Tissue-specific modulation of gene expression in response to lowered insulin signalling in Drosophila

Tain, Luke S; Sehlke, Robert; Meilenbrock, Ralf Leslie; Leech, Thomas; Paulitz, Jonathan; Chokkalingam, Manopriya; Nagaraj, Nagarjuna; Grönke, Sebastian; Fröhlich, Jenny; Atanassov, Ilian; Mann, Matthias; Beyer, Andreas; Partridge, Linda

doi:10.7554/elife.67275

Cited by 14 publications

(7 citation statements)

References 97 publications

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“…Thus, FOXO nuclear localization has been used as a proxy to monitor insulin sensitivity 64,65 . Given that the fat body is a major target for insulin signaling 66 , we wondered whether increased insulin signaling in HSD led to insulin resistance. Indeed, we found that 14 days of HSD treatment resulted in elevated nuclear FOXO levels compared to the NF treatment.…”

Section: Resultsmentioning

confidence: 99%

Fat Body Phospholipid State Dictates Hunger Driven Feeding Behavior

Kelly

Alassaf

Sullivan

et al. 2021

Preprint

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Diet-induced obesity (DIO) leads to dysfunctional feeding behavior. But the precise molecular nodes that are dysregulated by DIO that alter satiety sensing and feeding motivation are not fully disentangled. The fruit fly is a simple genetic model system yet displays significant evolutionary conservation to mammalian nutrient sensing and energy balance. Using a longitudinal high sugar regime, in Drosophila, we sought to address how lipid alteration in fat cells alters feeding motivation. We find that long-term exposure to an HSD increases baseline feeding in flies. However, prolonged exposure to HSD degrades the hunger-driven feeding (HDF) response. Lipidomics analysis reveals that longitudinal exposure to HSD significantly alters whole body phospholipid profiles. Then, performing a systematic screen for phospholipid enzymes, we identify that a specific enzyme PECT, a rate-limiting enzyme in the phosphatidylethanolamine (PE) biosynthesis pathway and the fly ortholog of human PCYT2, was critical to maintaining hunger-driven feeding motivation. We show that disrupting PECT only in the fat body causes insulin-resistant phenotypes and a loss of hunger-driven feeding. Excitingly, we find that overexpression of PECT restores HSD-induced loss of hunger-driven feeding response. Strikingly human studies have noted a correlation between PCYT2/PECT levels and clinical obesity. Now, our unbiased studies in Drosophila provide specific genetic evidence for PECT in maintaining nutrient sensing during DIO. Our study provides novel insights on the role of phospholipids in interorgan communication of nutrient status.

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Section: Resultsmentioning

confidence: 99%

Fat Body Phospholipid State Dictates Hunger Driven Feeding Behavior

Kelly

Alassaf

Sullivan

et al. 2021

Preprint

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“…While we could confirm the age-related decline in Lamin levels in our proteomics dataset, neither rapamycin treatment nor S6K repression prevented the age-related loss of Lamin, suggesting that TORC1-S6K regulates age-related inflammation independent of Lamin. DNA damage is another driver of cellular senescence that increases with age in the fly fat body and amelioration of DNA damage specifically in the fat body increases lifespan in flies 59 . Furthermore, rapamycin treatment reduces senescence and improves immune function in DNA repair-deficient progeroid mice 60 .…”

Section: Discussionmentioning

confidence: 99%

Inhibition of S6K lowers age-related inflammation and immunosenescence and increases lifespan through the endolysosomal system

Zhang

Catterson

Grönke

et al. 2022

Preprint

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The nutrient-sensing Target of Rapamycin complex 1 (TORC1) is an evolutionarily conserved regulator of longevity and healthspan. S6 kinase (S6K) is an essential downstream mediator for the effect of TORC1 on longevity. However, mechanistic insights on how TORC1-S6K signalling promotes lifespan and healthspan are still limited. Here we show that activity of S6K in the Drosophila fat body is essential for rapamycin-mediated longevity. Fat-body-specific activation of S6K blocked lifespan extension upon rapamycin feeding and induced accumulation of multilamellar lysosomal enlargements. By proteomics analysis we identified Syntaxin 13 (Syx13) as an important downstream mediator of TORC1-S6K signalling involved in regulating lysosomal morphology. Inhibition of TORC1-S6K signalling decreased age-associated hyperactivation of the NF-κB-like IMD pathway in the fat body and promoted bacterial clearance, mediated by Syx13, suggesting that lysosomal and immune function are connected during ageing. Middle-age-onset repression of IMD pathway in the fat body by Relish RNAi promoted bacteria clearance and extended fly lifespan. In mice, chronic rapamycin treatment elevated Syntaxin 12/13 (Stx12) level in liver. We identified alleviated immune processes in the aged liver as a common signature of S6K1-deficient and rapamycin-treated mice. Thus, our results indicate that suppression of the TORC1-S6K-Syx13 axis ameliorates both inflammageing and immunosenescence in hepatic tissues via the endolysosomal system and thereby extends longevity, providing a mechanistic explanation for the effects of rapamycin and suppression of S6K on immune function and lifespan in model organisms and, potentially, humans.

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“…Arc1 expression increases substantially following neuronal activation, similar to mammalian Arc (Guan et al, 2005;Mattaliano et al, 2007;Montana and Littleton, 2006), and this response to activity can be brain region specific (Mosher et al, 2015), comparable to the microbiotadependent cell type-specific variance we observed. Genetic manipulations that reduce IIS activity also yield tissue-specific differential Arc1 expression (Musselman et al, 2018;Tain et al, 2021), as does rearing flies on a high-fat diet (Rivera et al, 2019) or under starved conditions (Fig. 1B).…”

Section: Discussionmentioning

confidence: 99%

Arc1 and the microbiota together modulate growth and metabolic traits in Drosophila

et al. 2021

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Perturbations to animal-associated microbial communities (the microbiota) have deleterious effects on various aspects of host fitness, but the molecular processes underlying these impacts are poorly understood. Here we identify a novel connection between the microbiota and the neuronal factor Arc1 that affects growth and metabolism in Drosophila. We find that Arc1 exhibits tissue-specific microbiota-dependent expression changes, and that germ-free flies bearing a null mutation of Arc1 exhibit delayed and stunted larval growth, along with a variety of molecular, cellular, and organismal traits indicative of metabolic dysregulation. Remarkably, we show that the majority of these phenotypes can be fully suppressed by mono-association with a single Acetobacter sp. isolate, through mechanisms involving both bacterial diet modification and live bacteria. Additionally, we provide evidence that Arc1 function in key neuroendocrine cells of the larval brain modulates growth and metabolic homeostasis under germ-free conditions. Our results reveal a novel role for Arc1 in modulating physiological responses to the microbial environment, and highlight how host-microbe interactions can profoundly impact the phenotypic consequences of genetic mutations in an animal host.

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Tissue-specific modulation of gene expression in response to lowered insulin signalling in Drosophila

Cited by 14 publications

References 97 publications

Fat Body Phospholipid State Dictates Hunger Driven Feeding Behavior

Fat Body Phospholipid State Dictates Hunger Driven Feeding Behavior

Inhibition of S6K lowers age-related inflammation and immunosenescence and increases lifespan through the endolysosomal system

Arc1 and the microbiota together modulate growth and metabolic traits in Drosophila

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