A glucagon-like endocrine pathway in<i>Drosophila</i>modulates both lipid and carbohydrate homeostasis

Bharucha, Kamal N.; Tarr, Paul T.; Zipursky, S. Lawrence

doi:10.1242/jeb.016451

Cited by 214 publications

(259 citation statements)

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“…Obesity of Akh A and Akh AP mutants is in line with the previous reports on the effect of mutations in the AKH receptor (Grönke et al 2007;Bharucha et al 2008). Earlier data on the AKH roles in glycogen storage were rather contradictory, reporting both no changes (Grönke et al 2007), as well as significant increase in the body glycogen content (Bharucha et al 2008) of AKH receptor mutants. In contrast, the role of AKH in circulating sugars in adults was not addressed previously.…”

supporting

confidence: 89%

“…Mobilization of energy reserves for oogenesis was predicted to be AKH regulated ( (Grönke et al 2007;Bharucha et al 2008). In the current study, we did not detect any changes in fecundity in the absence of AKH signaling, suggesting that in Drosophila, oogenesisdependent fat mobilization is under the control of an alternative lipolytic pathway.…”

Section: Akh Signaling Is Not Required For Drosophila Reproductionmentioning

confidence: 99%

“…However, in contrast to the numerous scientific reports dealing with AKH roles in nondrosophilid species, only a limited number of studies have focused on AKH signaling in Drosophila so far. In the absence of a specific mutant, tools for AKH studies have remained limited to the ablations of CC cells (Kim and Rulifson 2004;Lee and Park 2004;Isabel et al 2005), stimulation of secretory activity of CC cells by their depolarization (Kim and Rulifson 2004), mutations of the receptor (Grönke et al 2007;Bharucha et al 2008;Waterson et al 2014), overexpression of Akh complementary DNA (cDNA) (Kim and Rulifson 2004;Lee and Park 2004;Grönke et al 2007;Katewa et al 2012;Baumbach et al 2014b), and Akh RNA interference (RNAi) (Braco et al 2012;Baumbach et al 2014b). Ablation of CC cells, or their depolarization, are not AKH-specific manipulations, as these endocrine cells also produce other hormones like limostatin, which affects metabolism by regulation of insulin signaling (Alfa et al 2015).…”

mentioning

confidence: 99%

“…Even though no role of APRP was described so far (Hatle and Spring 1999), its evolutionary conservation, common ancestry with mammalian growth hormone-releasing factors (Clynen et al 2004), and release upon stimulation with melatonin (Huybrechts et al 2005) all argue in favor of an endocrine function of this peptide. Thus, unequivocal study of AKH and APRP functions requires creation of specific mutants, which we describe in this study.Biochemical studies identified a single Drosophila AKHR receptor (Park et al 2002;Staubli et al 2002), which has been functionally analyzed in vivo (Grönke et al 2007;Bharucha et al 2008). However, these studies do not exclude AKH signal transmission via other receptor pathways.…”

mentioning

confidence: 99%

“…Biochemical studies identified a single Drosophila AKHR receptor (Park et al 2002;Staubli et al 2002), which has been functionally analyzed in vivo (Grönke et al 2007;Bharucha et al 2008). However, these studies do not exclude AKH signal transmission via other receptor pathways.…”

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confidence: 99%

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Energy Homeostasis Control in Drosophila Adipokinetic Hormone Mutants

et al. 2015

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Maintenance of biological functions under negative energy balance depends on mobilization of storage lipids and carbohydrates in animals. In mammals, glucagon and glucocorticoid signaling mobilizes energy reserves, whereas adipokinetic hormones (AKHs) play a homologous role in insects. Numerous studies based on AKH injections and correlative studies in a broad range of insect species established the view that AKH acts as master regulator of energy mobilization during development, reproduction, and stress. In contrast to AKH, the second peptide, which is processed from the Akh encoded prohormone [termed "adipokinetic hormone precursor-related peptide" (APRP)] is functionally orphan. APRP is discussed as ecdysiotropic hormone or as scaffold peptide during AKH prohormone processing. However, as in the case of AKH, final evidence for APRP functions requires genetic mutant analysis. Here we employed CRISPR/Cas9-mediated genome engineering to create AKH and AKH plus APRP-specific mutants in the model insect Drosophila melanogaster. Lack of APRP did not affect any of the tested steroid-dependent processes. Similarly, Drosophila AKH signaling is dispensable for ontogenesis, locomotion, oogenesis, and homeostasis of lipid or carbohydrate storage until up to the end of metamorphosis. During adulthood, however, AKH regulates body fat content and the hemolymph sugar level as well as nutritional and oxidative stress responses. Finally, we provide evidence for a negative autoregulatory loop in Akh gene regulation.KEYWORDS Drosophila; adipokinetic hormone; adipokinetic hormone precursor-related peptide; energy homeostasis; stress resistance E NERGY homeostasis requires continuous compensation for fluctuations in the energy expenditure and availability of food resources. Organisms thus build up reserves under positive energy balance and catabolize them when the balance turns negative to retain stable levels of circulating energy fuel. Insulin signaling induces the uptake of excessive circulating sugars, thus promoting reserve accumulation (reviewed, e.g., in Saltiel and Kahn 2001; Cohen 2006), whereas energy mobilization is under the control of glucagon and glucocorticoid signaling in mammals (reviewed, e.g., in Rui 2014;Charron and Vuguin 2015) and adipokinetic hormone (AKH) signaling in insects (reviewed, e.g., in Van der Horst 2003;Lorenz and Gäde 2009;Bednářová et al. 2013a). Consistent with their fundamental physiological function in energy mobilization, AKHs are found not only in insects, but are common in Protostomia, where they have been identified both in Ecdyszoa (in Arthropoda, Tardigrada, and Priapulida) and Lophotrochozoa (in Mollusca, Rotifera, and Annelida) (Gäde 2009;Hauser and Grimmelikhuijzen 2014). Nevertheless, physiological functions of AKHs have been studied mainly in Arthropoda. Similar to mammals, also insects store lipids in the form of triacylglycerides (TGs) and as carbohydrates in the form of glycogen. The main storage organ for lipid and glycogen in insects is the fat body, which can thus b...

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supporting

confidence: 89%

Section: Akh Signaling Is Not Required For Drosophila Reproductionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Energy Homeostasis Control in Drosophila Adipokinetic Hormone Mutants

et al. 2015

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INHIBITION OF FATTY ACID DESATURASES IN Drosophila melanogaster LARVAE BLOCKS FEEDING AND DEVELOPMENTAL PROGRESSION

Wang

Cruz

Pulfemuller

et al. 2016

Arch Insect Biochem Physiol

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Fatty acid desaturases are metabolic setscrews. To study their systemic impact on growth in Drosophila melanogaster, we inhibited fatty acid desaturases using the inhibitor CAY10566. As expected, the amount of desaturated lipids is reduced in larvae fed with CAY10566. These animals cease feeding soon after hatching, and their growth is strongly attenuated. A starvation program is not launched, but the expression of distinct metabolic genes is activated, possibly to mobilize storage material. Without attaining the normal size, inhibitor-fed larvae molt to the next stage indicating that the steroid hormone ecdysone triggers molting correctly. Nevertheless, after molting, expression of ecdysone-dependent regulators is not induced. While control larvae molt a second time, these larvae fail to do so and die after few days of straying. These effects are similar to those observed in experiments using larvae deficient for the fatty acid desaturase1 gene. Based on these data, we propose that the ratio of saturated to unsaturated fatty acids adjusts a sensor system that directs feeding behavior. We also hypothesize that loss of fatty acid desaturase activity leads to a block of the genetic program of development progression indirectly by switching on a metabolic compensation program.

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Identification of a hypertrehalosemic factor in Spodoptera exigua

Park

Kim

2017

Arch Insect Biochem Physiol

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Trehalose is a major blood sugar in insects with a range of physiological functions, including an energy source and a cryoprotectant. Hemolymph trehalose concentrations are tightly regulated according to physiological conditions. An insulin-like peptide, SeILP1, downregulates hemolymph trehalose concentrations in Spodoptera exigua. Here, we identified a factor that upregulates hemolymph trehalose concentration in S. exigua. Hemolymph trehalose concentrations were significantly increased after immune challenge or under starvation in a time-dependent manner. To determine endocrine factors responsible for the upregulation, stress-associated mediators, such as octopamine, serotonin, or eicosanoids were injected, but they did not upregulate hemolymph trehalose. On the other hand, injection with Schistocerca gregaria adipokinetic hormone (AKH) significantly increased hemolymph trehalose concentration in S. exigua. During upregulation of hemolymph trehalose by AKH injection, trehalose degradation appeared to be inhibited because expression of trehalase and SeILP1 were significantly suppressed while that of trehalose phosphate synthase was not significantly changed. Interrogation of a Spodoptera genome database identified an S. exigua AKH-like gene and its expression was confirmed. During starvation, its expression concentrations were increased, although RNA interference specific to the AKH-like hypertrehalosemic factor (SeHTF) gene significantly prevented the upregulation of hemolymph trehalose concentrations during starvation. A synthetic peptide of SeHTF was prepared and injected into S. exigua larvae. At nanomolar concentration, the synthetic SeHTF peptide effectively upregulated hemolymph trehalose concentrations. Here we report a novel hypertrehalosemic factor in S. exigua (SeHTF).

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A glucagon-like endocrine pathway inDrosophilamodulates both lipid and carbohydrate homeostasis

Cited by 214 publications

References 52 publications

Energy Homeostasis Control in Drosophila Adipokinetic Hormone Mutants

Energy Homeostasis Control in Drosophila Adipokinetic Hormone Mutants

INHIBITION OF FATTY ACID DESATURASES IN Drosophila melanogaster LARVAE BLOCKS FEEDING AND DEVELOPMENTAL PROGRESSION

Identification of a hypertrehalosemic factor in Spodoptera exigua

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