Biology subjects

Brodesser, S.

Publications and source records attributed to Brodesser, S..

3 recordsLinked to original sources

bioRxiv2021

Organ protection by caloric restriction depends on activation of the de novo NAD+ synthesis pathway

Therapeutic strategies to treat acute kidney injury (AKI) are lacking in clinical practice. Interestingly, preconditioning by hypoxia (HP) and caloric restriction (CR) is highly protective in rodent AKI models. However, the underlying molecular mechanisms of this process are unknown. A comparative transcriptome analysis of murine kidneys after HP and CR identified Kynureninase (KYNU) as a common downstream target. Using a newly generated KYNU-deficient mouse line, we show that KYNU strongly contributes to the protective effect of preconditioning. Metabolome, transcriptome and proteome analyses reveal the KYNU-dependent de novo nicotinamide adenine dinucleotide (NAD+) biosynthesis pathway as necessary for CR-associated maintenance of NAD+ levels. Importantly, the impact of CR on the de novo NAD+ biosynthesis pathway can be recapitulated in humans. These findings provide a valuable insight into the molecular mechanisms mediating protection upon preconditioning and point towards the de novo branch of NAD+ biosynthesis as a conserved target in nephroprotection.

physiology↗

bioRxiv2021

P2Y6 receptor signaling in natural killer cells impairs insulin sensitivity in obesity

Natural killer (NK) cells contribute to the development of obesity-associated insulin resistance and have previously been shown to up-regulate the expression of the P2Y purinoreceptor 6 (P2Y6R) upon high fat diet (HFD)-induced obesity. Here, we reveal that NK cell-specific inactivation of the P2Y6R gene improves insulin sensitivity in obese mice and reduces the expression of chemokines in adipose tissue infiltrating NK-cells. Obese mice lacking P2Y6R specifically in NK cells exhibited a reduction in adipose tissue inflammation, exhibited improved insulin-stimulated suppression of lipolysis in adipose tissue and a reduction in hepatic glucose production, leading to an overall improvement of systemic insulin sensitivity. In contrast, myeloid lineage specific P2Y6R inactivation does not affect energy or glucose homeostasis in obesity. Collectively, we show that P2Y6R signaling in NK cells contributes to the development of obesity-associated insulin resistance and thus might be a future target for the treatment of obesity-associated insulin resistance and type 2 diabetes.

immunology↗

bioRxiv2021

Mitochondrial function is essential for humoral immunity by controlling flux of the TCA cycle, phosphatidic acid and mTOR activity in B cells

The function of mitochondrial respiration during B cell fate decisions and differentiation remains equivocal. This study reveals that selection for mitochondrial fitness occurs during B cell activation and is essential for subsequent plasma cell differentiation. By expressing a mutated mitochondrial helicase in transitional B cells, we depleted mitochondrial DNA during B cell maturation, resulting in reduced oxidative phosphorylation. Although no changes in follicular B cell development were evident, germinal centers, class switch recombination to IgG, plasma cell generation and humoral immunity were diminished. Defective oxidative phosphorylation led to aberrant flux of the tricarboxylic acid cycle and lowered the amount of saturated phosphatidic acid. Consequently, MTOR activity and BLIMP-1 induction were curtailed whereas HIF1, glycolysis and AMPK activity were amplified. Exogenous phosphatidic acid increased mTOR activity in activated B cells. Hence, mitochondrial function is required and selected for in activated B cells for the successful generation of functional plasma cells.

immunology↗