The role of astrocytic gangliosides in high-fat-diet-induced hypothalamic inflammation
Final Report Abstract
During the last decades obesity has become a major health risks in our societies. The increased intake and long-term consumption of energy-dense food, with excess amounts of saturated fatty acids (SFA), can be blamed for this development. A small region in the brain, called hypothalamus, takes a key role in the regulation of body weight control by sensing peripheral energy signals. Increasing research evidence indicates, that inflammatory processes can be observed in the hypothalamus of high fat diet (HFD)-fed rodents even long before the onset of obesity. Hyper activated microglia and reactive astrocytes, have been demonstrated as a characteristic feature in the initiation of this hypothalamic inflammation. The cell membrane of neurons and glial cells has a distinct lipid composition, particularly enriched in a specific class of glycosphingolipids, termed gangliosides. The key enzyme in ganglioside biosynthesis is the glucosylceramide-synthase (GCS; gene Ugcg). Gangliosides are composed of a hydrophobic ceramide membrane anchor and a hydrophilic carbohydrate chain, typically containing one or more sialic acid residues. In previous projects, we have demonstrated that GCS-derived gangliosides are important regulators of neuronal receptor signalling in the hypothalamus and thereby play an important role in the regulation of body weight and energy expenditure. Following up on our recent work, this DFG research project proposes a new molecular mechanism of glial ganglioside regulated hypothalamic inflammation. The results suggest that increased SFA levels in the hypothalamus activate local microglia, mediated via the interaction of the toll like receptor 4 (TLR4) with gangliosides on the cell membrane, resulting in the release of proinflammatory cytokines IL-1α and TNF-α. The cytokines in turn bind and activate cytokine receptors on the cell surface of astrocytes, a process which appears to be ganglioside mediated as well. In addition, the high levels of SFA lead to increased ganglioside levels in the cell membrane of microglia and astrocytes, additionally reinforcing the TLR4 and cytokine receptor activation. Collectively, these events result in a cytokine overload in the hypothalamus causing damage of neurons associated with body weight control, leading to impairment in energy balance and on a long-term to obesity. In this proposal, we demonstrate, that in a mouse model with specific astrocytic ganglioside depletion (Ugcgf/f//GFAPCre mice) the hypothalamic response to long-term HFD consumption including glial activation, neuronal loss and the concomitant weight gain are significantly diminished. In preliminary experiments we could show that a pharmacological approach with the ganglioside biosynthesis inhibitor GENZ 123346, can be applied to reduce ganglioside levels in cultured astrocytes. Therefore, the development of an astrocyte targeted invivo application with this GCS-inhibitor would open future perspectives for pharmacological treatments. In summary, the results of this DFG-founded project enhance our current molecular understanding of ganglioside-mediated glial activation by HFD and the concurrent hypothalamic inflammation. Thus, normalizing and stabilizing ganglioside biosynthesis in specific glial populations may be a potential way to break the vicious circle of hypothalamic inflammation, impaired energy balance, and progressive weight gain.
Publications
- Modification of membrane lipids protects from neuronal insulin resistance in models of Alzheimer’s disease. e-Neuroforum, 2017, 23(4), pp. A175-A166
Nordström V. and Herzer S.
(See online at https://doi.org/10.1515/nf-2017-A007) - Deletion of specific sphingolipids in distinct neurons improves learning and memory in a mouse model of Alzheimer’s disease. Frontiers in Molecular Neurosciences, 2018, 11(206)
Herzer S., Hagan C., Dieterle V., and Nordström V.
(See online at https://doi.org/10.3389/fnmol.2018.00206) - Bacterial immunogenic α-galactosylceramide identified in the murine large intestine: dependency on diet and inflammation. J Lipid Res. 2019, 60(11):1892-1904
von Gerichten J, Lamprecht D, Opálka L, Soulard D, Marsching C, Pilz R, Sencio V, Herzer S, Galy B, Nordström V, Hopf C, Gröne HJ, Trottein F, Sandhoff R
(See online at https://doi.org/10.1194/jlr.ra119000236) - Ganglioside deficiency in hypothalamic POMC neurons promotes body weight gain. Inter. Journal of Obesity, 2020, 44
Dieterle V., Herzer S., Gröne H.-J., Jennemann R., and Nordström V.
(See online at https://doi.org/10.1038/s41366-019-0388-y)
