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System genetics in rat HXB/BXH reference population identifies Tti2 as a pleiotropic quantitative trait gene for adult hippocampal neurogenesis and serum glucose

ABSTRACT: Neurogenesis in the adult hippocampus contributes to learning and memory in the healthy brain and is dysregulated in metabolic and neurodegenerative diseases, but the molecular relationships between neural stem cells activity, adult neurogenesis and global metabolism are largely unknown. We applied unbiased systems genetics to reveal genetic correlations between adult neurogenesis and metabolism of peripheral tissues in a genetic reference population of 30 HXB/BXH recombinant inbred (RI) strains, derived from a cross between spontaneously hypertensive (SHR/OlaIpcv) and Brown Norway (BN-Lx/Cub) rats. We measured the rates of precursor cell proliferation, survival of new neurons, and gene expression profiles in the hippocampi of RI and parental strains and combined them with published metabolic phenotypes to reveal a “neuro-metabolic” quantitative trait locus (QTL) for serum glucose and neuronal survival, which was further narrowed down to the Tti2 (Telo2 interacting protein 2) gene, which is a regulator of activity and stability of PIKK kinases. To validate Tti2 as a causal QTL gene, we generated a targeted frameshift mutation on the SHR/OlaIpcv background. Heterozygous SHR-Tti2+/- rats showed decreased hippocampal neurogenesis and hallmarks of dysglycemia when compared to wild-type littermates. Here we present gene expression profiling of hippocampus, liver, soleus muscle and peritoneal fat in SHR-Tti2 heterozygous rats and wild-type SHR control littermates. Our findings suggest that Tti2 may represent a direct molecular link between glucose metabolism and structural brain plasticity.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE160361 | GEO | 2022/03/16

REPOSITORIES: GEO

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Project description:Physical exercise stimulates adult hippocampal neurogenesis in mammals, and is considered a relevant strategy for preventing age-related cognitive decline in aging humans. However, its mechanism is controversial. Here, by investigating microRNAs (miRNAs) and their downstream pathways, we uncover that downregulation of miR-135a-5p mediates exercise-induced proliferation of adult NPCs in adult neurogenesis in the mouse hippocampus, likely by activation of phosphatidylinositol (IP3) signaling. Specifically, while overexpression of miR-135 prevents exercise-induced proliferation in the adult mouse hippocampus in vivo and in NPCs in vitro, its inhibition activates NPCs proliferation in resting and aged mice. Label free proteomics and bioinformatics analysis identifies 11 potential targets of miR-135 in NPCs, several of them involved in phosphatidylinositol signaling. Thus, miR-135a is key in mediating exercise-induced adult neurogenesis and opens intriguing perspectives toward the therapeutic exploitation of miR-135 to delay or prevent pathological brain ageing.Physical exercise stimulates adult hippocampal neurogenesis in mammals, and is considered a relevant strategy for preventing age-related cognitive decline in aging humans. However, its mechanism is controversial. Here, by investigating microRNAs (miRNAs) and their downstream pathways, we uncover that downregulation of miR-135a-5p mediates exercise-induced proliferation of adult NPCs in adult neurogenesis in the mouse hippocampus, likely by activation of phosphatidylinositol (IP3) signaling. Specifically, while overexpression of miR-135 prevents exercise-induced proliferation in the adult mouse hippocampus in vivo and in NPCs in vitro, its inhibition activates NPCs proliferation in resting and aged mice. Label free proteomics and bioinformatics analysis identifies 11 potential targets of miR-135 in NPCs, several of them involved in phosphatidylinositol signaling. Thus, miR-135a is key in mediating exercise-induced adult neurogenesis and opens intriguing perspectives toward the therapeutic exploitation of miR-135 to delay or prevent pathological brain ageing.

Project description:Metabolic syndrome is associated with chronic low-grade inflammation which plays an important role in the pathogenesis of insulin resistance. Salsalate is a non-steroidal anti-inflammatory drug that reduces levels of inflammatory mediators. In the current study, we tested the effects of salsalate on inflammation, oxidative stress and metabolic disturbances in an animal model of inflammation and metabolic syndrome, using spontaneously hypertensive rats that transgenically express human C-reactive protein (SHR-CRP). We treated 15-month-old male transgenic SHR-CRP rats with salsalate (200 mg/kg/day) mixed as part of a standard diet for 4 weeks. A corresponding untreated control group of male transgenic SHR-CRP rats were fed a standard diet without salsalate. In a similar fashion, we studied a group of nontransgenic SHR treated with salsalate and an untreated group of nontransgenic SHR controls. Parameters of inflammation and glucose and lipid metabolism were measured using standard methods. Statistical significance was evaluated by two-way ANOVA. In the SHR-CRP transgenic strain, we found that salsalate treatment decreased circulating levels of inflammatory markers TNFï¡ and MCP-1 and levels of human CRP as well as reduced levels of lipopreroxidation products in the liver and kidney cortex. Lipidomics analysis of eicosanoids confirmed anti-inflammatory effects of salsalate. Reduced inflammation and oxidative stress were associated with increased sensitivity of skeletal muscles to insulin action and greater tolerance to glucose and with reduced glucose oxidation and incorporation in brown adipose tissue (BAT). In SHR controls with no CRP-induced inflammation, salsalate treatment was associated with reduced body weight, lower levels of serum free fatty acids, total and HDL cholesterol and increased palmitate oxidation and incorporation in BAT. Salsalate regulated lipid metabolism by affecting expression of genes from PPAR signaling pathways and inflammation by affecting expression from MAPK signaling and NOD-like receptor signaling pathways. In summary, in the presence of high levels of human CRP, salsalate reduced inflammation which was associated with reduced oxidative stress and amelioration of insulin resistance in skeletal muscle and glucose intolerance while in non-transgenic SHR rats, salsalate ameliorated dyslipidemia and activated BAT. Thus it is possible that amelioration of insulin resistance and glucose intolerance in SHR-CRP rats treated with salsalate is due to reduced inflammation while amelioration of dyslipidemia in SHR rats treated with salsalate is due to activation of BAT. These findings suggest that salsalate has metabolic effects beyond suppressing inflammation.

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System genetics in rat HXB/BXH reference population identifies Tti2 as a pleiotropic quantitative trait gene for adult hippocampal neurogenesis and serum glucose

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