Microbiota-modulated CART+ enteric neurons autonomously regulate blood glucose.
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ABSTRACT:
SUBMITTER: Muller PA
PROVIDER: S-EPMC7886298 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Microbial density and diversity increase in distal intestinal segments, affecting tissue physiology, metabolism, and function of both the immune and nervous systems. We characterized the influence of the microbiota on murine intrinsic enteric-associated neurons (iEAN). We found that iEAN are functionally adapted to the intestinal segment they occupy, with a stronger microbiota influence on ileal and colonic neurons. Chemogenetic characterization of microbiota-influenced iEAN identified a subset of viscerofugal CART+ neurons, enriched in the ileum and colon, able to modulate feeding and glucose metabolism. Retro- and anterograde tracing revealed that CART+ viscerofugal neurons send axons to the prevertebral ganglia and are poly-synaptically connected to the liver and pancreas. Microbiota depletion led to NLRP6 and Caspase 11-dependent loss of CART+ neurons, and impaired liver-mediated gluconeogenesis. Our results demonstrate a region-specific adaptation of enteric neurons and indicate that iEAN subsets are capable of regulating blood glucose levels independently from the central nervous system.
2020-08-13 | GSE156142 | GEO
Project description:Microbiota–modulated CART+ enteric neurons autonomously regulate blood glucose
| PRJNA656836 | ENA
Project description:The growth hormone receptor (GHR) is expressed in brain regions that are known to participate in the regulation of energy homeostasis and glucose metabolism. We generated a novel transgenic mouse line (GHRcre) to characterize GHR-expressing neurons specifically in the arcuate nucleus of the hypothalamus (ARC). Here, we demonstrate that ARCGHR+ neurons are co-localized with agouti-related peptide (AgRP), growth hormone releasing hormone (GHRH), and somatostatin neurons, which are activated by GH stimulation. Using the designer receptors exclusively activated by designer drugs (DREADD) technique to control the ARCGHR+ neuronal activity, we demonstrate that the activation of ARCGHR+ neurons elevates a respiratory exchange ratio (RER) under both fed and fasted conditions. However, while the activation of ARCGHR+ promotes feeding, under fasting conditions, the activation of ARCGHR+ neurons promotes glucose over fat utilization in the body. This effect was accompanied by significant improvements in glucose tolerance, and was specific to GHR+ versus GHRH+ neurons. The activation of ARCGHR+ neurons increased glucose turnover and whole-body glycolysis, as revealed by hyperinsulinemic-euglycemic clamp studies. Remarkably, the increased insulin sensitivity upon the activation of ARCGHR+ neurons was tissue-specific, as the insulin-stimulated glucose uptake was specifically elevated in the skeletal muscle, in parallel with the increased expression of muscle glycolytic genes. Overall, our results identify the GHR-expressing neuronal population in the ARC as a major regulator of glycolysis and muscle insulin sensitivity in vivo.
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Project description:BackgroundThe intestinal microbiota plays an important role in regulating gastrointestinal (GI) physiology in part through interactions with the enteric nervous system (ENS). Alterations in the gut microbiome frequently occur together with disturbances in enteric neural control in pathophysiological conditions. However, the mechanisms by which the microbiota regulates GI function and the structure of the ENS are incompletely understood. Using a mouse model of antibiotic (Abx)-induced bacterial depletion, we sought to determine the molecular mechanisms of microbial regulation of intestinal function and the integrity of the ENS. Spontaneous reconstitution of the Abx-depleted microbiota was used to assess the plasticity of structure and function of the GI tract and ENS. Microbiota-dependent molecular mechanisms of ENS neuronal survival and neurogenesis were also assessed.ResultsAdult male and female Abx-treated mice exhibited alterations in GI structure and function, including a longer small intestine, slower transit time, increased carbachol-stimulated ion secretion, and increased intestinal permeability. These alterations were accompanied by the loss of enteric neurons in the ileum and proximal colon in both submucosal and myenteric plexuses. A reduction in the number of enteric glia was only observed in the ileal myenteric plexus. Recovery of the microbiota restored intestinal function and stimulated enteric neurogenesis leading to increases in the number of enteric glia and neurons. Lipopolysaccharide (LPS) supplementation enhanced neuronal survival alongside bacterial depletion, but had no effect on neuronal recovery once the Abx-induced neuronal loss was established. In contrast, short-chain fatty acids (SCFA) were able to restore neuronal numbers after Abx-induced neuronal loss, demonstrating that SCFA stimulate enteric neurogenesis in vivo.ConclusionsOur results demonstrate a role for the gut microbiota in regulating the structure and function of the GI tract in a sex-independent manner. Moreover, the microbiota is essential for the maintenance of ENS integrity, by regulating enteric neuronal survival and promoting neurogenesis. Molecular determinants of the microbiota, LPS and SCFA, regulate enteric neuronal survival, while SCFA also stimulates neurogenesis. Our data reveal new insights into the role of the gut microbiota that could lead to therapeutic developments for the treatment of enteric neuropathies. Video abstract.
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Project description:Brain glucose-sensing neurons detect glucose fluctuations and prevent severe hypoglycemia, but mechanisms mediating functions of these glucose-sensing neurons are unclear. Here we report that estrogen receptor-? (ER?)-expressing neurons in the ventrolateral subdivision of the ventromedial hypothalamic nucleus (vlVMH) can sense glucose fluctuations, being glucose-inhibited neurons (GI-ER?vlVMH) or glucose-excited neurons (GE-ER?vlVMH). Hypoglycemia activates GI-ER?vlVMH neurons via the anoctamin 4 channel, and inhibits GE-ER?vlVMH neurons through opening the ATP-sensitive potassium channel. Further, we show that GI-ER?vlVMH neurons preferentially project to the medioposterior arcuate nucleus of the hypothalamus (mpARH) and GE-ER?vlVMH neurons preferentially project to the dorsal Raphe nuclei (DRN). Activation of ER?vlVMH to mpARH circuit and inhibition of ER?vlVMH to DRN circuit both increase blood glucose. Thus, our results indicate that ER?vlVMH neurons detect glucose fluctuations and prevent severe hypoglycemia in mice.
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Project description:Background & aimsGastrointestinal motility is regulated by enteric neural circuitry that includes enteric neurons and glia. Enteric glia monitor synaptic activity and exhibit responses to neurotransmitters that are encoded by intracellular calcium (Ca2+) signaling. What role evoked glial responses play in the neural regulation of gut motility is unknown. We tested how evoking Ca2+ signaling in enteric glia affects the neural control of intestinal motility.MethodsWe used a novel chemogenetic mouse model that expresses the designer receptor hM3Dq under the transcriptional control of the glial fibrillary acidic protein (GFAP) promoter (GFAP::hM3Dq mice) to selectively trigger glial Ca2+ signaling. We used in situ Ca2+ imaging and immunohistochemistry to validate this model and assessed gut motility by measuring pellet output and composition, colonic bead expulsion time, small intestinal transit time, total gut transit time, colonic migrating motor complex (CMMC) recordings and muscle tension recordings.ResultshM3Dq receptor expression is confined to GFAP-positive enteric glia in the intestines of GFAP::hM3Dq mice. In these mice, application of the hM3Dq agonist clozapine-N-oxide (CNO) selectively triggers intracellular Ca2+ responses in enteric glia. Glial activation drove neurogenic contractions in the ileum and colon but had no effect on neurogenic relaxations. CNO enhanced the amplitude and frequency of CMMCs in ex vivo preparations of the colon and CNO increased colonic motility in vivo. CNO had no effect on the composition of fecal matter, small intestinal transit or whole gut transit.ConclusionsGlial excitability encoded by intracellular Ca2+ signaling functions to modulate excitatory enteric circuits. Selectively triggering glial Ca2+ signaling might be a novel strategy to improve gut function in motility disorders.
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