The role of the gut microbiota in central energy balance regulation

Abstract

The gut microbiota can affect development and metabolism in the host. Today, much is still unknown regarding the effects of the gut microbiota on central energy balance regulation. We used mouse models to determine the role of the gut microbiota in diet- induced hypothalamic inflammation as well as in hypothalamic development. We found that mice lacking a gut microbiota do not develop diet-induced hypothalamic inflammation. Using genetically modified mice lacking glucagon-like peptide-1- receptor (GLP-1R) as well as pharmacological inhibition of GLP-1R signaling, we could show that this protection requires functional GLP-1R signaling. We further found that astrocytic GLP-1R signaling mediates at least parts of the observed protection. Next, we determined the role of gut microbiota and gut microbial signaling on blood- brain barrier (BBB) function in the mediobasal hypothalamus (MBH). The gut bacteria did not alter BBB function, as assessed by the number of cells in contact to the circulation, by tight junction protein staining, and by administration of a neurotoxin. In contrast, mice lacking the Toll-like receptor (TLR) adaptor protein Myd88 had an altered BBB function. Lastly, we determined whether the gut microbiota affects the early postnatal leptin surge with neurotrophic effects. Germ-free (GF) mice had a significantly elevated and prolonged leptin surge, but we observed no long-lasting differences between GF and conventionally-raised mice in the neuronal projections regulating energy balance. In conclusion, our results contribute to new insights within the field of neuroinflammation and identify central GLP-1R signaling as a potential target for modulation of neuroinflammation. Furthermore, our studies suggest that signaling via the TLR adaptor protein Myd88 can be targeted to modulate BBB permeability in the MBH. Lastly, the elevated postnatal leptin surge observed in GF mice warrant further studies determining potential functional consequences in the host.