Energy Homeostasis Control in Drosophila Adipokinetic Hormone Mutants

Abstract

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...

Systemic corazonin signalling modulates stress responses and metabolism inDrosophila

“…Also, the CrzR and AKH receptor (AkhR) have been proposed to have a common ancestor [79], suggesting that Crz and AKH signalling might share some of the ancient functions in regulation of stress and metabolism. AKH predominantly stimulates catabolic processes (mobilization of lipids, carbohydrates and amino acids) while simultaneously inhibiting their biosynthesis [18,47–49]. Although both AKH and Crz target the fat body, a comparison of our results and those of earlier studies analysing Akh and AkhR mutants (see electronic supplementary material, figure S7) reveals that these two signalling systems play distinct roles in metabolism and stress responses [18,45,83].…”

“…AKH predominantly stimulates catabolic processes (mobilization of lipids, carbohydrates and amino acids) while simultaneously inhibiting their biosynthesis [18,47–49]. Although both AKH and Crz target the fat body, a comparison of our results and those of earlier studies analysing Akh and AkhR mutants (see electronic supplementary material, figure S7) reveals that these two signalling systems play distinct roles in metabolism and stress responses [18,45,83]. Knockdown of Crz or ablation of Crz-producing cells leads to increased levels of stored lipids and carbohydrates [24,32], and here we show that the effect on carbohydrate metabolism is mediated by Crz signalling to the periphery, and this effect is stronger during stress conditions.…”

Interorgan Communication Pathways in Physiology: Focus on Drosophila

“…AKH regulates metabolism in an opposing way to Dilps by acting to promote catabolism and systemic release of fats and sugars from FBs (47, 51, 69, 78). In addition, AKH signaling regulates life span, food search behavior, sleep, and resistance to oxidative stress (47, 66, 78, 96, 150). Future studies may identify systemic factors that regulate AKH signaling.…”

Midgut-Derived Activin Regulates Glucagon-like Action in the Fat Body and Glycemic Control

“…As a homolog of mammalian glucagon, Drosophila adipokinetic hormone (AKH) is a well-established insulin counter-regulatory hormone involved in carbohydrate metabolic homeostasis (Galikova et al, 2015; Kim and Rulifson, 2004; Lee and Park, 2004). Under starvation conditions, AKH is secreted from corpora cardiaca (CC) endocrine cells and promotes nutrient utilization in the fat body, leading to increased glycemic levels in circulation.…”