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Adropin expression correlates with aging-related neuropathology in the human brain and improves neuroinflammation and cognitive function in aging mice

ABSTRACT: The putative secreted domain of adropin (residues 34-76) is sufficient for biological activity when administered by ip. injection to mice, inducing changes in mitochondrial fuel selection of skeletal muscle. To investigate whether adropin administered also regulates the brain transcriptome, RNA seq was used in 18-month-old male B6 mice treated with synthetic peptide at a dose previously shown to be effective. Mice were split into two weight matched groups, acclimated to handling and then treated with peptide (90 nmol/kg/d) suspended in 0.9% saline plus 0.1% BSA over 4 weeks. Controls were treated with diluent; injections were given daily at 0900h. Applying a cut-off using a fold-change (FC) >1.5 and a p-value of <0.05 identified a small number of responsive genes (84 upregulated, 172 downregulated). Gene enrichment analysis indicated that peptide treatment primarily changed the expression of genes involved in tissue morphogenesis (e.g. “pattern specification process”, “embryo development”, “animal morphogenesis”). Possibly related to increases in cellular proliferation and differentiation, there was also evidence for increases in large molecule synthesis. For example, RNA metabolism (“positive regulation of RNA biosynthetic process”; “positive regulation of transcription by RNA polymerase II”) and ‘macromolecule synthesis” were affected by treatment.

ORGANISM(S): Mus musculus

PROVIDER: GSE179088 | GEO | 2021/10/06

REPOSITORIES: GEO

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Adropin stimulates proliferation and inhibits adrenocortical steroidogenesis via the TGF-beta mediated pathway in the human adrenal carcinoma (HAC15) cell line.

Project description:Adropin is a multifunctional peptide hormone encoded by the ENHO (energy homeostasis associated) gene. It plays a role in mechanisms related to increased adiposity, insulin resistance, as well as glucose and lipid metabolism. The low adropin levels are strongly associated with obesity independent insulin resistance. On the other hand, overexpression or exogenous administration of adropin improves glucose homeostasis. The multidirectional, adropin-related effects associated with the regulation of metabolism in humans also appear to be attributable to the effects of this peptide on the activity of various elements of the endocrine system including adrenal cortex. Therefore, the main purpose of the present study was to investigate the effect of adropin on proliferation and secretory activity in the human HAC15 adrenal carcinoma cell line. We also found that HAC15 cells treated with adropin presented significantly higher proliferation levels than untreated cells. Based on whole transcriptome study and research involving transforming growth factor (TGF)-β type I receptor kinase inhibitor we demonstrated that attenuation of steroidogenesis caused by adropin is mediated by the TGF-β signalling pathway likely to act through transactivation mechanism.

2020-05-19 | GSE150775 | GEO

Attenuation of Fibroblast Activation and Fibrosis by Adropin in Systemic Sclerosis (SSc)

Project description:Fibrotic diseases impose a major socioeconomic challenge on modern societies with limited treatment options. Adropin, a peptide hormone encoded by the energy-homeostasis-associated (ENHO) gene, is implicated in metabolism and vascular homeostasis, but its role in the pathogenesis of fibrosis remains enigmatic. Here, we used machine learning approaches in combination with functional in vitro and in vivo experiments to characterize Adropin/ENHO as a potential regulator involved in fibroblast activation and tissue fibrosis in systemic sclerosis (SSc). We demonstrated consistent downregulation of Adropin/ENHO in SSc skin across different SSc cohorts. The prototypical profibrotic cytokine TGFβ reduced Adropin/ENHO expression in a JNK-dependent manner. Restoration of Adropin signaling by therapeutic application of bioactive Adropin34-76 peptides in turn inhibited TGFβ-induced fibroblast activation and fibrotic tissue remodeling in primary human dermal fibroblasts, three-dimensional full-thickness skin equivalents, the mouse models of bleomycin-induced pulmonary fibrosis and sclerodermatous chronic graft-versus-host-disease (sclGvHD), and precision-cut human skin slices (PCSS). Knockdown of GPR19, receptor of Adropin, abrogated the antifibrotic effects of Adropin in fibroblasts. RNA-seq demonstrated that the antifibrotic effects of Adropin34-76 were functionally linked to deactivation of GLI1 dependent profibrotic transcriptional networks, which was experimentally confirmed in vitro, in vivo and ex vivo. ChIP-seq confirmed Adropin34-76-induced changes in TGFβ/GLI1 signaling. Our study thus characterizes the TGFβ-induced downregulation of Adropin/ENHO expression as a potential pathomechanism of SSc as a prototypical systemic fibrotic disease that unleashes uncontrolled activation of profibrotic GLI1 signaling. We also provide evidence in multiple preclinical models that Adropin34-76 might offer potential for the treatment of fibrosis.

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Attenuation of Fibroblast Activation and Fibrosis by Adropin in Systemic Sclerosis (SSc)

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Adropin transgenesis improves recognition memory in diet-induced obese LDLR-deficient C57BL/6J mice

Project description:Obesity-related metabolic dysregulation causes mild cognitive impairment and increases risk for dementia. We used an LDLR-deficient C57BL/6J mouse model (LDLRKO) to investigate whether adropin, a neuropeptide linked to neurodegenerative disease, improves cognitive function in situations of metabolic dysregulation. Adropin transgenic mice (AdrTG) were crossed with LDLRKO; male and female progeny were fed a high fat diet for 3-months. Male chow-fed wild type (WT) mice were used as controls. Diet-induced obesity and LDLR-deficiency caused severe dyslipidemia, irrespective of sex. The AdrTG prevented reduced adropin protein levels in LDLRKO cortex. In males, metabolic dysregulation and AdrTG genotype significantly and bi-directionally affected performance in the novel object recognition (NOR) test, a declarative hippocampal memory task (discrimination index mean±SE for WT, 0.02±0.088; LDLRKO, -0.115±0.077; AdrTG;LDLRKO, 0.265±0.078; genotype effect, p=0.009; LDLRKO vs. AdrTG;LDLRKO, P<0.05). A 2-way ANOVA (fixed variables: sex, AdrTG genotype) indicated a highly significant effect of AdrTG (P=0.003). The impact of the diet-genotype interaction on the male mouse brain was investigated using RNA-seq. Gene-ontology analysis of transcripts showing fold-changes of >1.3 or <-1.3 (P<0.05) indicated metabolic dysregulation affected gene networks involved in intercellular/neuronal signaling, immune processes, angiogenesis, and extracellular matrix organization. The AdrTG selectively attenuated the impact of metabolic dysregulation on intercellular/neuronal signaling pathways. Intercellular/neuronal signaling pathways were also the predominant processes overrepresented when directly comparing AdrTG;LDLRKO with LDRKO. In summary, adropin over expression improves cognitive function in severe metabolic dysregulation through pathways related to cell-cell communication and neuronal processes, and independently of preventing inflammatory responses.

2021-12-15 | GSE185734 | GEO

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Project description: Not available

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Adropin expression correlates with aging-related neuropathology in the human brain and improves neuroinflammation and cognitive function in aging mice

Project description:Adropin expression correlates with aging-related neuropathology in the human brain and improves neuroinflammation and cognitive function in aging mice

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