Intestinal Fork Head Regulates Nutrient Absorption and Promotes Longevity

Bolukbasi, Ekin; Khericha, Mobina; Regan, Jennifer C.; Ivanov, Dobril; Adcott, Jennifer; Dyson, Miranda C.; Nespital, Tobias; Thornton, Janet M.; Alic, Nazif; Partridge, Linda

doi:10.1016/j.celrep.2017.09.042

Cited by 50 publications

(58 citation statements)

References 66 publications

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“…It is made available under a The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/253542 doi: bioRxiv preprint first posted online Jan. 24, 2018; Our findings that IMD specifically affects insulin activity collaborate reports that the Drosophila TNFα homolog, Eiger, regulates production of insulin peptides in the brain (Agrawal et al, 2016), and that the FOXO homolog, Forkhead, regulates intestinal metabolism, and survival after infection in adult Drosophila (Bolukbasi et al, 2017). In addition, several studies identified interaction points between immune and insulin responses in the fly.…”

Section: Discussionsupporting

confidence: 65%

The Immune Deficiency Pathway Regulates Metabolic Homeostasis inDrosophila

Davoodi

Galenza

Panteluk

et al. 2018

Preprint

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Immune and metabolic pathways collectively contribute to the containment of microbial invaders, and persistent activation of immune responses contribute to the development of severe metabolic disorders.To determine how a prolonged immune response impacts metabolism, we induced a constitutive inflammatory response in the Drosophila fat body, a key regulator of humoral immunity and metabolic homeostasis. We found that persistent immune activity replicated key features of a suppressed insulin pathway -delayed development, depleted fat reserves, and hyperglycemia. These observations led us to ask if the inhibition of insulin signaling improves host survival after infection. To test this, we challenged insulin pathway mutants with lethal doses of the enteric pathogen, Vibrio cholerae. We found that loss-of-function mutations in the insulin pathway extended viability and lowered bacterial loads, while gain-of-function mutations diminished viability and elevated bacterial loads. Combined, our results support a role for immune regulation of the insulin pathway in the survival of microbial challenges.

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Section: Discussionsupporting

confidence: 65%

The Immune Deficiency Pathway Regulates Metabolic Homeostasis inDrosophila

Davoodi

Galenza

Panteluk

et al. 2018

Preprint

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“…It is not clear to what extent ISC division per se regulates lifespan; although it is certainly strongly linked with longevity (Biteau et al 2010;Rera et al 2011), recent studies have shown that homeostasis of differentiated cells is important for maintenance of gut function, including barrier function (Bolukbasi et al 2017;Resnik-Docampo et al 2016). Therefore, we analysed pathology of the epithelium, and barrier function of the intestine in 1x trametinib-treated flies over age.…”

Section: Trametinib Attenuates Age-related Intestinal Pathology and Lmentioning

confidence: 99%

Ras inhibition by trametinib treatment in Drosophila attenuates gut pathology in females and extends lifespan in both sexes

Regan

Bolukbasi³

et al. 2018

Preprint

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Females of most species live longer than do males. Furthermore, lifespan-extending interventions in laboratory model organisms are often more effective in females (Regan and Partridge 2013). For instance, genetic and pharmacological suppression of activity of the insulin/insulin-like signalling -target of rapamycin (IIS-TOR) network generally extends female lifespan more than that of males in both Drosophila and mice (Clancy et al. 2001;Selman et al. 2009). We previously showed that attenuation of Ras-dependent IIS signalling by treatment with the FDA-approved MEK inhibitor, trametinib extends lifespan in females (Slack et al. 2015). Here, we demonstrate that trametinib treatment has beneficial effects on female-specific, age-related gut pathologies, similar to those obtained through dietary restriction (Regan et al. 2016). Importantly, we identify Ras inhibition as an effective lifespanextending manipulation in males as well as females, pointing to parallel mechanisms of lifespan extension by trametinib in both sexes.

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“…A large and growing body of literature points to endocrine pathways being involved in nutrient perception and balance in order to coordinate organismal response to diet change. Nutrient sensing mechanisms and pathways are associated with aging and longevity from yeast to mammals [11][12][13][14], reviewed in [15][16][17][18][19]. The insulin/insulinlike signaling (IIS) together with the target of rapamycin (TOR) pathways are among the most studied pathways.…”

Section: Introductionmentioning

confidence: 99%

Diverse biological processes coordinate the transcriptional response to nutritional changes in aDrosophila melanogastermultiparent population

Ng’oma

Williams-Simon

Rahman

et al. 2019

Preprint

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BackgroundEnvironmental variation in the amount of resources available to populations challenge individuals to optimize the allocation of those resources to key fitness functions. This coordination of resource allocation relative to resource availability is commonly attributed to key nutrient sensing gene pathways in laboratory model organisms, chiefly the insulin/TOR signaling pathway. However, the genetic basis of diet-induced variation in gene expression is less clear.ResultsTo describe the natural genetic variation underlying nutrient-dependent differences, we used an outbred panel derived from a multiparental population, the Drosophila Synthetic Population Resource. We analyzed RNA sequence data from multiple female tissue samples dissected from flies reared in three nutritional conditions: high sugar (HS), dietary restriction (DR), and control (C) diets. A large proportion of genes in the experiment (19.6% or 2,471 genes) were significantly differentially expressed for the effect of diet, 7.8% (978 genes) for the effect of the interaction between diet and tissue type (LRT, Padj. < 0.05). Interestingly, we observed similar patterns of gene expression relative to the C diet, in the DR and HS treated flies, a response likely reflecting diet component ratios. Hierarchical clustering identified 21 robust gene modules showing intra-modularly similar patterns of expression across diets, all of which were highly significant for diet or diet-tissue interaction effects (false discovery rate, FDR Padj. < 0.05). Gene set enrichment analysis for different diet-tissue combinations revealed a diverse set of pathways and gene ontology (GO) terms (two-sample t-test, FDR < 0.05). GO analysis on individual co-expressed modules likewise showed a large number of terms encompassing a large number of cellular and nuclear processes (Fisher exact test, Padj. < 0.01). Although a handful of genes in the IIS/TOR pathway including Ilp5, Rheb, and Sirt2 showed significant elevation in expression, known key genes such as InR, chico, insulin peptide genes, and the nutrient-sensing pathways were not observed.ConclusionsOur results suggest that a more diverse network of pathways and gene networks mediate the diet response in our population. These results have important implications for future studies focusing on diet responses in natural populations.

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Intestinal Fork Head Regulates Nutrient Absorption and Promotes Longevity

Cited by 50 publications

References 66 publications

The Immune Deficiency Pathway Regulates Metabolic Homeostasis inDrosophila

The Immune Deficiency Pathway Regulates Metabolic Homeostasis inDrosophila

Ras inhibition by trametinib treatment in Drosophila attenuates gut pathology in females and extends lifespan in both sexes

Diverse biological processes coordinate the transcriptional response to nutritional changes in aDrosophila melanogastermultiparent population

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