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Sex-specific Schistosomiasis induced metabolic modulation of the myeloid lineage

ABSTRACT: Despite strong evidence that prior helminth infection exerts a protective effect against the development of metabolic disease, a major gap exists in understanding the mechanism(s) underlying this protection. We previously found that Schistosoma mansoni infection induces dramatic transcriptional alterations in hepatic macrophage metabolism, and that this correlates with protection from high fat diet (HFD) induced atherosclerosis and glucose intolerance in male ApoE-/- mice. We sought in the present study to determine the broad effects of S. mansoni exposure on the myeloid lineage using the ApoE-/- HFD model. We uncovered that macrophages derived from the bone marrow of S. mansoni infected male mice have dramatically increased oxygen consumption and mitochondrial mass compared to those from uninfected mice. This shift is accompanied by increased glucose shuttling into TCA cycle intermediates and decreased cholesterol esters. When we examined the role of biological sex in schistosome induced modulation. We found that S. mansoni infection does not reliably protect ApoE-/- female mice from HFD induced weight gain or glucose intolerance. The sex-dependent effect of infection extends to myeloid precursors, where the metabolic phenotype of bone marrow derived macrophages from infected females are the opposite of those from infected males. Overall, these data present the first evidence that S. mansoni systemically modulates the myeloid compartment in a sex-dependent manner.

ORGANISM(S): Mus musculus

PROVIDER: GSE144447 | GEO | 2020/11/01

REPOSITORIES: GEO

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Schistosoma mansoni infection metabolically reprograms the myeloid lineage in a mouse model of metabolic disease

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Integrated approach reveals diet, APOE genotype and sex affect immune response in APP mice

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Project description:Type 2 diabetes (T2D) has become an epidemic in our modern lifestyle, likely due to calorie-rich diets overwhelming our adaptive metabolic pathways. One such pathway is mediated by nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in mammalian NAD+ biosynthesis, and the NAD+-dependent protein deacetylase SIRT1. Here we show that NAMPT-mediated NAD+ biosynthesis is severely compromised in metabolic organs by high-fat diet (HFD). Strikingly, nicotinamide mononucleotide (NMN), a product of the NAMPT reaction and a key NAD+ intermediate, ameliorates glucose intolerance by restoring NAD+ levels in HFD-induced T2D mice. NMN also enhances hepatic insulin sensitivity and restores gene expression related to oxidative stress, inflammatory response, and circadian rhythm, partly through SIRT1 activation. Furthermore, NAD+ and NAMPT levels show significant decreases in multiple organs during aging, and NMN improves glucose intolerance and lipid profiles in age-induced T2D mice. These findings provide critical insights into a novel intervention against diet- and age-induced T2D. 4 regular chow fed mice (RC1-4) vs 4 high-fat diet fed (HFD) (HFD1a-4a) mice were analyzed on one chip (Chip-A). 4 HFD mice (HFD1b-4b) vs 4 HFD-NMN treated mice (NMN1-4) were examined on the other chip (Chip-B).

2011-12-05 | E-GEOD-31647 | biostudies-arrayexpress

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Nicotinamide mononucleotide, a key NAD+ precursor, treats the pathophysiology of diet- and age-induced diabetes

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