Dataset Information

SNAP25 mutation disrupts metabolic homeostasis, steroid hormone production and central neurobehavior.

ABSTRACT:

Objective

SNAP-25 is one of the key proteins involved in formation of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complexes that are at the core of hormonal secretion and synaptic transmission. Altered expression or function of SNAP-25 can contribute to the development of neuropsychiatric and metabolic disease. A dominant negative (DN) I67T missense mutation in the b-isoform of SNAP-25 (DN-SNAP25mut) mice leads to abnormal interactions within the SNARE complex and impaired exocytotic vesicle recycling, yet the significance of this mutation to any association between the central nervous system and metabolic homeostasis is unknown.

Methods

Here we explored aspects of metabolism, steroid hormone production and neurobehavior of DN-SNAP25mut mice.

Results

DN-SNAP25mut mice displayed enhanced insulin function through increased Akt phosphorylation, alongside increased adrenal and gonadal hormone production. In addition, increased anxiety behavior and beigeing of white adipose tissue with increased energy expenditure were observed in mutants.

Conclusions

Our results show that SNAP25 plays an important role in bridging central neurological systems with peripheral metabolic homeostasis, and provide potential insights between metabolic disease and neuropsychiatric disorders in humans.

SUBMITTER: Hao X

PROVIDER: S-EPMC8759409 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

SNAP25 mutation disrupts metabolic homeostasis, steroid hormone production and central neurobehavior.

Hao Xiao X Zhu Bing B Yang Pinglin P Dong Dachuan D Sahbaie Peyman P Oliver Peter L PL Shen Wen-Jun WJ Azhar Salman S Kraemer Fredric B FB

Biochimica et biophysica acta. Molecular basis of disease 20211124 2

<h4>Objective</h4>SNAP-25 is one of the key proteins involved in formation of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complexes that are at the core of hormonal secretion and synaptic transmission. Altered expression or function of SNAP-25 can contribute to the development of neuropsychiatric and metabolic disease. A dominant negative (DN) I67T missense mutation in the b-isoform of SNAP-25 (DN-SNAP25mut) mice leads to abnormal interactions within the SNARE c ...[more]

PMID: 34826585

Similar Datasets

Project description:Rationale: The molecular mechanisms underlying the pathogenesis of systemic insulin resistance in type 2 diabetes remain elusive. Growth hormone receptor (GHR) deficiency has long been known to improved insulin sensitivity. However, whether hepatic GHR overexpression or activation is a cause of insulin resistance is still unknown. The aim of this study was to identify the new role of GHR in systemic insulin resistance and explore the underlying mechanism. Method: Different samples obtained from obese humans, ob/ob mice, db/db mice, high-fat diet (HFD)-fed mice and primary mouse hepatocytes were used to evaluate the correlations between GHR and metabolic disorders. Recombinant adeno-associated viruses encoding GHR and STAT5 and GHR knockout mice were used to investigate the roles of hepatic GHR in glucose homeostasis. Tissue H&E, Oil Red O and PAS staining were performed for histomorphological analysis. Gel filtration chromatography was employed for the separation of serum RBP4-TTR complexes. Plasmids (related to GHR, STAT5 and HIF1α), siRNA oligos (siGHR and siSTAT5), luciferase activity and ChIP assays were used to explore the potential mechanism of hepatic GHR. Results: Here, we found that hepatic GHR expression was elevated during metabolic disorder. Accordingly, hepatic GHR overexpression disrupted systemic glucose homeostasis by promoting gluconeogenesis and disturbing insulin responsiveness in the liver. Meanwhile, hepatic GHR overexpression promoted lipolysis in white adipose tissue and repressed glucose utilization in skeletal muscle by promoting the circulating level of RBP4, which contributed to impaired systemic insulin action. A mechanistic study revealed that hepatic GHR disrupted systemic insulin sensitivity by increasing RBP4 transcription by activating STAT5. Additionally, overexpression of hepatic GHR promoted TTR transcriptional levels by enhancing the expression of HIF1α, which not only increased the protein stability of RBP4 but also inhibited renal clearance of RBP4 in serum. Conclusions: Hepatic GHR overexpression and activation accelerated systemic insulin resistance by increasing hepatic RBP4 production and maintaining circulating RBP4 homeostasis. Our current study provides novel insights into the pathogenesis of type 2 diabetes and its associated metabolic complications.

Project description:The damaging effect of high oxygen concentration on growth of Escherichia coli is well established. Over-oxygenation increases the intracellular concentration of reactive oxygen species (ROS), causing the destruction of the [4Fe-4S] cluster of dehydratases and limiting the biosynthesis of both branched-chain amino acids and nicotinamide adenine dinucleotide. A key enzyme that reduces the damaging effect of superoxide is superoxide dismutase (SOD). Its transcriptional regulation is controlled by global transcription regulators that respond to changes in oxygen and iron concentrations and pH. Production of biological compounds from E. coli is currently achieved using cultures grown to high cell densities which require oxygen-enriched air supply. It is, therefore, important to study the effect of over-oxygenation on E. coli metabolism and the bacterial protecting mechanism. The effect of over-oxygenation on the superoxide dismutase regulation system was evaluated in cultures grown in a bioreactor by increasing the oxygen concentration from 30 to 300 % air saturation. Following the change in the dissolved oxygen (DO), the expression of sodC, the periplasmic CuZn-containing SOD, and sodA, the cytosolic Mn-containing SOD, was higher in all the tested strains, while the expression of the sodB, the cytosolic Fe-containing SOD, was lower. The down-regulation of the sodB was found to be related to the activation of the small RNA RyhB. It was revealed that iron homeostasis, in particular ferric iron, was involved in the RyhB activation and in sodB regulation but not in sodA. Supplementation of amino acids to the culture medium reduced the intracellular ROS accumulation and reduced the activation of both SodA and SodC following the increase in the oxygen concentration. The study provides evidence that at conditions of over-oxygenation, sodA and sodC are strongly regulated by the amount of ROS, in particular superoxide; and sodB is regulated by iron availability through the small RNA RyhB. In addition, information on the impact of NADH, presence of amino acids and type of iron on SOD regulation, and consequently, on the ROS concentration is provided.

Project description:Tsetse flies (Glossina spp.) house a population-dependent assortment of microorganisms that can include pathogenic African trypanosomes and maternally transmitted endosymbiotic bacteria, the latter of which mediate numerous aspects of their host's metabolic, reproductive, and immune physiologies. One of these endosymbionts, Spiroplasma, was recently discovered to reside within multiple tissues of field captured and laboratory colonized tsetse flies grouped in the Palpalis subgenera. In various arthropods, Spiroplasma induces reproductive abnormalities and pathogen protective phenotypes. In tsetse, Spiroplasma infections also induce a protective phenotype by enhancing the fly's resistance to infection with trypanosomes. However, the potential impact of Spiroplasma on tsetse's viviparous reproductive physiology remains unknown. Herein we employed high-throughput RNA sequencing and laboratory-based functional assays to better characterize the association between Spiroplasma and the metabolic and reproductive physiologies of G. fuscipes fuscipes (Gff), a prominent vector of human disease. Using field-captured Gff, we discovered that Spiroplasma infection induces changes of sex-biased gene expression in reproductive tissues that may be critical for tsetse's reproductive fitness. Using a Gff lab line composed of individuals heterogeneously infected with Spiroplasma, we observed that the bacterium and tsetse host compete for finite nutrients, which negatively impact female fecundity by increasing the length of intrauterine larval development. Additionally, we found that when males are infected with Spiroplasma, the motility of their sperm is compromised following transfer to the female spermatheca. As such, Spiroplasma infections appear to adversely impact male reproductive fitness by decreasing the competitiveness of their sperm. Finally, we determined that the bacterium is maternally transmitted to intrauterine larva at a high frequency, while paternal transmission was also noted in a small number of matings. Taken together, our findings indicate that Spiroplasma exerts a negative impact on tsetse fecundity, an outcome that could be exploited for reducing tsetse population size and thus disease transmission.

Dataset Information

SNAP25 mutation disrupts metabolic homeostasis, steroid hormone production and central neurobehavior.

Objective

Methods

Results

Conclusions

Publications

SNAP25 mutation disrupts metabolic homeostasis, steroid hormone production and central neurobehavior.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets