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The Drosophila acetyltransferase chameau (chm) promotes starvation resilience at the expense of a shortened life span

ABSTRACT: Proteins involved in cellular metabolism and molecular regulation have been shown to extend lifespan in various laboratory organisms. However, for any improvement in aging to confer an evolutionary benefit, organisms must also be able to survive under non-ideal conditions. Earlier, we discovered that the loss of chm function and reduced activity resulted in several notable effects. Firstly, flies with a loss-of-function allele of chm exhibited an extended healthy lifespan when provided with an unrestricted food supply, indicating that chm plays a role in lifespan regulation. In this study, we demonstrate that these flies also experience a significant reduction in weight and decreased starvation resistance compared to flies with normal chm function. Furthermore, based on observations from transcriptomic, proteomic, and acetylome data, we hypothesize that chm is important for regulating metabolism in Drosophila, particularly in energy storage and utilization. Moreover, we demonstrate that reduced chm activity affects carbohydrate metabolism in flies at the basal level and during changes in nutrient status. In summary, this study suggests that chm is also required for starvation resilience by regulating carbohydrate metabolism, and the previously observed increase in survival time likely accompanies the inability to prepare for and cope with nutrient stress. Finally, as the ability to adapt and survive in a food-restricted environment was likely a stronger evolutionary driver than the ability to live a long life, chm is still present in the organism's genome despite its apparent deleterious effect on lifespan.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Drosophila Melanogaster (fruit Fly)

SUBMITTER: Ignasi Forne

LAB HEAD: Prof. Dr. Axel Imhof

PROVIDER: PXD042471 | Pride | 2023-09-05

REPOSITORIES: Pride

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Project description:Long-term consumption of fatty foods is associated with obesity, macrophage activation and inflammation, metabolic imbalance, and a reduced lifespan. We took advantage of Drosophila genetics to investigate the role of macrophages and the pathway(s) that govern their response to dietary stress. Flies fed a lipid-rich diet presented with increased fat storage, systemic JAK-STAT activation, reduced insulin sensitivity and hyperglycaemia, and a shorter lifespan. Drosophila macrophages scavenged lipids and produced the type 1 cytokine upd3, in a scavenger-receptor (croquemort) and JNK-dependent manner. Genetic depletion of macrophages, or macrophage-specific silencing of upd3 decreased JAK-STAT activation and rescued insulin sensitivity and the lifespan of Drosophila, but did not decrease fat storage. NF-M-NM-:B signalling made no contribution to the phenotype observed. These results identify an evolutionarily conserved M-bM-^@M-^Xscavenger receptor-JNK-Type 1 cytokineM-bM-^@M-^Y cassette in macrophages, which controls glucose metabolism and reduces lifespan in Drosophila maintained on a lipid-rich diet via activation of the JAK-STAT pathway Long-term consumption of fatty foods is associated with obesity, macrophage activation and inflammation, metabolic imbalance, and a reduced lifespan. We took advantage of Drosophila genetics to investigate the role of macrophages and the pathway(s) that govern their response to dietary stress. Flies fed a lipid-rich diet presented with increased fat storage, systemic JAK-STAT activation, reduced insulin sensitivity and hyperglycaemia, and a shorter lifespan. Drosophila macrophages scavenged lipids and produced the type 1 cytokine upd3, in a scavenger-receptor (croquemort) and JNK-dependent manner. Genetic depletion of macrophages, or macrophage-specific silencing of upd3 decreased JAK-STAT activation and rescued insulin sensitivity and the lifespan of Drosophila, but did not decrease fat storage. NF-M-NM-:B signalling made no contribution to the phenotype observed. These results identify an evolutionarily conserved M-bM-^@M-^Xscavenger receptor-JNK-Type 1 cytokineM-bM-^@M-^Y cassette in macrophages, which controls glucose metabolism and reduces lifespan in Drosophila maintained on a lipid-rich diet via activation of the JAK-STAT pathway 5 biological samples were FACS-sorted from different batches of Drosophila melanogaster males after 30 days on 15% lipid enriched diet (n=5) and control diet (n=5)

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The Drosophila acetyltransferase chameau (chm) promotes starvation resilience at the expense of a shortened life span

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