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13:15 Uhr
FV 01:
Brain insulin action increases communication in reward associated brain regions independent of age and peripheral insulin sensitivity in healthy adults
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Autor:innen:
J. Martin (Germany, DE)
R. Veit (Germany, DE)
A. Birkenfeld (Germany, DE)
M. Heni (Germany, DE)
H. Preissl (Germany, DE)
S. Kullmann (Germany, DE)
Insulin action in the brain effects behavioral and metabolic processes. Specifically, insulin acts on dopamine levels in the striatum, which is part of the brain reward network. We investigated if intranasal insulin administration (INI) acts on the communication of the reward network in healthy adults, and if this is influenced by peripheral insulin sensitivity and age. Methods: Using a randomized within-participant design, 66 healthy adults (35 women, BMI 18–49 kg/m2, age 21–69 years, insulin sensitivity index (ISI)-Matsuda: 3.0-62.5) underwent a resting state MRI measurement before and 30 minutes after INI or placebo spray administration. Connectivity analysis was undertaken using the regions: Ventral tegmental area; Dorsolateral prefrontal cortex (DLPFC); Dorsal, and Ventral Striatum (DS, VS); Hypothalamus, with age, BMI, waist-to-hip ratio, and ISI controlled for as covariates. Partial correlations were used to analyse if age and ISI influence insulin action in the brain. Results: Connectivity analyses showed a time by condition interaction (Pcorrected < 0.001), with significantly increased connectivity within the reward network after INI (Pcorrected =0.042). Specifically, between DS and VS (T(60)=2.82, Pcorrected = 0.02); and between DS and DLPFC (T(60)=2.17, Pcorrected =0.06; P-uncorrected = 0.006). No difference in connectivity was observed in the placebo condition. No associations were observed with age and ISI. Conclusion: We could show that intranasal insulin affects communication within the reward network by increasing striatal functional connectivity. These effects were independent of age and peripheral insulin sensitivity. Whether brain insulin responsiveness in the reward network impacts eating behaviour is a matter for further investigation.
13:26 Uhr
FV 02:
Prospective changes in insulin response and cellularity of white adipose tissue following long-term weight loss
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Autor:innen:
L. Massier (Stockholm, SE)
J. Bäckdahl (Stockholm, SE)
J. Jalkanen (Stockholm, SE)
J. Zhong (Stockholm, SE)
M. Elmastas (Stockholm, SE)
N. Bhalla (Stockholm, SE)
P. Ståhl (Stockholm, SE)
M. Rydén (Stockholm, SE)
N. Mejhert (Stockholm, SE)
Background: White adipose tissue (WAT) regulates a plethora of physiological processes, which require the interaction between multiple resident cell types. In insulin resistance/type 2 diabetes, and upon WAT remodeling by weight alterations, the cellular and spatial organization of WAT is drastically altered. However, the cell types governing these changes and their link to insulin sensitivity remain largely unexplored.
Methods: Spatial transcriptomics and single nucleus RNA sequencing were employed in subcutaneous WAT from subjects before and five years after weight loss induced by gastric bypass surgery. The response to insulin was determined in vivo at both baseline and follow-up in biopsies obtained before and after hyperinsulinemic-euglycemic clamp. Results were validated by FACS and immunofluorescence.
Results: We confirmed the presence of three adipocyte subtypes with distinct transcriptional responses to insulin stimulation. The longitudinal aspect allowed us to study changes in cell heterogeneity following WAT remodeling. Among our unexpected findings, we identified the presence of lipid-associated macrophages (LAMs) in WAT. The proportion of these specialized macrophages was markedly reduced upon weight loss and they displayed a unique response to insulin compared to all other cell types. More specifically, we found that genes encoding macrophage scavenger receptor 1 (MSR1), lysosomal acid lipase/cholesteryl ester hydrolase (LIPA), gamma-aminobutyric acid receptor-associated protein (GABARAP) and Cathepsin S (CTSS) were enriched, suggesting an upregulation of acetylated-LDL uptake and degradation in hyperinsulinemic conditions.
Conclusions: Our joint single cell methods allow us to identify novel insulin responding cell targets that, due to their low proportions, cannot be identified using bulk approaches.
13:37 Uhr
FV 03:
DEP-1 a Novel Modulator of Energy Metabolism
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Autor:innen:
S. Chopra (Nuthetal, DE)
R. Hauffe (Nuthetal, DE)
M. Rath (Nuthetal, DE)
M. Schell (Boston, US)
A. Kleinridders (Nuthetal, DE)
Obesity is associated with insulin and leptin resistance, which affects peripheral tissues as well as the brain. The novel density-enhanced phosphatase-1 (DEP-1), is a known negative modulator of insulin and leptin signaling. Intriguingly, diet-induced obese mice have increased DEP-1 expression in metabolic sensitive tissues, including the brain. In this study, the regulation of DEP-1-dependent metabolic effects was investigated in vitro and in vivo.
To study the functional consequences of DEP-1 deficiency in vitro, we established a DEP-1 knockout (DEP-1 KO) in mouse undifferentiated dopaminergic-like Neuro-2a cells using CRISPR/Cas9. Additionally, we investigated the metabolic consequences of DEP-1 deficiency in the brain by crossing Dep-1 lox/lox mice to forebrain hippocampus-specific CamKIIa Cre mice and fed them a normal chow diet (NCD).
DEP-1 KO cells portrayed a significant increase in phospho-ERK signaling upon acute insulin challenge shown by western blot analysis, suggestive of enhanced insulin signalling. Moreover, female DEP-1 KO mice fed a NCD revealed an increase in white-adipose tissue weight along with elevated adipogenic gene markers. On the other hand, male DEP-1 KO mice displayed significant upregulation in brown adipose tissue (BAT) gene markers in addition to an increase in protein expression of the different oxidative phosphorylation complexes subunits, indicating increased oxidative phosphorylation capacity in BAT of male DEP-1 KO mice.
This suggests that while in vitro DEP-1 deficiency subtly improves insulin sensitivity, DEP-1 KO mice demonstrate DEP-1 as a potential neuronal modulator of energy metabolism.
13:48 Uhr
FV 04:
Verbesserte kognitive Leistung durch netzwerk-basierte Neurostimulation bei Personen mit Übergewicht und Adipositas
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Autor:innen:
T. Ester-Nacke (Tübingen, DE)
R. Veit (Tübingen, DE)
D. Löffler (Tübingen, DE)
A. Birkenfeld (Tübingen, DE)
M. Heni (Ulm, DE)
H. Preissl (Tübingen, DE)
S. Kullmann (Tübingen, DE)
Fragestellung:
Eine beeinträchtigte Insulinwirkung im Gehirn scheint ein wichtiger Risikofaktor für kognitive Störungen zu sein. Vorherige Studien zeigten, dass eine Modulation der Gehirnaktivität durch transkranielle Gleichstromstimulation (tDCS) die kognitive Leistung verbessert. Jedoch gibt es bislang nur wenige Daten zu Auswirkungen auf die kognitive Leistung von tDCS bei Personen mit Übergewicht und Adipositas. Hier untersuchten wir die Effekte einer netzwerk-basierten tDCS auf Insulin-sensitive Hirnregionen.
Methodik:
Im Rahmen eines randomisierten und doppelblinden Studienansatzes erhielten 36 Versuchsteilnehmer mit Übergewicht und Adipositas (36,4 Jahre; BMI 30,6; 17 Männer) an drei aufeinander folgenden Tagen für 25 Minuten entweder eine aktive Stimulation (d.h. anregend oder hemmend) oder eine Schein-Stimulation, die auf das Insulin-sensitive Hirnnetzwerk abzielte. Während der Stimulation absolvierten die Teilnehmer eine Stopp-Signal-Aufgabe zur Messung der Reaktionshemmung. Weitere kognitiven Funktionen (einschließlich Exekutivfunktionen, Gedächtnis, Aufmerksamkeit und Reaktionsgeschwindigkeit) wurden zu Studieneinschluss und einen Tag nach der letzten Stimulation erhoben.
Ergebnis:
Die Stopp-Signal-Reaktionszeit war in der aktiven anregenden Stimulationsgruppe kürzer im Vergleich zur Scheinbehandlung (Estimates = -0.16, p = 0.013). Weiterhin konnte eine signifikante Verbesserung der Gedächtnisleistung (Delayed matching to sample (DMS)) und Aufmerksamkeit (Rapid visual information processing (RVP)) in der aktiven erregenden (DMS: Estimates = 12.21, p = 0.003; RVP: Estimates = 0.03, p = 0.038) und hemmenden Stimulationsgruppe (DMS: Estimates = 10.82, p = 0.008; RVP: Estimates = 0.04, p = 0.015) gegenüber der Scheinstimulationsgruppe gezeigt werden.
Schlussfolgerung:
Die Ergebnisse zeigen, dass die Reaktionshemmung, Gedächtnis und Aufmerksamkeitsprozesse durch eine aktive netzwerk-basierte Neurostimulation auf Insulin-sensitive Hirnareale bei Personen mit Übergewicht und Adipositas verbessert werden können.
13:59 Uhr
FV 05:
Bariatric surgery induces distinct transcriptional and epigenetic changes in skeletal muscle of obese people with and without type 2 diabetes
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Autor:innen:
L. Kovac (Nuthetal, DE)
M. Ouni (Nuthetal, DE)
S. Gancheva (Düsseldorf, DE)
S. Kahl (Düsseldorf, DE)
M. Jähnert (Nuthetal, DE)
M. Roden (Düsseldorf, DE)
A. Schürmann (Nuthetal, DE)
Introduction: Bariatric surgery remains the most effective obesity intervention. To investigate molecular mechanisms underlying the clinical outcomes, we compared skeletal muscle transcriptome and DNA methylome before and one year after bariatric surgery of obese individuals without (OB, n=13) and with type 2 diabetes (T2D, n=13), and identified genes that contribute to improved metabolic characteristics in each group.
Methods: We applied several in silico analyses to gene expression (RNA-sequencing) and DNA methylation data (MethylationEPIC 850K), including a machine learning approach (LASSO) to identify genes whose expression levels were predictive of clinical traits.
Results: Participants with and without T2D exhibited a high number of differentially expressed genes (DEG) (q < 0.05) before (2718 DEG) and after (2881 DEG) surgery. Pathway enrichment analysis indicated that both groups altered expression of DNA repair, insulin and PPAR signaling pathway genes. We identified major contributors of several clinical traits, including whole-body insulin sensitivity. For example, INTS11 and HMGA1 were identified as top predictors of HbA1c, free fatty acid clearance and insulin sensitivity in OB and T2D, respectively. Furthermore, in T2D participants only 49% of DEG were also differentially methylated, compared to 71% in OB.
Conclusion: We provide a comprehensive overview of differential skeletal muscle transcriptome responses to bariatric surgery of obese individuals with and without T2D and identify predictors of improved metabolic traits. Additionally, T2D skeletal muscle appears to be less susceptible to changes in DNA methylation, potentially due to genetic differences and/or medication.
14:10 Uhr
FV 06:
Increased functional connectivity in reward-related brain regions in children with low peripheral insulin sensitivity
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Autor:innen:
L. Semeia (Tübingen, DE)
R. Veit (Tübingen, DE)
S. Zhao (Tübingen, DE)
A. Xiang (Pasadena (CA), US)
A. Birkenfeld (Tübingen, DE)
H. Preissl (Tübingen, DE)
K. Page (Los Angeles (CA), US)
S. Kullmann (Tübingen, DE)
Introduction. In children with obesity, viewing of food images elicits heightened brain responses in regions involved in reward processing. This activation seems to facilitate weight gain and the development of diabetes. The current study investigates changes in brain functional connectivity (FC) during a food cue reactivity task before and after a glucose ingestion in children with low and high insulin sensitivity. Methods. Data from 53 children (36 females) with normal-weight, overweight and obesity between 7-11 years old were analysed. An oral glucose tolerance test was performed to estimate the children’s insulin sensitivity (ISI-Matsuda: 0.94-26.57). Neural processing to food vs. non-food pictures was measured with fMRI before and 30 min after a glucose ingestion in a separate session. Statistical analysis was performed using a factorial design with ‘before/after glucose ingestion’ as a within-subject factor and two between subject factors (high/low ISI (median split)) and male/female), and two covariates (age and BMIz). Results. We found increased FC between reward-related regions in children with lower ISI independent of prandial state (pFWE < 0.05). Moreover, we observed an interaction between ISI and prandial state (pFWE < 0.05). Only children with high ISI increased FC between cognitive and reward-related regions from the fasted to the postprandial state. Conclusions. Our results highlight the role of peripheral insulin sensitivity in children independent of BMI in neural processing of food cues, with a heightened reward network connectivity and lower cognitive network connectivity in the postprandial state. These differences might influence eating behavior and future risk of developing diabetes.
14:21 Uhr
FV 07:
Missense Variant in Ceramide Synthase 2 (CERS2) is Associated with Higher Overnight Energy Expenditure and Hepatic Insulin Resistance in Healthy Humans
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Autor:innen:
S. Heinitz (Leipzig, DE)
M. Traurig (Phoenix, AZ, US)
J. Krakoff (Phoenix, AZ, US)
P. Rabe (Leipzig, DE)
C. Stäubert (Leipzig, DE)
M. Stumvoll (Leipzig, DE)
M. Blüher (Leipzig, DE)
L. Baier (Phoenix, AZ, US)
P. Piaggi (Phoenix, AZ, US)
Research aim: Genetic determinants of inter-individual differences in energy expenditure (EE) remain largely unknown. Participating in cellular signaling pathways, ceramides were identified as putative EE regulators. Current study investigated whether genetic variants within enzymes involved in ceramide synthesis and degradation affect EE.
Methods: EE was assessed for 24h by whole-room indirect calorimetry in a large cohort of Indigenous Americans informative for genome-wide imputation data, body composition, and glucose disposal rate during euglycemic-hyperinsulinemic clamp. Real time cellular metabolism was measured using a Seahorse Analyzer. Association analyses of imputed genotype dosages with metabolic measurements were performed via linear mixed effects. Differences in mitochondrial respiration were assessed via mixed model analyses of repeated measurements obtained during the Seahorse experiments.
Results: Compared to the A allele, heterozygosity for missense variant rs267738 (E115A; A>C) in exon 4 of ceramide synthase 2 (CERS2) was associated with substantially higher sleeping EE (average=+116 kcal/day independent from differences in body composition) and increased rates of endogenous glucose production during insulin-stimulated (mean=+43%) and fasting (mean=+5%) conditions, both being markers of increased hepatic insulin resistance. The C allele for rs267738 did not affect ceramide synthesis in human hepatoma HepG2 cells but led to decreased (mean=−30%) basal mitochondrial respiration in vitro.
Conclusions: These findings are in line with previous mice studies that implicate CerS2 in hepatic insulin resistance and impaired mitochondrial respiration. In summary, we provide evidence that rs267738 in CERS2 affect human metabolism and induce hepatic insulin resistance, presumably via impairment of insulin signaling and alteration of mitochondrial function.
14:32 Uhr
FV 08:
Auswirkungen des COVID-19 Lockdowns auf das Gewicht von Kindern zum Zeitpunkt der Schuleingangsuntersuchung der Region Hannover
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Autor:innen:
F. Reschke (Hannover, DE)
A. Wünsch (Hannover, DE)
C. Weiner (Hannover, DE)
D. Meister (Hannover, DE)
L. Galuschka (Hannover, DE)
A. Wattjes (Hannover, DE)
S. Bantel (Hannover, DE)
Einleitung
Frühkindliches Übergewicht ist einer der größten Risikofaktoren für die Entstehung von Typ 2 Diabetes (1,2). Die COVID19-assoziierten Kontaktbeschränkungsmaßnahmen führten zu einer massiven Veränderung der Alltagsgestaltung wie Ernährung oder Bewegungsverhalten(3,4) - auch bei Kindern. Konsistente und lückenlose populationsbezogene Daten im Vorschulalter fehlen bisher.
Fragestellung:
Diese Studie untersucht die Auswirkungen der COVID19-Pandemie auf das Gewicht aller Vorschulkinder der Region Hannover zum Zeitpunkt der Schuleingangsuntersuchung
Methode:
Bei der Schuleingangsuntersuchung werden standardisiert Körpergewicht und -größe aller Kinder der entsprechenden Alterskohorte erfasst (Vollerhebung) und der Anteil an Kindern mit Übergewicht/Adipositas BMI-SDS > 90. Perzentile) dokumentiert. Diese Studie vergleicht die Ergebnisse der Jahre 2017 bis 2023 untereinander.
Ergebnisse:
Im Mittel 10.879 Vorschulkinder (95% Konfidenzintervall 9.804 : 11.292) wurden jährlich im Rahmen der Schuleingangsuntersuchung gesehen. Der Anteil an Kindern mit Übergewicht/Adipositas stieg vor der Pandemie von 2017/18 (9,7%; n = 1.063) auf 2019/20 (10,3%; n= 1.122) kontinuierlich an (p = 0,134). Seit der Pandemie wurde ein signifikanter Anstieg auf 14,5 % (n = 1.658; p = 0,001) festgestellt. Nach dem kompletten Ende der Beschränkungsmaßnahmen bleibt der Anteil mit 11,9 % (n = 1.424; p< 0,001) signifikant erhöht gegenüber den Vorpandemiejahren.
Diskussion und Schlussfolgerung:
Ein nachhaltiger und signifikanter Anstieg des Anteils an Vorschulkindern mit Übergewicht/Adipositas im Rahmen der Vollerhebung zum Schuleintritt in der Region Hannover wurde festgestellt. Dies spricht für eine deutliche Beeinflussung der Gewichtszusammensetzung von Vorschülern im Zusammenhang mit der COVID19 Pandemie. Weitere Untersuchungen müssen diese Ergebnisse bestätigen und Behandlungsmaßnahmen, wie bspw. Aufklärungskampagnen oder Telehealthmaßnahmen geprüft werden, um dieser Entwicklung Sorge zu tragen.