bypass surgery to normalize energy and glucose homeostasis in rats JF - Nutrients N2 - Sensitization to the adipokine leptin is a promising therapeutic strategy against obesity and its comorbidities and has been proposed to contribute to the lasting metabolic benefits of Roux-en-Y gastric bypass (RYGB) surgery. We formally tested this idea using Zucker fatty fa/fa rats as an established genetic model of obesity, glucose intolerance, and fatty liver due to leptin receptor deficiency. We show that the changes in body weight in these rats following RYGB largely overlaps with that of diet-induced obese Wistar rats with intact leptin receptors. Further, food intake and oral glucose tolerance were normalized in RYGB-treated Zucker fatty fa/fa rats to the levels of lean Zucker fatty fa/+ controls, in association with increased glucagon-like peptide 1 (GLP-1) and insulin release. In contrast, while fatty liver was also normalized in RYGB-treated Zucker fatty fa/fa rats, their circulating levels of the liver enzyme alanine aminotransferase (ALT) remained elevated at the level of obese Zucker fatty fa/fa controls. These findings suggest that the leptin system is not required for the normalization of energy and glucose homeostasis associated with RYGB, but that its potential contribution to the improvements in liver health postoperatively merits further investigation. KW - Roux-en-Y gastric bypass surgery KW - energy homeostasis KW - glucose homeostasis KW - fatty liver KW - leptin system KW - Zucker fatty fa/fa rats Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239550 SN - 2072-6643 VL - 13 IS - 5 ER - 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 - Dischinger, Ulrich A1 - Hasinger, Julia A1 - Königsrainer, Malina A1 - Corteville, Carolin A1 - Otto, Christoph A1 - Fassnacht, Martin A1 - Hankir, Mohamed A1 - Seyfried, Florian Johannes David T1 - Toward a Medical Gastric Bypass: Chronic Feeding Studies With Liraglutide + PYY\(_{3-36}\) Combination Therapy in Diet-Induced Obese Rats JF - Frontiers in Endocrinology N2 - Background Combination therapies of anorectic gut hormones partially mimic the beneficial effects of bariatric surgery. Thus far, the effects of a combined chronic systemic administration of Glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine 3-36 (PYY\(_{3-36}\)) have not been directly compared to Roux-en-Y gastric bypass (RYGB) in a standardized experimental setting. Methods High-fat diet (HFD)-induced obese male Wistar rats were randomized into six treatment groups: (1) RYGB, (2) sham-operation (shams), (3) liraglutide, (4) PYY\(_{3-36}\), (5) PYY\(_{3-36}\)+liraglutide (6), saline. Animals were kept on a free choice high- and low-fat diet. Food intake, preference, and body weight were measured daily for 4 weeks. Open field (OP) and elevated plus maze (EPM) tests were performed. Results RYGB reduced food intake and achieved sustained weight loss. Combined PYY\(_{3-36}\)+liraglutide treatment led to similar and plateaued weight loss compared to RYGB. Combined PYY\(_{3-36}\)+liraglutide treatment was superior to PYY\(_{3-36}\) (p ≤ 0.0001) and liraglutide (p ≤ 0.05 or p ≤ 0.01) mono-therapy. PYY\(_{3-36}\)+liraglutide treatment and RYGB also reduced overall food intake and (less pronounced) high-fat preference compared to controls. The animals showed no signs of abnormal behavior in OF or EPM. Conclusions Liraglutide and PYY\(_{3-36}\) combination therapy vastly mimics reduced food intake, food choice and weight reducing benefits of RYGB. KW - obesity KW - rygb KW - liraglutide KW - peptide tyrosine tyrosine (PYY) KW - treatment KW - gastric bypass KW - peptide tyrosine tyrosine 3-36 (PYY3-36) Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-223113 SN - 1664-2392 VL - 11 ER - TY - JOUR A1 - Basile, Vittoria A1 - Puglisi, Soraya A1 - Altieri, Barbara A1 - Canu, Letizia A1 - Libè, Rossella A1 - Ceccato, Filippo A1 - Beuschlein, Felix A1 - Quinkler, Marcus A1 - Calabrese, Anna A1 - Perotti, Paola A1 - Berchialla, Paola A1 - Dischinger, Ulrich A1 - Megerle, Felix A1 - Baudin, Eric A1 - Bourdeau, Isabelle A1 - Lacroix, André A1 - Loli, Paola A1 - Berruti, Alfredo A1 - Kastelan, Darko A1 - Haak, Harm R. A1 - Fassnacht, Martin A1 - Terzolo, Massimo T1 - What is the optimal duration of adjuvant mitotane therapy in adrenocortical carcinoma? An unanswered question JF - Journal of Personalized Medicine N2 - A relevant issue on the treatment of adrenocortical carcinoma (ACC) concerns the optimal duration of adjuvant mitotane treatment. We tried to address this question, assessing whether a correlation exists between the duration of adjuvant mitotane treatment and recurrence-free survival (RFS) of patients with ACC. We conducted a multicenter retrospective analysis on 154 ACC patients treated for ≥12 months with adjuvant mitotane after radical surgery and who were free of disease at the mitotane stop. During a median follow-up of 38 months, 19 patients (12.3%) experienced recurrence. We calculated the RFS after mitotane (RFSAM), from the landmark time-point of mitotane discontinuation, to overcome immortal time bias. We found a wide variability in the duration of adjuvant mitotane treatment among different centers and also among patients cared for at the same center, reflecting heterogeneous practice. We did not find any survival advantage in patients treated for longer than 24 months. Moreover, the relationship between treatment duration and the frequency of ACC recurrence was not linear after stratifying our patients in tertiles of length of adjuvant treatment. In conclusion, the present findings do not support the concept that extending adjuvant mitotane treatment over two years is beneficial for ACC patients with low to moderate risk of recurrence. KW - mitotane KW - adjuvant treatment KW - adrenocortical cancer KW - recurrence KW - recurrence free survival KW - timing Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236507 SN - 2075-4426 VL - 11 IS - 4 ER -