NUTRIPATHOS - Nährstofftransport in Astrozyten und Regulation des Energiestoffwechsels
Zusammenfassung der Projektergebnisse
The prevalence of obesity and type 2 diabetes has reached alarming rates worldwide, affecting both developing and developed countries. So far, neither the drastic changes in lifestyle (exercise and dieting) recommended by public institutions and the medical services, nor identifying better targets for more efficient obesity treatments, have been able to successfully reduce the prevalence of obesity. Importantly, recent human genome-wide association studies (GWAS) from obese patients have demonstrated that the brain, in particular the hypothalamus, is absolutely critical for the control of systemic metabolism, suggesting that obesity may be a “brain” disease. In this regard, over the last few decades, a considerable amount of studies were conducted, but focused exclusively on exploring the functionality of neurons in order to understand how the hypothalamus governs feeding behavior and systemic metabolism, neglecting the presence and potential function of other cell types in the brain, such as glial cells. However, our previous studies suggest that glial cells, and especially astrocytes, are key in the brain’s control of metabolism. In this context, over the last three years our team, headed by Prot Dr. Tschöp and Dr. Garcia-Cäceres in collaboration with our French partners (Dr. Luquet and Dr. Li), has made outstanding discoveries on the underlying mechanism(s) that might be involved in the regulation of hypothalamic astrocyte function in the control of energy metabolism as well as in the pathogenesis of obesity based on the use of cutting-edge genetic tools in v/vo designed for cell and region specificity, as well as loss-of-function models for targeting master regulators of nutrient partitioning in astrocytes. Here, we summarize the main findings of this proposal which are that (1) the function of hypothalamic astrocytes in the regulation of energy and glucose metabolism is regionspecific, which supports that astrocytes are not functionally, nor regionally, interchangeable as it has been traditionally assumed. Moreover, our findings support that hypothalamic astrocytes.show both inter- and intra-regional functional features which might be defined by the surrounding microenvironment, including their interactions with neighboring neurons, synapses, and other cells; and (2) the cellular metabolism of astrocytes is dependent on mitochondrial uncoupling protein 2 (UCP2) for an appropriate regulation of hypothalamic feeding circuits in response to whole-body energy demands. Specifically, we observed that fluctuations in metabolic status (fasting-refeeding) induce adaptive changes in the bioenergetic state of astrocytes, which might be determinant for the activity of feeding neurons in the hypothalamus. So far, our findings underline the importance of astrocytes as an essential relay component allowing for a fine-tuned control of systemic energy balance, and confirm the importance of a better understanding of the complicated and dynamic dialog that exists between the different cell types. Further studies are being carried out to test whether long-lasting astrocyte Captations to nutritional or glycemic challenges are inherent to the core of the pathogenesis of obesity. Therefore, the resulting insights of ongoing studies will help to open new avenues for the development of novel therapeutic targets based on cellselective compounds for treating obesity and their specific signaling pathways.
Projektbezogene Publikationen (Auswahl)
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Role of astrocytes, microglia, and tanycytes in brain control of systemic metabolism. Nat Neurosci. 2019 Jan;22(l):7-14
García-Cáceres C., Balland E., Prevot V., Luquet S., Woods S.C., Koch M., Horvath T.L., Yi CX., Chowen J.A., Verkhratsky A., Araque A., Bechmann I., Tschöp M.H.
