Adipositas stellt einen der größten Risikofaktoren für Folgeerscheinungen wie dem metabolischen Syndrom oder Diabetes dar. Gründe für das hohe Aufkommen von Adipositas sind eine erhöhte Nahrungsaufnahme in Kombination mit verringerter körperlicher Bewegung, welches zu einer Insulinresistenz führen kann. Eine schwerwiegende Folge der Insulinresistenz und Adipositas stellt die diabetische Erkrankung dar. Da die Nahrungsaufnahme durch das Gehirn reguliert wird, zielen Forschungsansätze darauf ab, neue Signalwege mit Einfluss auf den Energiestoffwechsel zu identifizieren und zu untersuchen. Dieses Symposium setzt sich mit aktuellen Forschungsrichtungen in der Hirnforschung auseinander und bietet Einblicke in die Modulation von Gehirnsignalen in Adipositas und Diabetes.
10:35 Uhr
Dopamine Signaling als neue Zielstruktur zur Veränderung der Energiehomöostase
11:05 Uhr
Die vielfältige Wirkung von Oxytocin
11:35 Uhr
FV 25:
Deletion of neuronal hypothalamic gastric inhibitory polypeptide receptors (GIPR) prevents high fat diet-induced obesity and insulin resistance
Details anzeigen
Autor:innen:
R. Barbosa-Yañez (Nuthetal, DE)
V. Scheling (Nuthetal, DE)
A. Voigt (Nuthetal, DE)
W. Jonas (Nuthetal, DE)
A. Schürmann (Nuthetal, DE)
A. Kleinridders (Nuthetal, DE)
O. Pivovarova-Ramich (Nuthetal, DE)
A. Pfeiffer (Berlin, DE)
The gut hormone gastric inhibitory polypeptide (GIP) is released in the upper gastrointestinal tract from K cells [1] by fats, carbohydrates and proteins and is an essential mediator of metabolic food responses such as insulin secretion and fat storage [2,3]. Total deletion of the GIP Receptor (GIPR) prevents the development of diet-induced obesity, fatty liver disease and insulin resistance [4-7]. However, the role of central, and more specific, hypothalamic GIPR is still completely unclear.
In this ongoing study a humanized GIPR mouse model (hGIPR+/+) was generated and human exons 5-7 were flanked by loxP sites. Control (hGIPR+/+), central (hGIPRCNS-/-, CamKIIa) and hypothlamic (hGIPRHYPO-/-, Nkx2.1) GIPR knockout (KO) mice were fed with a control diet (CD) (10% fat) or a high-fat diet (HFD) (fat 60%) for 14 weeks. Body weight (BW) was measured weekly and body fat and lean mass were determined by NMR after three weeks and after 14 weeks on the diet.
Furthermore, during the intervention mice were exposed to insulin and glucose tolerance tests and indirect calorimetry.
We show that hypothalamic GIPR-KO mice are resistant to the weight gain upon HFD while central GIPR-KO mice were similar to controls. Furthermore, GIPR deletion in hypothalamus preserves insulin sensitivity independent of dietary fat content while central GIPR-KO developed similar insulin resistance as controls . The data suggest a primary role of hypothalamic GIPR in the control of body weight and insulin sensitivity in response to HFD.
11:45 Uhr
FV 26:
Hypothalamic chaperone Hsp10 regulates mitochondrial function, insulin sensitivity and impacts liver metabolism
Details anzeigen
Autor:innen:
K. Wardelmann (Nuthetal, DE)
M. Rath (Nuthetal, DE)
J. Castro (Nuthetal, DE)
S. Blümel (Nuthetal, DE)
R. Hauffe (Nuthetal, DE)
C. Chudoba (Nuthetal, DE)
K. Warnke (Nuthetal, DE)
T. Flore (Nuthetal, DE)
K. Ritter (Nuthetal, DE)
A. Wernitz (Nuthetal, DE)
T. Hosoi (Hiroshima, JP)
K. Ozawa (Hiroshima, JP)
J. Weiß (Düsseldorf, DE)
A. Kleinridders (Nuthetal, DE)
Mitochondrial function in the hypothalamus is a pivotal regulator of insulin sensitivity and impacts whole body metabolism. Conversely, mitochondrial dysfunction has been associated with central insulin resistance, therefore being involved in the pathogenesis of type-2 diabetes (T2D). Mitochondrial health is sensed and adjusted by the mitochondrial unfolded protein response/mitochondrial stress response (MSR). Recently, we demonstrated induction of MSR by insulin signaling reduces food intake and high-fat-diet-induced weight gain. The effect of one of the key players of the MSR, heat shock protein 10 (Hsp10), on metabolism is however still unknown.
Therefore, we investigated the role of chaperone Hsp10 by introducing a lentiviral-mediated Hsp10 knockdown (KD) in the hypothalamic cell line CLU-183. To study the central effect of Hsp10, we injected lentiviral particles into the mediobasal hypothalamus (MBH) of C57BL/6N male mice and analyzed mitochondrial function and insulin signaling in vitro and in vivo utilizing qPCR, Western Blot, XF24 Analyzer, immunohistochemistry and microscopy techniques.
Brain samples of T2D mice exhibited decreased Hsp10 expression. Interestingly, Hsp10 is regulated by leptin in neurons. Hsp10 KD in CLU-183 cells induced mitochondrial dysfunction with increased mitochondrial oxidative stress and deteriorated mitochondrial dynamics resulting in neuronal insulin resistance. Strikingly, the MBH-specific reduction of Hsp10 induced transient liver insulin resistance with increased expression of markers of gluconeogenesis in the liver along with features of hepatic inflammation.
Conclusively, Hsp10 is crucial for mitochondrial function and insulin sensitivity. Moreover, reduction of hypothalamic Hsp10 modulates hepatic gluconeogenesis and insulin sensitivity, advocating Hsp10 as a novel regulator of brain-liver crosstalk.