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• W2897765902 abstract "•Enteroendocrine cells sense dietary sugars•Enteroendocrine Bursicon α is secreted systemically in response to nutrients•Bursα signals to its neuronal receptor DLgr2, triggering a relay with AKH neurons•Bursα/DLgr2 preserve energetic homeostasis through fat body AKHR signaling The control of systemic metabolic homeostasis involves complex inter-tissue programs that coordinate energy production, storage, and consumption, to maintain organismal fitness upon environmental challenges. The mechanisms driving such programs are largely unknown. Here, we show that enteroendocrine cells in the adult Drosophila intestine respond to nutrients by secreting the hormone Bursicon α, which signals via its neuronal receptor DLgr2. Bursicon α/DLgr2 regulate energy metabolism through a neuronal relay leading to the restriction of glucagon-like, adipokinetic hormone (AKH) production by the corpora cardiaca and subsequent modulation of AKH receptor signaling within the adipose tissue. Impaired Bursicon α/DLgr2 signaling leads to exacerbated glucose oxidation and depletion of energy stores with consequent reduced organismal resistance to nutrient restrictive conditions. Altogether, our work reveals an intestinal/neuronal/adipose tissue inter-organ communication network that is essential to restrict the use of energy and that may provide insights into the physiopathology of endocrine-regulated metabolic homeostasis. The control of systemic metabolic homeostasis involves complex inter-tissue programs that coordinate energy production, storage, and consumption, to maintain organismal fitness upon environmental challenges. The mechanisms driving such programs are largely unknown. Here, we show that enteroendocrine cells in the adult Drosophila intestine respond to nutrients by secreting the hormone Bursicon α, which signals via its neuronal receptor DLgr2. Bursicon α/DLgr2 regulate energy metabolism through a neuronal relay leading to the restriction of glucagon-like, adipokinetic hormone (AKH) production by the corpora cardiaca and subsequent modulation of AKH receptor signaling within the adipose tissue. Impaired Bursicon α/DLgr2 signaling leads to exacerbated glucose oxidation and depletion of energy stores with consequent reduced organismal resistance to nutrient restrictive conditions. Altogether, our work reveals an intestinal/neuronal/adipose tissue inter-organ communication network that is essential to restrict the use of energy and that may provide insights into the physiopathology of endocrine-regulated metabolic homeostasis. Maintaining systemic energy homeostasis is crucial for the physiology of all living organisms. A balanced equilibrium between anabolism and catabolism involves tightly coordinated signaling networks and the communication between multiple organs (Gautron et al., 2015Gautron L. Elmquist J.K. Williams K.W. Neural control of energy balance: translating circuits to therapies.Cell. 2015; 161: 133-145Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar, Wang et al., 2014Wang L. Karpac J. Jasper H. Promoting longevity by maintaining metabolic and proliferative homeostasis.J. Exp. Biol. 2014; 217: 109-118Crossref PubMed Scopus (64) Google Scholar). Excess nutrients are stored in the liver and adipose tissue as glycogen and lipids, respectively. In times of high energy demand or low nutrient availability, nutrients are mobilized from storage tissues (Mattila and Hietakangas, 2017Mattila J. Hietakangas V. Regulation of carbohydrate energy metabolism in Drosophila melanogaster.Genetics. 2017; 207: 1231-1253PubMed Google Scholar). Understanding how organs communicate to maintain systemic energy homeostasis is of critical importance, as its failure can result in severe metabolic disorders with life-threatening consequences. The intestine is a key endocrine tissue and central regulator of systemic energy homeostasis. Enteroendocrine (ee) cells secrete multiple hormones in response to the nutritional status of the organism and orchestrate systemic metabolic adaptation across tissues. Recent work reveals greater than expected diversity (Haber et al., 2017Haber A.L. Biton M. Rogel N. Herbst R.H. Shekhar K. Smillie C. Burgin G. Delorey T.M. Howitt M.R. Katz Y. et al.A single-cell survey of the small intestinal epithelium.Nature. 2017; 551: 333-339Crossref PubMed Scopus (711) Google Scholar), plasticity (Yan et al., 2017Yan K.S. Gevaert O. Zheng G.X.Y. Anchang B. Probert C.S. Larkin K.A. Davies P.S. Cheng Z.F. Kaddis J.S. Han A. et al.Intestinal enteroendocrine lineage cells possess homeostatic and injury-inducible stem cell activity.Cell Stem Cell. 2017; 21: 78-90.e6Abstract Full Text Full Text PDF PubMed Scopus (202) Google Scholar), and sensing functions of ee cells (Lebrun et al., 2017Lebrun L.J. Lenaerts K. Kiers D. Pais de Barros J.P. Le Guern N. Plesnik J. Thomas C. Bourgeois T. Dejong C.H.C. Kox M. et al.Enteroendocrine L cells sense LPS after gut barrier injury to enhance GLP-1 secretion.Cell Rep. 2017; 21: 1160-1168Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar). Nevertheless, how ee cells respond to different environmental challenges and how they coordinate systemic responses is unclear. A better understanding of ee cell biology will directly impact our understanding of intestinal physiopathology, the regulation of systemic metabolism, and metabolic disorders. Functional studies on inter-organ communication are often challenging in mammalian systems, due to their complex genetics and physiology. The adult Drosophila midgut has emerged as an invaluable model system to address key aspects of systemic physiology, host-pathogen interactions, stem cell biology and metabolism, among other things (Lemaitre and Miguel-Aliaga, 2013Lemaitre B. Miguel-Aliaga I. The digestive tract of Drosophila melanogaster.Annu. Rev. Genet. 2013; 47: 377-404Crossref PubMed Scopus (285) Google Scholar). As in its mammalian counterpart, the Drosophila adult intestinal epithelium displays multiple subtypes of ee cells (Miguel-Aliaga, 2012Miguel-Aliaga I. Nerveless and gutsy: intestinal nutrient sensing from invertebrates to humans.Semin. Cell Dev. Biol. 2012; 23: 614-620Crossref PubMed Scopus (35) Google Scholar, Song et al., 2014Song W. Veenstra J.A. Perrimon N. Control of lipid metabolism by tachykinin in Drosophila.Cell Rep. 2014; 9: 40-47Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar) with largely unknown functions. Recent work has demonstrated nutrient-sensing roles of ee cells (Song et al., 2014Song W. Veenstra J.A. Perrimon N. Control of lipid metabolism by tachykinin in Drosophila.Cell Rep. 2014; 9: 40-47Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar, Song et al., 2017Song W. Cheng D. Hong S. Sappe B. Hu Y. Wei N. Zhu C. O'Connor M.B. Pissios P. Perrimon N. Midgut-derived activin regulates glucagon-like action in the fat body and glycemic control.Cell Metab. 2017; 25: 386-399Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar). The role of Bursicon/DLgr2 signaling has long been restricted to insect development, where the heterodimeric form of the hormone Bursicon, made by α and β subunits, is produced by a subset of neurons within the CNS during the late pupal stage and released systemically to activate its receptor DLgr2 in peripheral tissues to drive post-molting sclerotization of the cuticle and wing expansion (Baker and Truman, 2002Baker J.D. Truman J.W. Mutations in the Drosophila glycoprotein hormone receptor, rickets, eliminate neuropeptide-induced tanning and selectively block a stereotyped behavioral program.J. Exp. Biol. 2002; 205: 2555-2565Crossref PubMed Google Scholar, Luo et al., 2005Luo C.W. Dewey E.M. Sudo S. Ewer J. Hsu S.Y. Honegger H.W. Hsueh A.J. Bursicon, the insect cuticle-hardening hormone, is a heterodimeric cystine knot protein that activates G protein-coupled receptor LGR2.Proc. Natl. Acad. Sci. U S A. 2005; 102: 2820-2825Crossref PubMed Scopus (197) Google Scholar, Mendive et al., 2005Mendive F.M. Van Loy T. Claeysen S. Poels J. Williamson M. Hauser F. Grimmelikhuijzen C.J. Vassart G. Vanden Broeck J. Drosophila molting neurohormone Bursicon is a heterodimer and the natural agonist of the orphan receptor DLGR2.FEBS Lett. 2005; 579: 2171-2176Crossref PubMed Scopus (126) Google Scholar). We recently demonstrated a post-developmental activity for the α subunit of Bursicon (Bursα), which is produced by a subpopulation of ee cells in the posterior midgut, where it paracrinally activates DLgr2 in the visceral muscle (VM) to maintain homeostatic intestinal stem cell (ISC) quiescence (Scopelliti et al., 2014Scopelliti A. Cordero J.B. Diao F. Strathdee K. White B.H. Sansom O.J. Vidal M. Local control of intestinal stem cell homeostasis by enteroendocrine cells in the adult Drosophila midgut.Curr. Biol. 2014; 24: 1199-1211Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, Scopelliti et al., 2016Scopelliti A. Bauer C. Cordero J.B. Vidal M. Bursicon-alpha subunit modulates dLGR2 activity in the adult Drosophila melanogaster midgut independently to Bursicon-beta.Cell Cycle. 2016; 15: 1538-1544Crossref PubMed Scopus (9) Google Scholar). Here, we report an unprecedented systemic role for Bursα regulating adult energy homeostasis. Our work identifies a novel gut/fat body axis, where ee cells orchestrate organismal metabolic homeostasis. Bursα is systemically secreted by ee cells in response to nutrient availability and acts through DLgr2+ neurons to repress adipokinetic hormone (AKH)/AKH receptor (AKHR) signaling within the fat body/adipose tissue to restrict the use of energy stores. Impairment of systemic Bursα/DLgr2 signaling results in exacerbated oxidative metabolism, strong lipodystrophy, and organismal hypersensitivity to nutrient deprivation. Our work reveals a central role for ee cells in sensing organismal nutritional status and maintaining systemic metabolic homeostasis through coordination of an intestinal/neuronal/adipose tissue-signaling network. Ee cells are major sensors of luminal content (Engelstoft et al., 2008Engelstoft M.S. Egerod K.L. Holst B. Schwartz T.W. A gut feeling for obesity: 7TM sensors on enteroendocrine cells.Cell Metab. 2008; 8: 447-449Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar, Moran-Ramos et al., 2012Moran-Ramos S. Tovar A.R. Torres N. Diet: friend or foe of enteroendocrine cells–how it interacts with enteroendocrine cells.Adv. Nutr. 2012; 3: 8-20Crossref PubMed Scopus (72) Google Scholar) and coordinate gastrointestinal and systemic responses through secretory programs (Steinert and Beglinger, 2011Steinert R.E. Beglinger C. Nutrient sensing in the gut: interactions between chemosensory cells, visceral afferents and the secretion of satiation peptides.Physiol. Behav. 2011; 105: 62-70Crossref PubMed Scopus (72) Google Scholar) that affect gut motility, digestion, appetite, glucose homeostasis, and energy expenditure (Campbell and Drucker, 2013Campbell J.E. Drucker D.J. Pharmacology, physiology, and mechanisms of incretin hormone action.Cell Metab. 2013; 17: 819-837Abstract Full Text Full Text PDF PubMed Scopus (930) Google Scholar, Field et al., 2010Field B.C. Chaudhri O.B. Bloom S.R. Bowels control brain: gut hormones and obesity.Nat. Rev. Endocrinol. 2010; 6: 444-453Crossref PubMed Scopus (139) Google Scholar, Gribble and Reimann, 2016Gribble F.M. Reimann F. Enteroendocrine cells: chemosensors in the intestinal epithelium.Annu. Rev. Physiol. 2016; 78: 277-299Crossref PubMed Scopus (315) Google Scholar, Park et al., 2016Park J.H. Chen J. Jang S. Ahn T.J. Kang K. Choi M.S. Kwon J.Y. A subset of enteroendocrine cells is activated by amino acids in the Drosophila midgut.FEBS Lett. 2016; 590: 493-500Crossref PubMed Scopus (25) Google Scholar, Worthington et al., 2017Worthington J.J. Reimann F. Gribble F.M. Enteroendocrine cells-sensory sentinels of the intestinal environment and orchestrators of mucosal immunity.Mucosal Immunol. 2017; 11: 3-20Crossref PubMed Scopus (118) Google Scholar, Zietek and Daniel, 2015Zietek T. Daniel H. Intestinal nutrient sensing and blood glucose control.Curr. Opin. Clin. Nutr. Metab. Care. 2015; 18: 381-388Crossref PubMed Scopus (35) Google Scholar). Our previous work revealed a local role for ee-derived Bursα in the adult midgut, which was necessary and sufficient to prevent ISC proliferation (Scopelliti et al., 2014Scopelliti A. Cordero J.B. Diao F. Strathdee K. White B.H. Sansom O.J. Vidal M. Local control of intestinal stem cell homeostasis by enteroendocrine cells in the adult Drosophila midgut.Curr. Biol. 2014; 24: 1199-1211Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, Scopelliti et al., 2016Scopelliti A. Bauer C. Cordero J.B. Vidal M. Bursicon-alpha subunit modulates dLGR2 activity in the adult Drosophila melanogaster midgut independently to Bursicon-beta.Cell Cycle. 2016; 15: 1538-1544Crossref PubMed Scopus (9) Google Scholar). Knocking down bursα from ee cells resulted in ISC hyperproliferation in the normally quiescent homeostatic adult midgut, while bursα overexpression suppressed the characteristic proliferative response of ISCs following damage and upon aging (Scopelliti et al., 2014Scopelliti A. Cordero J.B. Diao F. Strathdee K. White B.H. Sansom O.J. Vidal M. Local control of intestinal stem cell homeostasis by enteroendocrine cells in the adult Drosophila midgut.Curr. Biol. 2014; 24: 1199-1211Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, Scopelliti et al., 2016Scopelliti A. Bauer C. Cordero J.B. Vidal M. Bursicon-alpha subunit modulates dLGR2 activity in the adult Drosophila melanogaster midgut independently to Bursicon-beta.Cell Cycle. 2016; 15: 1538-1544Crossref PubMed Scopus (9) Google Scholar). In such a context, Bursα appears to have a permissive role in the maintenance of ISC quiescence. We next sought to identify conditions leading to an inducible function of Bursα. First, to unambiguously assess the main source of Bursα production during adulthood, we compared mRNA expression levels in mature whole adults, adult midguts, and adult animals from which the gut was removed prior to RNA extraction (“gut-less”). Confirming our previous results (Scopelliti et al., 2014Scopelliti A. Cordero J.B. Diao F. Strathdee K. White B.H. Sansom O.J. Vidal M. Local control of intestinal stem cell homeostasis by enteroendocrine cells in the adult Drosophila midgut.Curr. Biol. 2014; 24: 1199-1211Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, Scopelliti et al., 2016Scopelliti A. Bauer C. Cordero J.B. Vidal M. Bursicon-alpha subunit modulates dLGR2 activity in the adult Drosophila melanogaster midgut independently to Bursicon-beta.Cell Cycle. 2016; 15: 1538-1544Crossref PubMed Scopus (9) Google Scholar) and subsequent independent reports (Chen et al., 2016Chen J. Kim S.M. Kwon J.Y. A systematic analysis of Drosophila regulatory peptide expression in enteroendocrine cells.Mol. Cells. 2016; 39: 358-366Crossref PubMed Scopus (34) Google Scholar, Dutta et al., 2015Dutta D. Dobson A.J. Houtz P.L. Glasser C. Revah J. Korzelius J. Patel P.H. Edgar B.A. Buchon N. Regional cell-specific transcriptome mapping reveals regulatory complexity in the adult Drosophila midgut.Cell Rep. 2015; 12: 346-358Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar), we observed strong enrichment of bursα transcripts in adult midguts (Figure 1A). Given our previous reports showing a local role of Bursα in controlling ISC proliferation (Scopelliti et al., 2014Scopelliti A. Cordero J.B. Diao F. Strathdee K. White B.H. Sansom O.J. Vidal M. Local control of intestinal stem cell homeostasis by enteroendocrine cells in the adult Drosophila midgut.Curr. Biol. 2014; 24: 1199-1211Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, Scopelliti et al., 2016Scopelliti A. Bauer C. Cordero J.B. Vidal M. Bursicon-alpha subunit modulates dLGR2 activity in the adult Drosophila melanogaster midgut independently to Bursicon-beta.Cell Cycle. 2016; 15: 1538-1544Crossref PubMed Scopus (9) Google Scholar) and nutrients being key regulators of the proliferative state of the adult Drosophila midgut (O'Brien et al., 2011O'Brien L.E. Soliman S.S. Li X. Bilder D. Altered modes of stem cell division drive adaptive intestinal growth.Cell. 2011; 147: 603-614Abstract Full Text Full Text PDF PubMed Scopus (296) Google Scholar, Obata et al., 2018Obata F. Tsuda-Sakurai K. Yamazaki T. Nishio R. Nishimura K. Kimura M. Funakoshi M. Miura M. Nutritional control of stem cell division through S-adenosylmethionine in Drosophila intestine.Dev. Cell. 2018; 44: 741-751.e3Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar, Shim et al., 2013Shim J. Gururaja-Rao S. Banerjee U. Nutritional regulation of stem and progenitor cells in Drosophila.Development. 2013; 140: 4647-4656Crossref PubMed Scopus (57) Google Scholar), we next explored the possibility that Bursα might be regulated by nutrients. We performed immunofluorescence staining on posterior midguts from animals fed ad libitum and following caloric deprivation. After 24 hr of complete, non-dehydrating starvation, ee cells showed increased immunoreactivity for Bursα compared with ad libitum-fed animals (Figure 1B). Interestingly, increased Bursα immunoreactivity in ee cells inversely correlated with transcript levels in the midgut (Figure 1C). Consistent with previous reports indicating the death of Bursicon-producing neurons after adult eclosion (Honegger et al., 2011Honegger H.W. Estevez-Lao T.Y. Hillyer J.F. Bursicon-expressing neurons undergo apoptosis after adult ecdysis in the mosquito Anopheles gambiae.J. Insect Physiol. 2011; 57: 1017-1022Crossref PubMed Scopus (18) Google Scholar), Bursα immunostaining was undetectable in the CNS of adult animals independently of their feeding status (Figure S1A) and no effect was observed on adult bursα transcript levels beyond the midgut (Figure S1B). Therefore, our results suggest that ee-derived Bursα is responsive to nutrient availability. Ee cells sense luminal content by expressing several chemoreceptors and transporters on their apical membrane. The mammalian low-affinity glucose transporter solute carrier family 2 member 2 (SLC2A2) is highly expressed on the surface of K and L ee cells, where it regulates the post-prandial secretion of the gastric inhibitory polypeptide (Cani et al., 2007Cani P.D. Holst J.J. Drucker D.J. Delzenne N.M. Thorens B. Burcelin R. Knauf C. GLUT2 and the incretin receptors are involved in glucose-induced incretin secretion.Mol. Cell. Endocrinol. 2007; 276: 18-23Crossref PubMed Scopus (85) Google Scholar). We next suppressed the expression of Glut1, the closest Drosophila homolog of SLC2A2, within adult ee cells of fully fed animals using a temperature-controlled Voila-Gal4 driver and RNA interference (IR) (Voilats>Glut1 IR) (Figure S1C). Similarly to what we observed upon starvation, Bursα immunoreactivity was significantly increased within ee cells subjected to Glut1 knockdown (Figure 1D), while bursα mRNA expression was downregulated (Figure 1C). These results suggest that sugars may be some of the key nutrients sensed by ee cells leading to regulation of Bursα in the midgut. To further identify specific dietary factors that may affect Bursα levels within ee cells, we overexpressed bursα under the control of the temperature-sensitive Voila-Gal4 driver and subjected animals to starvation followed by refeeding with sucrose or BSA, as exclusive sources of sugar and protein, respectively. Importantly, the observed regulation of endogenous Bursα upon starvation (Figure 1B) was preserved with the overexpressed protein (Figure S1D). Interestingly, refeeding with sucrose, but not BSA, reverted Bursα to levels similar to the ones observed in fully fed conditions (Figure 1E), suggesting that ee-derived Bursα is primarily responsive to dietary sugars. Altogether, these results indicate that, as part of their nutrient-sensing role, ee cells regulate Bursα, which is increased upon nutrient restriction. To begin addressing the physiological meaning of nutrient-dependent regulation of Bursα, we next assessed the role of Bursα/DLgr2 signaling in the organismal response to starvation. We performed survival analysis upon complete, non-dehydrating nutrient deprivation on whole mutants for bursα or its receptor dlgr2/rk. Adults were allowed to feed ad libitum for 7 days before being transferred to agar-only medium. Strikingly, dlgr2 and bursα mutants showed a marked hypersensitivity to food deprivation compared with age-matched wild-type controls (w1118), resulting in their reduced overall and median survival (Figure 1F). We have previously demonstrated that the bursβ subunit is not expressed in the adult midgut and that it is dispensable for tissue homeostasis (Scopelliti et al., 2014Scopelliti A. Cordero J.B. Diao F. Strathdee K. White B.H. Sansom O.J. Vidal M. Local control of intestinal stem cell homeostasis by enteroendocrine cells in the adult Drosophila midgut.Curr. Biol. 2014; 24: 1199-1211Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, Scopelliti et al., 2016Scopelliti A. Bauer C. Cordero J.B. Vidal M. Bursicon-alpha subunit modulates dLGR2 activity in the adult Drosophila melanogaster midgut independently to Bursicon-beta.Cell Cycle. 2016; 15: 1538-1544Crossref PubMed Scopus (9) Google Scholar). Consistently, null mutant animals for the bursβ subunit (Df(2)110/Df(2)Exel6035, thereafter bursβ−/−) did not display starvation sensitivity (Figure 1F). Therefore, Bursβ does not play a significant role in post-developmental functions so far revealed for Bursα and DLgr2 (Scopelliti et al., 2014Scopelliti A. Cordero J.B. Diao F. Strathdee K. White B.H. Sansom O.J. Vidal M. Local control of intestinal stem cell homeostasis by enteroendocrine cells in the adult Drosophila midgut.Curr. Biol. 2014; 24: 1199-1211Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, Scopelliti et al., 2016Scopelliti A. Bauer C. Cordero J.B. Vidal M. Bursicon-alpha subunit modulates dLGR2 activity in the adult Drosophila melanogaster midgut independently to Bursicon-beta.Cell Cycle. 2016; 15: 1538-1544Crossref PubMed Scopus (9) Google Scholar). Importantly, since bursβ−/− animals share the developmental defects of dlgr2 and bursα mutants, it is unlikely that the starvation sensitivity observed in the latter two genotypes is a consequence of defective development. To unambiguously demonstrate a post-developmental role of Bursα/DLgr2 in the response to nutrient deprivation, we suppressed bursα expression within adult ee cells by RNAi (Voilats>bursα IR). Similar to what we observed in whole mutant animals, targeted bursα knockdown induced a clear reduction in both median and overall survival following total caloric deprivation (Figure 1G). Consistently, animals bearing adult ee-restricted Glut1 knockdown were also hypersensitive to starvation (Figure 1G). Altogether, these results support an adult-specific, nutrient responsive role of Bursα/DLgr2 signaling that is necessary to sustain organismal survival upon nutrient deprivation. The capacity of animals to withstand periods of scarce nutrients directly correlates with their accessibility to energy resources mainly stored as triacylglycerides (TAGs) in the fat body. Animals with excess fat body TAG are resistant to starvation (Bharucha et al., 2008Bharucha K.N. Tarr P. Zipursky S.L. A glucagon-like endocrine pathway in Drosophila modulates both lipid and carbohydrate homeostasis.J. Exp. Biol. 2008; 211: 3103-3110Crossref PubMed Scopus (161) Google Scholar), while reduced fat body TAG content results in hypersensitivity to starvation (Zhao and Karpac, 2017Zhao X. Karpac J. Muscle directs diurnal energy homeostasis through a myokine-dependent hormone module in Drosophila.Curr. Biol. 2017; 27: 1941-1955.e6Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar). We therefore extended our investigation into the metabolic status of Bursα/DLgr2-deficient animals by assessing their energy stores. Consistently, we detected a significant overall reduction in the content of stored lipids, as indicated by decreased whole-body TAG levels in bursα and dlgr2 mutants but not in bursβ−/− animals (Figure 2A). Fat body staining with the lipophilic dye LipidTOX, to directly visualize TAG content (Junger et al., 2003Junger M.A. Rintelen F. Stocker H. Wasserman J.D. Vegh M. Radimerski T. Greenberg M.E. Hafen E. The Drosophila forkhead transcription factor FOXO mediates the reduction in cell number associated with reduced insulin signaling.J. Biol. 2003; 2: 20Crossref PubMed Google Scholar), also revealed significant reduction of lipid droplet size exclusively in bursα and dlgr2 mutant animals (Figure 2B). Importantly, adult ee-specific knockdown of bursα or Glut1 resulted in a lipodystrophic phenotype similar to the ones observed in bursα and dlgr2 mutants (Figures 2C, 2D, and S1E). Following ingestion and absorption by the intestine, excess nutrients are stored in the fat body as TAG. The drastic reduction in energetic reserves upon defective Bursα/DLgr2 signaling prompted us to assess potential impairments in feeding and nutrient absorption as causative factors of the metabolic defects observed in these animals. Firstly, we quantified food intake in bursα mutants as well as in Voilats>bursα IR animals. Surprisingly, Bursα impairment resulted in a significant increase in food intake (Figures S2A and S2B). Therefore, the lean phenotype of Bursα-deficient animals is not due to reduced nutrient supply. Hyperphagia, however, can be a compensatory reaction to defects in the ability to efficiently absorb nutrients. To test this hypothesis, we quantified glucose absorption by pulse feeding the non-metabolizable fluorescent glucose analog 2-NBDG and measured its tissue accumulation. Bursα-impaired animals showed no reduction in 2-NBDG fluorescent signal when compared with controls (Figures S2C and S2D), suggesting that glucose absorption is not impaired. We next quantified the undigested nutrients in the excreta of Voilats>bursα IR flies. We observed no significant differences in the levels of excreted glucose (Figure S2E), TAG (Figure S2F), or free fatty acids (FFA) (Figure S2G) in the knockdown animals. Therefore, our data suggest that bursα knockdown does not affect the normal digestive and absorptive functions of the gut. Dietary nutrients are absorbed and processed by enterocytes and released into the hemolymph for uptake into peripheral organs. We therefore assessed the possibility that the defect in lipid storage observed in animals with compromised Bursα/DLgr2 signaling may arise from defective dietary lipid processing and transport by the enterocytes or impaired uptake of nutrients from the circulation by peripheral tissues. Defective lipid absorption or assembly and transport within enterocytes would result in reduced circulating lipid levels (hypolipidemia), while defective uptake of nutrients by peripheral tissues would result in hyperglycemia and hyperlipidemia. We therefore collected hemolymph from Bursα/DLgr2-impaired adult animals and measured circulating glucose and fatty acid levels. Unexpectedly, we observed a prominent hypoglycemia (Figures 2E and S2H) and no defects in circulating TAG and FFA in these animals (Figures S2I and S2J). Therefore, scenarios of compromised enterocyte function or uptake of circulating nutrients by peripheral tissues are unlikely to be the case in Bursα/DLgr2-compromised animals. Carbohydrates are the main components of the Drosophila diet and appear to be the preferred source of nutrients sensed by Bursα+ ee cells (Figure 1E). Acetyl-coenzyme A (CoA) derived from glucose is metabolized within the mitochondria through the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) to generate energy in the form of ATP at the expense of O2 molecules. Alternatively, glucose-derived acetyl-CoA is used as the substrate for de novo lipid synthesis, which occurs mainly in the fat body (Lee and Park, 2004Lee G. Park J.H. Hemolymph sugar homeostasis and starvation-induced hyperactivity affected by genetic manipulations of the adipokinetic hormone-encoding gene in Drosophila melanogaster.Genetics. 2004; 167: 311-323Crossref PubMed Scopus (446) Google Scholar, Mattila and Hietakangas, 2017Mattila J. Hietakangas V. Regulation of carbohydrate energy metabolism in Drosophila melanogaster.Genetics. 2017; 207: 1231-1253PubMed Google Scholar, Musselman et al., 2013Musselman L.P. Fink J.L. Ramachandran P.V. Patterson B.W. Okunade A.L. Maier E. Brent M.R. Turk J. Baranski T.J. Role of fat body lipogenesis in protection against the effects of caloric overload in Drosophila.J. Biol. Chem. 2013; 288: 8028-8042Crossref PubMed Scopus (81) Google Scholar, Zhao and Karpac, 2017Zhao X. Karpac J. Muscle directs diurnal energy homeostasis through a myokine-dependent hormone module in Drosophila.Curr. Biol. 2017; 27: 1941-1955.e6Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar). Therefore, we next traced glucose metabolism as a means to achieve a more comprehensive understanding of the metabolic phenotype of Bursα/DLgr2-compromised animals. We fed flies with uniformly heavy labeled 13C6-D-glucose for 6 hr and tracked whole-body incorporation of glucose-derived heavy carbons into metabolites by liquid chromatography mass spectrometry. We found that knockdown of bursα resulted in overall increased incorporation of glucose-derived 13C into metabolites of the TCA cycle (Figure 2F). Consistently, we observed increased mitochondrial O2 consumption in bursα knockdown and whole mutant animals (Figures 2G and 2H). These data are indicative of increased mitochondrial respiration; i.e., increased utilization of glucose and O2 to support the TCA cycle and OXPHOS to generate energy. Importantly, analysis o" @default.
• W2897765902 created "2018-10-26" @default.
• W2897765902 creator A5002800996 @default.
• W2897765902 creator A5004531840 @default.
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• W2897765902 date "2019-02-01" @default.
• W2897765902 modified "2023-10-18" @default.
• W2897765902 title "A Neuronal Relay Mediates a Nutrient Responsive Gut/Fat Body Axis Regulating Energy Homeostasis in Adult Drosophila" @default.
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