Ganglioside im Hypothalamus - Regulatoren des Körpergewichtes und der Fettgewebshomöostase
Zusammenfassung der Projektergebnisse
The results of this research project significantly enhance our current molecular understanding of CNS regulation of body weight and energy homeostasis. We demonstrate that hypothalamic gangliosides are not only regulating body weight, but also adipose tissue homeostasis. The results suggest that increased IR signaling in ganglioside-deficient neurons of the hypothalamic Arc are involved in the observed restriction of lipolysis in Ugcgf/f- CamKCreERT2 mice, which is another mechanism that contributes to progression of obesity and hypometabolism. Enhanced IR signaling in mediobasal hypothalamus has been suggested to restrain lipolysis in WAT8. Thus, our work contributes to a more detailed understanding of this process by showing that gangliosides are critically involved in modulating the IR availability on the neuronal surface11. These results are in line with earlier studies showing that less complex non-neuronal gangliosides (e.g. GM3) restrain insulin sensitivity in WAT cells19. Moreover, another study corroborates our previous results stating that neuronal gangliosides facilitate leptin receptor signaling20, thereby impacting body weight control. We have observed that GCS deletion in POMC neurons elicits body weight increase in mice upon a regular chow diet. Based on the results derived from Ugcgf/f-Pomc-Cre mice and ganglioside-deficient immortalized POMC neurons, we propose that gangliosides may be involved in the association of PIP3 with the KATP channel subunit SUR-1. These results warrant further in-depth analyses of the electrophysiological properties of gangliosidedeficient POMC neurons in order to prove consequences of the observed increased binding of PIP3 to SUR-1 on membrane excitability. Anyhow, the results obtained advance our current molecular understanding as to how hypothalamic neuronal gangliosides control body weight. As outlined above, we did not pursue an in-depth analysis of Ugcgf/f-AgRP-Cre mice, both due to the mentioned problems with the barrier facility as well as due to the initial observation that body weight was not significantly altered in these mice upon a regular chow diet. However, even though the effects of a GCS deletion in hypothalamic neuronal subpopulations on body weight and metabolism are moderate, the expected advances in the molecular understanding as to how gangliosides regulate these specific neurons additionally warrants further investigations in Ugcgf/f-AgRP-Cre mice, especially when it comes to metabolic challenges such as a high fat diet or fasting. Moreover, a detailed analysis of the glucose homeostasis of Ugcgf/f-AgRP-Cre mice would be advantageous, since AgRP neurons are important regulators of hepatic glucose production. Taken together, the results of this DFG project significantly advance our previous understanding as to how gangliosides in neurons of the hypothalamic Arc control body weight control by outlining novel molecular mechanisms, including the modulation of surface IR levels, neuronal insulin sensitivity, and PIP3-SUR-1 interactions. As we have discussed in our work, an adequate balance of ganglioside expression instead of a complete deletion, may be a key to potential therapeutic interventions.
Projektbezogene Publikationen (Auswahl)
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Fasting-induced lipolysis and insulin signaling are regulated by neuronal glucosylceramide synthase. Diabetes, 2015, 64(10): pp. 3363-3376
Herzer, Silke; Meldner, Sascha; Gröne, Hermann-Josef & Nordström, Viola
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Lipid microdomain modification sustains neuronal viability in models of Alzheimer’s disease. Acta Neuropathol Comm., 2016, 4(103)
Herzer, Silke; Meldner, Sascha; Rehder, Klara; Gröne, Hermann-Josef & Nordström, Viola
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Hyperosmolarity impedes the cross-priming competence of dendritic cells in a TRIF-dependent manner. Scientific Reports, 2017, 7(311)
Popovic, Zoran V.; Embgenbroich, Maria; Chessa, Federica; Nordström, Viola; Bonrouhi, Mahnaz; Hielscher, Thomas; Gretz, Norbert; Wang, Shijun; Mathow, Daniel; Quast, Thomas; Schloetel, Jan-Gero; Kolanus, Waldemar; Burgdorf, Sven & Gröne, Hermann-Josef
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Modification of membrane lipids protects from neuronal insulin resistance in models of Alzheimer’s disease. e-Neuroforum, 2017, 23(4), pp. A175-A166
Nordström, Viola & Herzer, Silke
