High-resolution dynamics of the transcriptional response to nutrition in <i>Drosophila</i>: a key role for dFOXO

Gershman, Boris; Puig, Óscar; Hang, Lilian; Peitzsch, Robert M.; Tatar, Marc; Garofalo, Robert S.

doi:10.1152/physiolgenomics.00061.2006

Cited by 160 publications

(167 citation statements)

References 73 publications

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“…Among many candidates, citrate stands out as a metabolite signal in the secretion of insulin in response to energy balance (Farfari et al 2000). Microarray studies measuring genomic responses to starvation and nutrient supply in Drosophila show that starvation and the subsequent signaling clearly lead to decreases in glucose oxidizing and fat biosynthetic enzymes (Zinke et al 2002;Gershman et al 2007). Likewise in mammalian pancreatic b-cells, blockage of cytosolic IDH impairs insulin secretion and pyruvate cycling (the malate/pyruvate cycle in which MEN is the central step) and leads to responses that are normally associated with starvation conditions (Ronnebaum et al 2006).…”

Section: Discussionmentioning

confidence: 99%

Quantifying Interactions Within the NADP(H) Enzyme Network in Drosophila melanogaster

Merritt

Kuczynski

Sezgın³

et al. 2009

Genetics

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In this report, we use synthetic, activity-variant alleles in Drosophila melanogaster to quantify interactions across the enzyme network that reduces nicotinamide adenine dinucleotide phosphate (NADP) to NADPH. We examine the effects of large-scale variation in isocitrate dehydrogenase (IDH) or glucose-6-phosphate dehydrogenase (G6PD) activity in a single genetic background and of smaller-scale variation in IDH, G6PD, and malic enzyme across 10 different genetic backgrounds. We find significant interactions among all three enzymes in adults; changes in the activity of any one source of a reduced cofactor generally result in changes in the other two, although the magnitude and directionality of change differs depending on the gene and the genetic background. Observed interactions are presumably through cellular mechanisms that maintain a homeostatic balance of NADPH/NADP, and the magnitude of change in response to modification of one source of reduced cofactor likely reflects the relative contribution of that enzyme to the cofactor pool. Our results suggest that malic enzyme makes the largest single contribution to the NADPH pool, consistent with the results from earlier experiments in larval D. melanogaster using naturally occurring alleles. The interactions between all three enzymes indicate functional interdependence and underscore the importance of examining enzymes as components of a network.

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Section: Discussionmentioning

confidence: 99%

Quantifying Interactions Within the NADP(H) Enzyme Network in Drosophila melanogaster

Merritt

Kuczynski

Sezgın³

et al. 2009

Genetics

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“…Significant structural homologies exist between Spargel and PGC-1 (Gershman et al 2007). We noticed with interest that these two molecules share a comparable subcellular localization, which may have some greater functional significance.…”

Section: Subcellular Localization Of Spargel and Pgc-1 Is Comparablementioning

confidence: 99%

“…The single Drosophila PGC-1 homolog is designated as Spargel (Tiefenbock et al 2010), which shares significant homology with PGC-1 at the RNA recognition motif (RRM) and serine-arginine repeat (RS) (Gershman et al 2007 Insulin-TOR signaling is central to cell growth and cell size determination, hence the loss of function of some of its members and gain of function of the others, all influencing the cell size as demonstrated either at the whole organism level or in cell clones (Hietakangas and Cohen 2009). Taking advantage of their effect on cell size, we tested the action of spargel hypomorph and/or Spargel gain of function on TOR, S6K, Tsc, and FoxO-induced cell growth defects.…”

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confidence: 99%

Spargel/dPGC-1 Is a New Downstream Effector in the Insulin–TOR Signaling Pathway in Drosophila

Mukherjee

Duttaroy

2013

Genetics

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Insulin and target of rapamycin (TOR) signaling pathways converge to maintain growth so a proportionate body form is attained. Insufficiency in either insulin or TOR results in developmental growth defects due to low ATP level. Spargel is the Drosophila homolog of PGC-1, which is an omnipotent transcriptional coactivator in mammals. Like its mammalian counterpart, Spargel/dPGC-1 is recognized for its role in energy metabolism through mitochondrial biogenesis. An earlier study demonstrated that Spargel/dPGC-1 is involved in the insulin-TOR signaling, but a comprehensive analysis is needed to understand exactly which step of this pathway Spargel/PGC-1 is essential. Using genetic epistasis analysis, we demonstrated that a Spargel gain of function can overcome the TOR and S6K mediated cell size and cell growth defects in a cell autonomous manner. Moreover, the tissue-restricted phenotypes of TOR and S6k mutants are rescued by Spargel overexpression. We have further elucidated that Spargel gain of function sets back the mitochondrial numbers in growth-limited TOR mutant cell clones, which suggests a possible mechanism for Spargel action on cells and tissue to attain normal size. Finally, excess Spargel can ameliorate the negative effect of FoxO overexpression only to a limited extent, which suggests that Spargel does not share all of the FoxO functions and consequently cannot significantly rescue the FoxO phenotypes. Together, our observation established that Spargel/dPGC-1 is indeed a terminal effector in the insulin-TOR pathway operating below TOR, S6K, Tsc, and FoxO. This led us to conclude that Spargel should be incorporated as a new member of this growth-signaling pathway.T O attain proper cellular growth, availability of nutrients is imperative, because the nutrient supply fuels energy metabolism. Thus lack of nourishment cause limited growth of the organism due to reduced energy metabolism (Hietakangas and Cohen 2009;DePalma et al. 2012). Sensing and transport of growth signals happen in two distinct pathways: at the cellular level, the TOR pathway governs growth (Saltiel and Kahn 2001;Grewal 2009), whereas insulin signaling is responsible for subsequent adjustment of the cellular metabolism causing growth at a more systemic level. Ultimate convergence of these two signaling pathways leads to balanced growth. Therefore each member of the insulin-TOR pathway has recognized influence on cell size and cell growth as demonstrated either in cell clones or at the whole organism level. Severe growth defect during prenatal development such as intrauterine growth restriction and low birth weight have been linked to paucity of insulinTor signaling (Murakami et al. 2004;Gannage-Yared et al. 2012) and ATP production (Selak et al. 2003). Like in most animals, the insulin-TOR signaling pathway in Drosophila is dedicated to the control of growth and metabolism ( Figure 1A). With its enriched genetic and genomic resources, flies have contributed significantly toward the understanding of nutritional physiology and ce...

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“…The response to changing nutrient input results in intercellular signals that drive a cascade of downstream gene transcription shifts that facilitate energy utilization and storage [3]. The proximal signal is generally derived from specific metabolite levels as they change under shifting nutrient load [4].…”

Section: Introductionmentioning

confidence: 99%

Genetic perturbation of key central metabolic genes extends lifespan in Drosophila and affects response to dietary restriction

Talbert¹,

Barnett²,

Hoff³

et al. 2015

Proc. R. Soc. B.

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There is a connection between nutrient inputs, energy-sensing pathways, lifespan variation and aging. Despite the role of metabolic enzymes in energy homeostasis and their metabolites as nutrient signals, little is known about how their gene expression impacts lifespan. In this report, we use P-element mutagenesis in Drosophila to study the effect on lifespan of reductions in expression of seven central metabolic enzymes, and contrast the effects on normal diet and dietary restriction. The major observation is that for five of seven genes, the reduction of gene expression extends lifespan on one or both diets. Two genes are involved in redox balance, and we observe that lower activity genotypes significantly extend lifespan. The hexokinases also show extension of lifespan with reduced gene activity. Since both affect the ATP/ADP ratio, this connects with the role of AMP-activated protein kinase as an energy sensor in regulating lifespan and mediating caloric restriction. These genes possess significant expression variation in natural populations, and our experimental genotypes span this level of natural activity variation. Our studies link the readout of energy state with the perturbation of the genes of central metabolism and demonstrate their effect on lifespan.

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High-resolution dynamics of the transcriptional response to nutrition in Drosophila: a key role for dFOXO

Cited by 160 publications

References 73 publications

Quantifying Interactions Within the NADP(H) Enzyme Network in Drosophila melanogaster

Quantifying Interactions Within the NADP(H) Enzyme Network in Drosophila melanogaster

Spargel/dPGC-1 Is a New Downstream Effector in the Insulin–TOR Signaling Pathway in Drosophila

Genetic perturbation of key central metabolic genes extends lifespan in Drosophila and affects response to dietary restriction

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