These constructed genotypes demonstrate the potential for condition-dependent effects of mito-nuclear interactions on metabolism and fitness.

Nonetheless, both the nuclear and mitochondrial variants studied here exist in natural populations of fruit flies Meiklejohn et al. Our findings motivate further investigation—including in an outbred genetic context—of the role of energy demand in mediating the phenotypic effects of genetic variation in metabolism, mito-nuclear or otherwise, as this will have significant implications for the persistence of genetic variation for metabolism and the evolution of metabolic performance in natural populations.

The authors thank members of the K. Montooth, C. Meiklejohn, and J. Storz labs for feedback on this manuscript, and acknowledge funding support from NSF IOS Award to K.

and K. conceived and designed the study, L. collected and analyzed the data, L. drafted the initial version of the manuscript, and all authors contributed to later versions of the manuscript. Agrawal , A. Conner , and S.

Tradeoffs and adaptive negative correlations in evolutionary ecology. Bell , W. Eanes , D Futuyma , and J. Levinton , eds. Evolution After Darwin: the First Years. Sinauer , Sunderland, Massachusetts. Google Scholar. Google Preview. Angilletta , M. Thermal adaptation: A theoretical and empirical synthesis.

Oxford Univ. Press , Oxford, UK. Arnqvist , G. Dowling , P. Eady , L. Gay , T. Tregenza , M. Tuda et al. Genetic Architecture of metabolic rate: environment specific epistasis between mitochondrial and nuclear genes in an insect.

Evolution 64 : — Ashmore , L. A Fly's eye view of circadian entrainment. Asplen , M. Bruns , A. David , R. Denison , B. Epstein , M. Kaiser et al. Do trade-offs have explanatory power for the evolution of organismal interactions? Evolution 66 : — Ballard , J. Review: can diet influence the selective advantage of mitochondrial DNA haplotypes?

Bateman , A. Intra-sexual selection in Drosophila. Heredity 2 : — Bruning , A. Gaitán-Espitia , A. González , J. Bartheld , and R. Metabolism, growth, and the energetic definition of fitness: a quantitative genetic study in the land snail Cornu aspersum.

Burton , R. A disproportionate role for mtDNA in Dobzhansky. Muller incompatibilities? Callier , V. Supply-side constraints are insufficient to explain the ontogenetic scaling of metabolic rate in the tobacco hornworm, Manduca sexta. PLoS ONE 7 : e Chadwick , L. The respiratory quotient of Drosophila in flight.

Chandler , C. Chari , and I. Does your gene need a background check? How genetic background impacts the analysis of mutations, genes, and evolution. Trends Genet. Church , R. A biochemical study of the growth of Drosophila melanogaster. Clarke , A. Why does metabolism scale with temperature?

DeLong , J. Gibert , T. Luhring , G. Bachman , B. Reed et al. The combined effects of reactant kinetics and enzyme stability explain the temperature dependence of metabolic rates. Diggle , P.

The expression of andromonoecy in Solanum-Hirtum Solanaceae —phenotypic plasticity and ontogenic contingency. Dobzhansky , T. Oxygen consumption of Drosophila pupae. Dowling , D. Abiega , and G. Temperature-specific outcomes of cytoplasmic-nuclear interactions on egg-to-adult development time in seed beetles.

Evolution 61 : — Nowostawski , and G. Effects of cytoplasmic genes on sperm viability and sperm morphology in a seed beetle: implications for sperm competition theory? Friberg , and G. A comparison of nuclear and cytoplasmic genetic effects on sperm competitiveness and female remating in a seed beetle.

Drummond-Barbosa , D. Stem cells and their progeny respond to nutritional changes during Drosophila oogenesis. Flatt , T. Heyland , eds. Mechanisms of life history evolution: The genetics and physiology of life history traits and trade-offs.

Press , Oxford, U. Friberg , U. No evidence of mitochondrial genetic variation for sperm competition within a population of Drosophila melanogaster. Glazier , D. Greenlee , K. Montooth , and B. Predicting performance and plasticity in the development of respiratory structures and metabolic systems.

Harshman , L. The cost of reproduction: the devil in the details. TREE 22 : 80 — Hartman , J. Garvik , and L. Principles for the buffering of genetic variation. Science : — Hayward , A. The cost of sex: quantifying energetic investment in gamete production by males and females.

PLoS ONE 6 : e Hoekstra , L. Inducing extra copies of the Hsp70 gene in Drosophila melanogaster increases energetic demand.

BMC Evol. Siddiq , and K. Pleiotropic effects of a mitochondrial-nuclear incompatibility depend upon the accelerating effect of temperature in Drosophila.

Genetics : — Holmbeck , M. Donner , E. Villa-Cuesta , and D. A Drosophila model for mito-nuclear diseases generated by an incompatible interaction between tRNA and tRNA synthetase.

Models Mechan. Kammenga , J. The background puzzle: how identical mutations in the same gene lead to different disease symptoms. FEBS J. Kondrashov , A. Genotype-environment interactions and the estimation of the genomic mutation rate in Drosophila melanogaster.

Roy Soc. B : — Kyriacou , C. Oldroyd , J. Wood , M. Sharp , and M. Clock mutations alter developmental timing in Drosophil a. Heredity 64 : — Lachance , J. Jung , and J. Genetic background and G × E interactions modulate the penetrance of a naturally occurring wing mutation in Drosophila melanogaster.

G3 3 : — Leopold , P. Drosophila and the genetics of the internal milieu. Nature : — Mackay , T. Epistasis and quantitative traits: using model organisms to study gene-gene interactions.

Maino , J. Ontogenetic and interspecific metabolic scaling in insects. McLeod , C. Wang , C. Wong , and D. Stem cell dynamics in response to nutrient availability.

Meiklejohn , C. Siddiq , D. Abt , D. Rand et al. An incompatibility between a mitochondrial tRNA and its nuclear-encoded tRNA synthetase compromises development and fitness in Drosophila.

PLoS Genet. Merkey , A. Wong , D. Hoshizaki , and A. Energetics of metamorphosis in Drosophila melanogaster. Insect Physiol.

Montooth , K. Meiklejohn , D. Abt , and D. Mitochondrial-nuclear epistasis affects fitness within species but does not contribute to fixed incompatibilities between species of Drosophila.

Mossman , J. Biancani , C-T. Zhu , and D. Mitonuclear epistasis for development time and its modification by diet in Drosophila. Mueller , L. Does phenotypic plasticity for adult size versus food level in Drosophila melanogaster evolve in response to adaptation to different rearing densities?

Nijhout , H. Roff , and G. Conflicting processes in the evolution of body size and development time. Philosophical Transactions of the Royal Society of London B: Biological Sciences : — Paliwal , S. Fiumera , and H.

Mitochondrial-nuclear epistasis contributes to phenotypic variation and coadaptation in natural isolates of Saccharomyces cerevisiae.

Paranjpe , D. In the IPCs, this is an activating stimulus that induces DILP release, while in the APCs, sNPF-R acts through inhibitory G-proteins, and, therefore, sNPF signaling blocks Akh release [ ]. This peptide also regulates adult olfactory sensitivity, described below [ , ].

Thus, in response to consumed sugars, this pleiotropic peptide coordinately raises insulin levels and lowers Akh levels, which promotes tissue uptake of hemolymph sugars and downregulates lipid-mobilizing processes [ ], while also governing food-seeking behavior.

Insulin and Akh are also jointly controlled by Upd2. This protein is released by cells of the fat body in both larvae and adults in the fed state and acts through the receptor Domeless to inhibit certain GABAergic neurons of the brain, which synapse on the IPCs [ 21 ].

Upd2 signaling thus leads to derepression of the IPCs and promotion of insulin release in fed conditions. Furthermore, Upd2 is released from the adult musculature and acts on the APCs to govern Akh secretion and thereby to control lipid mobilization for energy use [ ].

Thus, this signal is released from energy-storing and -consuming tissues and acts through both DILPs and Akh to coordinate metabolite storage, mobilization, and use. Stored energy provides a buffer against times of scarcity or exertion.

In nutrient-rich conditions, the fly sets aside excess energy in the form of TAG, stored within lipid droplets in the cells of the fat body.

These stored lipids can be degraded and mobilized by metabolic enzymes such as lipases [ , , ]. Among the most important fat-body lipases for metabolic adaptation is Brummer Bmm , the Drosophila orthologue of mammalian adipose triglyceride lipase ATGL [ ].

In the fed state, DILP signaling in the fat body via InR induces sugar uptake from the hemolymph and represses the expression of genes required for lipolysis [ , , , ]. Insulin signaling prevents FoxO activation of genes important for lipolysis, including bmm [ ], and low Akh signaling allows expression of genes required for lipogenesis, such as midway [ ].

High DILP activity and low Akh signaling thus gear the physiology of the fat body towards storage under fed conditions.

The DAGs can then be transported in the hemolymph complexed with one of several lipid-carrier proteins [ ]; alternatively, lipid components fatty acids and glycerol can be further broken down and reformed into trehalose through the process of gluconeogenesis more specifically, trehaloneogenesis , reviewed elsewhere [ , ].

In studied insects of a range of species, AkhR signaling passes through stimulatory G-proteins and has been shown directly to increase intracellular concentrations of cAMP and calcium [ , , ]. In any case, second-messenger cascades initiated by AkhR signaling induce repression of the lipogenic gene midway and activate the expression of lipase genes, thereby blocking lipid synthesis while activating lipid breakdown [ , , ].

This upregulation is aided by relief of DILP-induced inhibition [ , ]. Together, in a fasting state, reduced DILP signaling and increased Akh activity switch the fat body into lipid-breakdown mode. The main intracellular sensor of nutrition primarily amino acids , TOR, is also a component of lipid-metabolism regulation.

Because insulin signaling and TOR are interlinked via Akt, TOR mediates some DILP-induced effects downstream of InR and also has effects of its own. Reduction of TOR activity in the fat body leads to smaller lipid droplets and reduced lipid storage [ ]. Interestingly, TOR also regulates fat-body autophagy, a starvation-induced process that cells use to release and recycle store nutrients.

In starved conditions, inactivation of TOR induces autophagy-mediated breakdown of nutrients, which can be released from the fat to sustain overall organismal survival under such conditions [ ]. Through these mechanisms, fat-body intracellular nutritional levels thus also regulate lipid metabolism.

To provide greater control over lipid physiology, signals from other tissues modulate the AkhR signaling pathway in the fat body to gate lipid release. During development, at least, the TGF-β ligand Activin-β Actβ is secreted by endocrine cells of the gut and acts directly on cells of the fat body through its receptor Baboon isoform A only to regulate lipid metabolism and hemolymph sugar levels [ ].

Chronic high-sugar feeding disturbs the balance of cell proliferation in the gut and leads to an increased number of Actβ-secreting cells; this extra Actβ induces abnormally high fat-body expression of AkhR, which triggers aberrant lipolysis and gluconeogenesis, thereby leading to carbohydrate imbalance and hyperglycemia [ ].

However, the AkhR pathway, including modulators of its activity, is not the sole regulator of fat-body lipid mobilization. Additional, unidentified pathways appear to participate in the regulation of starvation-induced lipolysis in adipose tissue.

Expression of Bmm lipase requires Akh signaling during short-term starvation 4 h [ ], but not over longer-term starvation, since fat-body bmm is upregulated even in AkhR mutants starved for 6 h [ ].

Akh signaling during early starvation regulates lipases beyond Brummer, but Brummer is specifically required for later lipolysis [ ]. Only in AkhR bmm double mutants is starvation-induced lipid mobilization fully suppressed, with identical lipid levels between fed flies and flies starved to death [ ], suggesting the existence of other, uncharacterized signal s that regulate lipolysis through Bmm.

In addition to Actβ, the gut also secretes a lipid-associated form of the protein Hedgehog Hh under starvation conditions. This signal promotes lipid mobilization in the fat body in both larvae and adults and supports hemolymph sugar levels, but only in starved animals, indicating the requirement for other permissive mobilization signal s [ 94 , ].

Recent work shows that Hh acts on the fat to upregulate bmm expression. Furthermore, the sugar-induced gut-secreted factor BursA [ ] may also act on the fat body. Burs dimers activate the transcription factor Relish, the Drosophila orthologue of mammalian NF-κB, in the fat body.

This activates innate-immunity pathways to prevent infection during these transitions [ ]. Relish also antagonizes FoxO-induced bmm expression to limit fasting-induced lipolysis [ ]. Investigating the emerging link between immune response and metabolism will be an important direction for future research.

Furthermore, characterizing the signals that affect the fat will be key to the understanding of lipolytic control and the mobilization of resources in the face of environmental and nutritional challenges.

As in other multicellular organisms, the polysaccharide glycogen is the main storage form of carbohydrates in Drosophila [ ]. In both the larval and adult stages, glycogen is synthesized and stored in several tissues including the central nervous system CNS , fat body, and skeletal muscles, and the dynamic regulation of glycogen metabolism—especially during starvation—plays a key role in maintaining metabolic homeostasis [ , ].

For example, glycogen stores in larval body-wall muscles and fat body, but not CNS, are rapidly depleted during larval starvation, suggesting that glycogen mobilization is differentially regulated between organs, and that especially the fat body acts as an important carbohydrate reservoir buffering circulating energy levels [ , ].

Similarly, although glycogen appears to be largely dispensable for adult fitness under fed conditions, muscle glycogen is a crucial factor in maintaining stereotypic locomotor activity and wing-beat frequency during starvation [ , ], indicating that glycogen metabolism is regulated in both a tissue- and stage-specific manner.

Glycogen metabolism is controlled by two enzymes, glycogen synthase GlyS and glycogen phosphorylase GlyP , the latter of which catalyzes the rate-limiting step in glycogen breakdown. The control of these processes appears to depend largely on hemolymph sugar levels, and they are generally regulated organ-autonomously rather than by systemic signals such as Akh [ ].

The systemic stress peptide Corazonin Crz and its receptor CrzR—paralogues of Akh and AkhR [ , , ]—may regulate glycogen content of the adult fat body [ ]. Knockdown of CrzR using transgenes targeting this tissue does not affect lipid metabolism but does increase glycogen stores [ ]; however, the authors do not rule out these transgenes also target the salivary glands, which also express CrzR and are also involved in energy balance via production of feeding-related enzymes and fluids [ ].

Furthermore, glycogen breakdown is also regulated by autophagy-dependent mechanisms, at least in skeletal muscle, and genetic experiments reveal that both mechanisms are necessary for maximal glycogenolysis. Interestingly, GlyS may be a central regulator of both pathways via its direct interaction with Atg8, hereby linking glycogenolytic activities with glycogen autophagy to homeostatically control glycogen breakdown in flies [ ].

The adult fly is exposed to the daily cycling of the ambient photic and thermal environment, which brings both opportunity finding food sources and mates and danger predation and desiccation. To anticipate these cycles and schedule appropriate behavior and physiology, flies possess a central neuronal circadian clock that governs rhythmic behaviors such as feeding and sleeping Fig.

This review focuses on metabolic rhythms; an excellent general review of Drosophila circadian rhythm has recently been published [ ]. The adult IPCs are synchronized with the internal circadian clock via synaptic connections, with greater IPC electrical activity in the subjective morning; however, feeding animals at night, when the IPCs are normally quiet, induces morning-like electrical activity in these cells [ ].

The IPCs also express receptors for PDF, the main output factor of the clock, and for sNPF, which is co-expressed in certain PDF-expressing cells [ ]; these inputs also connect circadian rhythms to the IPCs, and they appear to be part of a diapause-antagonizing system as well.

Daily activity regulates Akh signaling as well, via the cytokine Upd2 [ ]. Thus, circadian information is integrated into metabolic programming. Beyond the central-brain clock that drives systemic signaling, scattered peripheral intracellular oscillators regulate local processes Fig.

One such peripheral clock governs fat-body physiology [ ]. Flies lacking this clock eat more than controls, especially at night, and are sensitive to starvation, due to low glycogen levels, indicating a loss of proper energy storage regulation [ ].

The adult gut also exhibits endogenous circadian oscillation in gene expression and cell proliferation [ , ]. Local oscillators also participate in behavioral governance. Olfactory receptor neurons ORNs express their own clock systems, leading to cyclical patterns in the amplitude of odor responses [ , , ].

These patterns of antennal response translate into cyclical odor-driven behavioral patterns [ ]. Likewise, gustatory receptor neurons GRNs display cyclical patterns of electrophysiological responses to tastants, and this cyclicity translates into circadian rhythms of behavioral response to tasted compounds [ ].

Abolishing the clock in these GRNs mimics starvation and leads to overeating and increased metabolite stores [ ]. In changing environmental conditions, the location and quality of food sources are dynamic. Flies are attracted by certain chemicals in the food while being repelled by other cues that represent potential danger.

Drosophila sense the positive and negative qualities of potential food sources through taste and smell and will initially avoid marginal sources. When nutritional balance is low, flies exhibit several stereotypical behavioral changes that increase their ability to find new sources of food, as well as make them more amenable to consuming marginal or dangerous food.

It is thought that increased locomotor activity increases the chances that a fly will encounter a food source, and adjustment of sensory sensitivity makes a fly both more likely to be attracted to weak food odors and less likely to be repelled by noxious ones.

Feeding regulation in the fly has been intensively researched, identifying a broad array of factors governing food-related behaviors. We cover here adaptive feeding responses regulated by DILPs and Akh Fig.

The general regulation of feeding is reviewed comprehensively elsewhere [ , , ]. Through these and other changes, the starved fly becomes more likely to be able to survive, although at the risk of toxicity or exhaustion.

Akh signaling is essential for the phenomenon of starvation-induced hyperactivity, thought to represent an adaptive food-seeking behavioral response to nutritional deprivation.

Hypotrehalosemia-induced Akh release triggers starvation-induced hyperactivity, including during periods normally characterized by inactivity or sleep [ , ].

Octopamine is generally considered the insect analogue of noradrenaline, and it acts through several receptors in many cells to increase arousal. Interestingly, these AkhR-expressing octopaminergic neurons also express InR, whose activation by DILPs inhibits their signaling [ ].

Thus, when sugar is low, Akh acts to increase arousal via these octopaminergic cells, which promotes wakefulness and locomotor activity as a way to find food; then, when food has been consumed, the increase in hemolymph sugar induces DILP release, which terminates the excitatory octopamine signal and thus promotes quiescence.

Olfaction, which detects chemical signals from potentially remote sources, is an important component of food-seeking behavior and adaptation to dynamic environments Fig.

At the same time, sensitivity to, and avoidance of, aversive odors—those that represent potential toxicity or danger—is decreased, allowing the animal to be attracted to riskier food sources. These processes are induced by hormonal signals that reflect the nutritional status of the animal as well as other signals related to the internal and external state.

Olfaction is mediated by olfactory receptors ORs stereotypically expressed in identifiable olfactory receptor neurons ORNs ; the neuroanatomy and odor-responsiveness of this system has been very well mapped [ ].

These receptors and neurons are generally grouped into two behavioral classes: appetitive attractive and aversive repellent. The appetitive ab1a ORNs, which express the fruit-ester-sensitive OR42b, are required for olfactory-guided food-searching behavior [ ].

These cells are directly made more active under low-nutrient conditions via the action of sNPF signaling [ ]. Starvation induces the expression of sNPF-R in the ab1a ORNs to increase their sensitivity to attractive odors [ ]. About a quarter of ORNs express sNPF-R [ ]; given the ability of this receptor to either activate or inhibit neurons [ ], many odorant responses may be up- or down-regulated by this mechanism.

Thus, low nutrition upregulates appetitive responses to increase food-seeking success, and once a food source is found and the internal nutritional state returns to normal, sensitivity is downregulated again, to prevent unneeded attraction to odors.

In fed conditions, the brain produces the satiety signal Unpaired-1 Upd1 , which inhibits the NPF-releasing cells of the brain [ ]. In poor conditions, these cells are derepressed, leading to the release of NPF [ ]. Among the many feeding-promoting effects of NPF is the increase in sensitivity of the ab3A neurons.

Tk and one of its receptors, TkR99D, act in sensory neurons expressing the aversive receptor OR85a to inhibit them under starvation [ ].

In addition to these characterized pathways by which hunger modulates adult olfactory sensitivity, the satiety peptide Dsk appears to reduce larval olfactory sensitivity to attractive odors [ ]. This allows the starved animal to find less-nutritious food, which it otherwise would not find attractive.

Like olfaction, which allows an animal to find a distant food source, gustation is an integral part of feeding behavior. When flies are in a non-starved state, they will consume only foods they perceive to be highly nutritious e.

As hemolymph sugar drops, flies become more likely to consume foods of poor quality, balancing the risk of death by starvation against the risk of being poisoned by low-quality or toxic food.

GRNs express gustatory receptors GRs tuned to a variety of chemical classes, including sugars, salts, and potentially toxic bitter compounds.

Like ORs and ORNs, GRs and GRNs have either appetitive or aversive valence, and like those olfactory components, the gustatory system is also subject to sensitivity-adjusting neuromodulation in response to nutritional sufficiency or deficiency Fig.

In low-sugar states, Akh is released into the hemolymph from the APCs, and among its functions is the modulation of gustatory sensitivity. Through these actions, the fly becomes increasingly likely to be triggered to feed by low levels of sugar in the food source.

In parallel, aversive GRNs are inhibited under fasting conditions by sNPF and Akh [ ] and NPF [ ]. This indicates that starvation increases the perceived palatability of food by several routes.

Dsk released from the IPCs in the fed state is also required for the inhibition of consumption of unpalatable food [ ], although the hierarchical level at which it acts—through regulation of gustation, higher-level gustatory processing and integration, or feeding motivation, for example—is unknown.

The developmental and metabolic demands placed on Drosophila , and their responses to these, are complex and dynamic, as illustrated above. Larvae optimize development to produce the most reproductively successful adults that conditions will allow.

To do this, they adjust their growth rate and growth duration by regulating intracellular and systemic growth factors such as TOR, insulin, PTTH, and ecdysone. We propose that the IPCs, PTTHn, and the PG are signaling hubs that integrate environmental cues to coordinate growth rate and duration to adjust final size in response to given conditions.

Because of the strong conservation between mammalian and insect hormonal systems such as insulin-like signaling, growth- and steroid-hormone pathways, and peptide neuromodulation, studies of these aspects of Drosophila can provide important frameworks for understanding the link between environmental factors and disorders including diabetes and obesity.

The mechanistic bases of how animals assess the critical-weight checkpoint is unresolved and is a key direction for future research. Insights from Drosophila into nutrition-dependent developmental checkpoints have the potential to illuminate mammalian size regulation, including the molecular mechanisms underlying the link between childhood obesity and early puberty.

Drosophila also regulates its metabolism according to prevailing conditions, and this includes behavioral responses, such as feeding decisions.

Central to both these metabolic and behavioral changes are the insulin and Akh systems, which regulate numerous downstream systems to modify metabolic pathways and feeding decisions.

Intertwined with these and other hormonal systems, gustatory and olfactory systems also play important roles in regulating the interface between the organism and the environment. The inter-organ signaling networks that function upstream of insulin and Akh need to be explored systematically to further understand how organisms adapt metabolism to environmental conditions.

While much is known about insulin regulation, the mechanisms underlying Akh regulation and energy mobilization from adipose tissue are important but largely unresolved questions. Regulation imposed by the counter-regulatory actions of insulin and Akh are key to maintaining metabolic homeostasis in variable environments.

Studies in Drosophila will undoubtedly continue to reveal new mechanistic insights into animal metabolic regulation.

In the original article the ORICD id of the author Michael J. Texada was wrong. Lemaitre B, Miguel-Aliaga I The digestive tract of Drosophila melanogaster. Annu Rev Genet — Article CAS PubMed Google Scholar. Sondergaard L Homology between the mammalian liver and the Drosophila fat body.

Trends Genet 9 6 Gutierrez E, Wiggins D, Fielding B, Gould AP Specialized hepatocyte-like cells regulate Drosophila lipid metabolism.

Nature — Danielsen ET, Moeller ME, Rewitz KF Nutrient signaling and developmental timing of maturation. Curr Top Dev Biol — Rewitz KF, Yamanaka N, O'Connor MB Developmental checkpoints and feedback circuits time insect maturation.

Article CAS PubMed PubMed Central Google Scholar. Hietakangas V, Cohen SM Regulation of tissue growth through nutrient sensing. Tennessen JM, Thummel CS Coordinating growth and maturation—insights from Drosophila.

Curr Biol 21 18 :R— Boulan L, Milan M, Leopold P The systemic control of growth. Cold Spring Harb Perspect Biol. Article PubMed PubMed Central Google Scholar. Colombani J, Bianchini L, Layalle S, Pondeville E, Dauphin-Villemant C, Antoniewski C, Carre C, Noselli S, Leopold P Antagonistic actions of ecdysone and insulins determine final size in Drosophila.

Science — Moeller ME, Nagy S, Gerlach SU, Soegaard KC, Danielsen ET, Texada MJ, Rewitz KF Warts signaling controls organ and body growth through regulation of ecdysone. Curr Biol 27 11 — Ikeya T, Galic M, Belawat P, Nairz K, Hafen E Nutrient-dependent expression of insulin-like peptides from neuroendocrine cells in the CNS contributes to growth regulation in Drosophila.

Curr Biol 12 15 — Wang S, Tulina N, Carlin DL, Rulifson EJ The origin of islet-like cells in Drosophila identifies parallels to the vertebrate endocrine axis. Proc Natl Acad Sci USA 50 — Yamanaka N, Rewitz KF, O'Connor MB Ecdysone control of developmental transitions: lessons from Drosophila research.

Annu Rev Entomol — Wiley Interdiscip Rev Dev Biol. Cell Mol Life Sci 73 2 — Steck K, Walker SJ, Itskov PM, Baltazar C, Moreira JM, Ribeiro C Internal amino acid state modulates yeast taste neurons to support protein homeostasis in Drosophila.

Elife 7:e Dus M, Lai JS, Gunapala KM, Min S, Tayler TD, Hergarden AC, Geraud E, Joseph CM, Suh GS Nutrient sensor in the brain directs the action of the brain-gut axis in Drosophila. Neuron 87 1 — Yang Z, Huang R, Fu X, Wang G, Qi W, Mao D, Shi Z, Shen WL, Wang L A post-ingestive amino acid sensor promotes food consumption in Drosophila.

Cell Res 28 10 — Konner AC, Klockener T, Bruning JC Control of energy homeostasis by insulin and leptin: targeting the arcuate nucleus and beyond. Physiol Behav 97 5 — Shalitin S, Phillip M Role of obesity and leptin in the pubertal process and pubertal growth—a review.

Int J Obes Relat Metab Disord 27 8 — Rajan A, Perrimon N Drosophila cytokine unpaired 2 regulates physiological homeostasis by remotely controlling insulin secretion. Cell 1 — Mirth C, Truman JW, Riddiford LM The role of the prothoracic gland in determining critical weight for metamorphosis in Drosophila melanogaster.

Curr Biol 15 20 — Nijhout HF The control of body size in insects. Dev Biol 1 :1—9. Callier V, Nijhout HF Control of body size by oxygen supply reveals size-dependent and size-independent mechanisms of molting and metamorphosis.

Proc Natl Acad Sci USA 35 — Colombani J, Raisin S, Pantalacci S, Radimerski T, Montagne J, Leopold P A nutrient sensor mechanism controls Drosophila growth. Cell 6 — Shingleton AW, Estep CM, Driscoll MV, Dworkin I Many ways to be small: different environmental regulators of size generate distinct scaling relationships in Drosophila melanogaster.

Proc Biol Sci — Texada MJ, Jorgensen AF, Christensen CF, Koyama T, Malita A, Smith DK, Marple DFM, Danielsen ET, Petersen SK, Hansen JL, Halberg KA, Rewitz KF A fat-tissue sensor couples growth to oxygen availability by remotely controlling insulin secretion. Nat Commun 10 1 Li Q, Gong Z Cold-sensing regulates Drosophila growth through insulin-producing cells.

Nat Commun Shingleton AW, Masandika JR, Thorsen LS, Zhu Y, Mirth CK The sex-specific effects of diet quality versus quantity on morphology in Drosophila melanogaster.

R Soc Open Sci 4 9 Nijhout HF, Williams CM Control of moulting and metamorphosis in the tobacco hornworm, Manduca sexta L.

J Exp Biol 61 2 — CAS PubMed Google Scholar. Mirth CK, Riddiford LM Size assessment and growth control: how adult size is determined in insects.

BioEssays 29 4 — Brogiolo W, Stocker H, Ikeya T, Rintelen F, Fernandez R, Hafen E An evolutionarily conserved function of the Drosophila insulin receptor and insulin-like peptides in growth control. Curr Biol 11 4 — Chell JM, Brand AH Nutrition-responsive glia control exit of neural stem cells from quiescence.

Cell 7 — Sousa-Nunes R, Yee LL, Gould AP Fat cells reactivate quiescent neuroblasts via TOR and glial insulin relays in Drosophila. Okamoto N, Yamanaka N, Yagi Y, Nishida Y, Kataoka H, O'Connor MB, Mizoguchi A A fat body-derived IGF-like peptide regulates postfeeding growth in Drosophila.

Dev Cell 17 6 — Slaidina M, Delanoue R, Gronke S, Partridge L, Leopold P A Drosophila insulin-like peptide promotes growth during nonfeeding states. Clancy DJ, Gems D, Harshman LG, Oldham S, Stocker H, Hafen E, Leevers SJ, Partridge L Extension of life-span by loss of CHICO, a Drosophila insulin receptor substrate protein.

Junger MA, Rintelen F, Stocker H, Wasserman JD, Vegh M, Radimerski T, Greenberg ME, Hafen E The Drosophila forkhead transcription factor FOXO mediates the reduction in cell number associated with reduced insulin signaling.

J Biol 2 3 Puig O, Marr MT, Ruhf ML, Tjian R Control of cell number by Drosophila FOXO: downstream and feedback regulation of the insulin receptor pathway. Genes Dev 17 16 — Gao X, Pan D TSC1 and TSC2 tumor suppressors antagonize insulin signaling in cell growth.

Genes Dev 15 11 — Gao X, Zhang Y, Arrazola P, Hino O, Kobayashi T, Yeung RS, Ru B, Pan D Tsc tumour suppressor proteins antagonize amino-acid-TOR signalling.

Nat Cell Biol 4 9 — Lee B, Barretto EC, Grewal SS TORC1 modulation in adipose tissue is required for organismal adaptation to hypoxia in Drosophila.

Mol Cell Biol 23 24 — Caldwell PE, Walkiewicz M, Stern M Ras activity in the Drosophila prothoracic gland regulates body size and developmental rate via ecdysone release. Layalle S, Arquier N, Leopold P The TOR pathway couples nutrition and developmental timing in Drosophila.

Dev Cell 15 4 — PLoS ONE 4 4 :e Geminard C, Rulifson EJ, Leopold P Remote control of insulin secretion by fat cells in Drosophila. Cell Metab 10 3 — Koyama T, Mirth CK Growth-blocking peptides as nutrition-sensitive signals for insulin secretion and body size regulation.

PLoS Biol 14 2 :e Delanoue R, Meschi E, Agrawal N, Mauri A, Tsatskis Y, McNeill H, Leopold P Drosophila insulin release is triggered by adipose Stunted ligand to brain Methuselah receptor.

Agrawal N, Delanoue R, Mauri A, Basco D, Pasco M, Thorens B, Leopold P The Drosophila TNF eiger is an adipokine that acts on insulin-producing cells to mediate nutrient response. Cell Metab 23 4 — Sun J, Liu C, Bai X, Li X, Li J, Zhang Z, Zhang Y, Guo J, Li Y Drosophila FIT is a protein-specific satiety hormone essential for feeding control.

Ghosh AC, O'Connor MB Systemic Activin signaling independently regulates sugar homeostasis, cellular metabolism, and pH balance in Drosophila melanogaster. Proc Natl Acad Sci USA 15 — Sano H, Nakamura A, Texada MJ, Truman JW, Ishimoto H, Kamikouchi A, Nibu Y, Kume K, Ida T, Kojima M The nutrient-responsive hormone CCHamide-2 controls growth by regulating insulin-like peptides in the brain of Drosophila melanogaster.

PLoS Genet 11 5 :e McBrayer Z, Ono H, Shimell M, Parvy JP, Beckstead RB, Warren JT, Thummel CS, Dauphin-Villemant C, Gilbert LI, O'Connor MB Prothoracicotropic hormone regulates developmental timing and body size in Drosophila.

Dev Cell 13 6 — Rewitz KF, Yamanaka N, Gilbert LI, O'Connor MB The insect neuropeptide PTTH activates receptor tyrosine kinase torso to initiate metamorphosis. Hentze JL, Moeller ME, Jorgensen AF, Bengtsson MS, Bordoy AM, Warren JT, Gilbert LI, Andersen O, Rewitz KF Accessory gland as a site for prothoracicotropic hormone controlled ecdysone synthesis in adult male insects.

PLoS ONE 8 2 :e Moreover, animal studies have suggested that interactions of altered expression of mitochondria-related genes and environmental factors might be involved in mental disorders. Further investigations into interactions of mitochondrial abnormalities with environmental factors are required to elucidate of the pathogenesis of these mental disorders.

Keywords: Energy metabolism; Environmental factors; Genetic factors; Mental disorders; Mitochondria.