► SCFAs increase NE release from primary-cultured sympathetic neurons via GPR41. ► Sympathetic activation by SCFA involves Gβγ, PLCβ3, ERK1/2, and synapsin 2. ► Synapsin 2 directly interacts with ...activated ERK1/2. ► Synapsin 2b can be phosphorylated when SCFA activates sympathetic neurons.
Synapsins are neuronal phosphoproteins that coat synaptic vesicles and are believed to function in the regulation of neurotransmitter release. The signaling mechanism for short-chain free fatty acid (SCFA)-stimulated NE release was examined using primary-cultured mouse sympathetic cervical ganglion neurons. Pharmacological and knockdown experiments showed that activation of sympathetic neurons by SCFA propionate involves SCFA receptor GPR41 linking to Gβγ-PLCβ3-ERK1/2-synapsin 2 signaling. Further, synapsin 2b directly interacts with activated ERK1/2 and can be phosphorylated on serine when SCFA activates sympathetic neurons.
Among the fatty acid ethanolamides (FAEs), oleoylethanolamide (OEA), linoleoylethanolamide (LEA), and palmitoylethanolamide (PEA) are reported to be involved in feeding regulation. In particular, OEA ...is well characterized as a satiety signal. Following food consumption, OEA is synthesized from oleic acid (OA)
an
-acyl phosphatidylethanolamine-specific phospholipase D-dependent pathway in the gastroenterocytes, and OEA induces satiety by recruiting sensory fibers. Thus, we hypothesized that dietary OA is an important satiety-inducing molecule. However, there has been no direct demonstration of the effect of dietary OA on satiety induction without the influence of the endogenous biosynthesis of OA from stearic acid (SA) or other FAEs.
In this study, we used two experimental diets to test our hypothesis: (i) an OA diet (OAD; 38.4 mg of OA/g and 7.2 mg of SA/g) and (ii) a low OA diet (LOAD; 3.1 mg of OA/g and 42.4 mg of SA/g).
Relative to mice fed the OAD, mice fed the LOAD for two weeks exhibited reduced levels of jejunal OEA but not jejunal LEA and PEA. The LOAD-fed mice showed an increase in food intake and body weight gain. Moreover, LOAD-induced increase in food intake was immediately observed after the switch from the OAD, whereas these effects were diminished by the switch back to the OAD. Furthermore, treatment with OA and OEA diminished the effects of LOAD on food intake.
Collectively, these results show that dietary OA is a key factor in the reduction of food intake and increase in satiety mediated by OEA signaling.
Scope
The purpose of this study is to compare the impact of four low‐viscosity soluble dietary fibers (DFs) on the intestinal microenvironment, in terms of microbiota composition, short‐chain fatty ...acid (SCFA) production, proportion of colonic peripherally induced regulatory T cells (pTregs), and experimental colitis in mice.
Methods and results
Mice are administered 5% w/v low‐viscosity soluble DFs in drinking water for 2 weeks. The gut microbiota composition is determined using 16S rRNA sequencing. Luminal SCFAs are quantified by gas chromatography, and colonic pTregs are analyzed using flow cytometry. All low‐viscosity soluble DFs promote the growth of beneficial bacteria such as Akkermansia muciniphila and Bacteroides acidifaciens, while eliminating pathogenic bacteria such as Clostridium perfringens. Moreover, two low‐viscosity soluble DFs significantly increase the abundance of commensal bacteria and promote the accumulation of propionate and butyrate, leading to marked induction of colonic pTregs. Consistently, these two fibers, in particular α‐cyclodextrin, show remarkable anti‐inflammatory properties in a colitis mouse model.
Conclusion
Mice administered any low‐viscosity soluble DF show comparable gut microbiota compositions, but differ in terms of bacterial abundance, SCFA concentration, pTreg population, and colitis development. This exploratory study suggests that administration of α‐cyclodextrin may be a possible strategy for the prevention of colitis.
Low‐viscosity soluble dietary fibers affect the composition and/or abundance of gut microbiota. This comparative study reveals that inulin and especially alpha‐cyclodextrin markedly elevate bacterial abundance and luminal short‐chain fatty acid (SCFA) levels, leading to the induction of peripherally induced regulatory T cells (Tregs) that suppress unfavorable immune responses to gut microbiota caused by 2,4,6‐trinitrobenzenesulfonic acid (TNBS).
Microbiota-accessible carbohydrates (MACs) exert health-promoting effects, but how each MAC impacts gut microbiota and regulates host physiology remains unclear. Here, we show that l-arabinose and ...sucrose cooperatively act on gut microbiota and exert anti-obesogenic effects. Specifically, l-arabinose, a monosaccharide that is poorly absorbed in the gut and inhibits intestinal sucrase, suppresses diet-induced obesity in mice in the presence of sucrose. Additionally, the suppressive effect of l-arabinose on adiposity is abrogated in mice lacking the short-chain fatty acid (SCFA) receptors GPR43 and GPR41. Mechanistically, l-arabinose increases the relative abundance of acetate and propionate producers (e.g., Bacteroides), while sucrose enhances SCFA production. Furthermore, l-arabinose and sucrose activate the glycolytic and pentose phosphate pathways of Bacteroides, respectively, indicating that they synergistically promote acetate production through distinct pathways. These findings suggest that each MAC has a unique property and thus may serve as a precision gut-microbiota modulator to promote host homeostasis.
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•l-Arabinose suppresses adiposity in animals fed a high-fat diet with sucrose•l-Arabinose increases the relative abundance of acetate and propionate producers•Sucrose enhances the production of acetate and propionate induced by l-arabinose•l-Arabinose/sucrose activate distinct metabolic pathways of acetate-producing bacteria
Microbiota-accessible carbohydrates (MACs) impact host physiology. Tomioka et al. demonstrate that two different MACs, l-arabinose and sucrose, act in concert on the gut microbiota to regulate short-chain fatty acid production and host metabolic functions. Furthermore, the two MACs stimulate distinct intracellular metabolic pathways of gut microbiota related to acetate production.
Progesterone receptor membrane components 1 and 2, neudesin, and neuferricin belong to the membraneassociated progesterone receptor (MAPR) family. Recently, sex steroid membrane receptors have gained ...attention because of their potential involvement in sex hormone-mediated rapid non-genomic effects, which cannot currently be explained by the genomic action of nuclear receptors. Progesterone may increase cell proliferation and survival via nongenomic effects including the activation of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3- kinase (PI3K) pathways through MAPRs. Moreover, the unique expression of MAPRs suggests that they could be used as biomarkers and drug targets for sex steroid-related cancers and other diseases. In this review, we summarize the physiological roles of the MAPRs, provide a comprehensive overview of their progesterone-mediated non-genomic actions, and discuss new insights into their potential as therapeutic targets.
Mechanisms of carbohydrate-induced secretion of the two incretins namely glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are considered to be mostly similar. ...However, we found that mice exhibit opposite secretory responses in response to co-administration of maltose plus an α-glucosidase inhibitor miglitol (maltose/miglitol), stimulatory for GLP-1, as reported previously, but inhibitory for GIP. Gut microbiota was shown to be involved in maltose/miglitol-induced GIP suppression, as the suppression was attenuated in antibiotics (Abs)-treated mice and abolished in germ-free mice. In addition, maltose/miglitol administration increased plasma levels of short-chain fatty acids (SCFAs), carbohydrate-derived metabolites, in the portal vein. GIP suppression by maltose/miglitol was not observed in mice lacking a SCFA receptor Ffar3, but it was normally seen in Ffar2-deficient mice. Similar to maltose/miglitol administration, co-administration of glucose plus a sodium glucose transporter inhibitor phloridzin (glucose/phloridzin) induced GIP suppression, which was again cancelled by Abs treatment. In conclusion, oral administration of carbohydrates with α-glucosidase inhibitors suppresses GIP secretion through a microbiota/SCFA/FFAR3 pathway.
Recently, sex steroid membrane receptors garnered world-wide attention because they may be related to sex hormone-mediated unknown rapid non-genomic action that cannot be currently explained by their ...genomic action via nuclear receptors. Progesterone affects cell proliferation and survival via non-genomic effects. In this process, membrane progesterone receptors (mPRα, mPRβ, mPRγ, mPRδ, and mPRε) were identified as putative G protein-coupled receptors (GPCRs) for progesterone. However, the structure, intracellular signaling, and physiological functions of these progesterone receptors are still unclear. Here, we identify a molecular mechanism by which progesterone promotes neurite outgrowth through mPRβ (Paqr8) activation. Mouse mPRβ mRNA was specifically expressed in the central nervous system. It has an incomplete GPCR topology, presenting 6 transmembrane domains and did not exhibit typical GPCR signaling. Progesterone-dependent neurite outgrowth was exhibited by the promotion of ERK phosphorylation via mPRβ, but not via other progesterone receptors such as progesterone membrane receptor 1 (PGRMC-1) and nuclear progesterone receptor in nerve growth factor-induced neuronal PC12 cells. These findings provide new insights of regarding the non-genomic action of progesterone in the central nervous system.
Background: α-cyclodextrin (α-CD) is one of the dietary fibers that may have a beneficial effect on cholesterol and/or glucose metabolism, but its efficacy and mode of action remain unclear. Methods: ...In the present study, we examined the anti-hyperglycemic effect of α-CD after oral loading of glucose and liquid meal in mice. Results: Administration of 2 g/kg α-CD suppressed hyperglycemia after glucose loading, which was associated with increased glucagon-like peptide 1 (GLP-1) secretion and enhanced hepatic glucose sequestration. By contrast, 1 g/kg α-CD similarly suppressed hyperglycemia, but without increasing secretions of GLP-1 and insulin. Furthermore, oral α-CD administration disrupts lipid micelle formation through its inclusion of lecithin in the gut luminal fluid. Importantly, prior inclusion of α-CD with lecithin in vitro nullified the anti-hyperglycemic effect of α-CD in vivo, which was associated with increased intestinal mRNA expressions of SREBP2-target genes (Ldlr, Hmgcr, Pcsk9, and Srebp2). Conclusions: α-CD elicits its anti-hyperglycemic effect after glucose loading by inducing lecithin inclusion in the gut lumen and activating SREBP2, which is known to induce cholecystokinin secretion to suppress hepatic glucose production via a gut/brain/liver axis.
Evidence has accumulated that gut microbiota and its metabolites, in particular the short-chain fatty acid propionate, are significant contributors to the pathogenesis of a variety of diseases. ...However, little is known regarding its impact on pediatric bronchial asthma, one of the most common allergic diseases in childhood. This study aimed to elucidate whether, and if so how, intestinal propionate during lactation is involved in the development of bronchial asthma. We found that propionate intake through breast milk during the lactation period resulted in a significant reduction of airway inflammation in the offspring in a murine house dust mite-induced asthma model. Moreover, GPR41 was the propionate receptor involved in suppressing this asthmatic phenotype, likely through the upregulation of Toll-like receptors. In translational studies in a human birth cohort, we found that fecal propionate was decreased one month after birth in the group that later developed bronchial asthma. These findings indicate an important role for propionate in regulating immune function to prevent the pathogenesis of bronchial asthma in childhood.
Early life environment influences mammalian brain development, a growing area of research within the Developmental Origins of Health and Disease framework, necessitating a deeper understanding of ...early life factors on children's brain development. This study introduces a mouse model,
knockout mice, to investigate the relationship between breast milk, the gut microbiome, and brain development. The results reveal that breast milk's reactive oxygen species (ROS) are vital in shaping the neonatal gut microbiota. Decreased hydrogen peroxide (H
O
) levels in milk disrupt the gut microbiome and lead to abnormal metabolite production, including D-glucaric acid. This metabolite inhibits hippocampal myelin formation during infancy, potentially contributing to behavioral abnormalities observed in adulthood. These findings suggest that H
O
in breast milk is crucial for normal gut microbiota formation and brain development, with implications for understanding and potentially treating neurodevelopmental disorders in humans.
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