Interorgan Communication Pathways in Physiology: Focus on Drosophila

Abstract

Studies in mammals and Drosophila have demonstrated the existence and significance of secreted factors involved in communication between distal organs. In this review, primarily focusing on Drosophila, we examine the known interorgan communication factors and their functions, physiological inducers, and integration in regulating physiology. Moreover, we describe how organ-sensing screens in Drosophila can systematically identify novel conserved interorgan communication factors. Finally, we discuss how interorgan communication enabled and evolved as a result of specialization of organs. Together, we anticipate that future studies will establish a model for metazoan interorgan communication network (ICN) and how it is deregulated in disease.

Keywords: adipokine; interorgan communication; interorgan communication network; myokine; secreted factor; secretion.

Figure 1

A simplified view of organ specialization and integration in mammals (136, 148). Nutrients are taken up by the gut (black arrows) and then sensed, processed, stored, and released to peripheral organs by the liver and adipose tissues (gray dashed arrows). Increased physiological demands enhance nutrient traffic to certain organs. For instance, during exercise, muscles require increased levels of fatty acids and glucose from the liver and adipose tissues.

Figure 2

Selected recent examples of mammalian interorgan communication factors, their origins, and destinations; also see Table 1. Selected recent references for these factors: adipoQ (adiponectin) (154), adipsin (89), angiotensin (55), aP2 (19), asprosin (126), BAIBA (β-aminoisobutyric acid) (124), betatrophin (53, 157), CCK (cholecystokinin) (84, 88, 120), FGF21 (42), GDF-11 (growth differentiation factor 11; tissue source is unclear) (39, 67, 90, 113, 138), ghrelin (94, 97), GIP (gastric inhibitory polypeptide) (18), GLP1 (glucagon-like peptide-1) (36, 140), glucagon (136, 148), IGF1 (insulin growth factor 1) (13, 24), IGFBPs (insulin growth factor binding proteins) (61), IL6 (112, 128), IL15 (112), insulin (136, 148), irisin (12), leptin (2, 100, 144, 158), Metrnl (meterorin-like) (119), myonectin (133), myostatin (95), OCN (osteocalcin) (79, 106), osteopontin (93), PTHrP (parathyroid hormone related protein) (70), resistin (8, 64, 101, 130, 143), SDF-1 (116), substance P (59), TNFα (tumor necrosis factor α) (46, 60, 142), and TPO (thrombopoietin; also made by kidney) (31, 68).

Figure 3

Drosophila melanogaster has functionally equivalent organ systems to the human liver/adipose tissues (fat bodies and oenocytes in Drosophila), gut, brain, muscle, gonads, and others (4, 17, 35, 81, 109). This allows the study of interorgan communication using the powerful genetic tools available in flies.

Figure 4

A simplified view of organ specialization and integration in Drosophila (4, 17, 35, 81, 109).

Figure 5

Drosophila central nervous system–derived systemic factors include the Dilps (Drosophila insulin-like peptides), SDR [secreted decoy of insulin receptor (InR)], and GABA (γ-aminobutyric acid). SDR binds to and negatively regulates Dilps. Dilps are secreted from insulin-producing cells (IPCs) and act through InR found in most tissues to regulate growth and metabolism. Note that not all organs on which Dilps act are shown. GABA is produced by the brain to preserve hematopoietic progenitor cells. Data from References , , , , , , , , and .

Figure 6

Drosophila fat body (FB)-derived systemic factors include the transforming growth factor (TGF)-related Daw (dawdle), PGRPs (peptidoglycan recognition proteins), Dilp6 (Drosophila insulin-like peptide 6), ImpL2, GBPs (growth-blocking peptides), CCHa2 (CCHamide2), Egr (Eiger), and leptin-like Upd2 (unpaired-2). Daw acts through the receptor Babo/Punt to regulate metabolism, gut digestive enzymes, pH equilibrium, and Dilp (Drosophila insulin-like peptide) secretion (not shown as it may be indirect). It is not clear whether Daw is a systemic factor, as it is found in multiple organs. PGRPs are secreted by age-inflamed FBs and act directly or indirectly to regulate gut inflammation and stem cell proliferation. Upd2 regulates Dilp secretion through the receptor dome (domeless). Egr negatively regulates Dilp secretion through the receptor Grnd (Grindelwald). GBP1/2 induces Dilp secretion through unknown mechanisms. CCHa2 induces Dilp secretion through the CCHa2 receptor. CCHa2 may also be produced by the gut (not shown). Dilp6 acts through insulin receptor (InR) on oenocytes and imaginal discs to regulate lipid uptake and growth, respectively. Dilp6 may also regulate IPC Dilp secretion (not shown). Also, ImpL2 is secreted from larval FBs upon starvation to inhibit extracellular Dilp. Data from References , , , –, , , , , , , , and .

Figure 7

The Drosophila gut-derived factors are the insulin growth factor binding protein (IGFBP)-like factor ImpL2 and Hh (hedgehog). ImpL2 is secreted from the gut upon intestinal stem cell overproliferation and binds to and inhibits Dilps (Drosophila insulin-like peptides). Hh binds to Ptc (patched) on fat bodies and the prothoracic gland (not shown) to regulate growth and lipid mobilization. CCHa2 (CCHamide2) may also be produced by the gut (not shown). Data from References , , .

Figure 8

Drosophila corpora cardiaca (CC)- and corpora allata (CA)-derived factors are glucagon-like AKH (adipokinetic hormone), JH (juvenile hormone), and NMU (neuromedin U)-like Lst (limostatin). AKH is secreted by CC cells and acts through the AKHR (AKH receptor) found in many tissues to regulate growth and metabolism. Lst is secreted from CC cells and acts through its putative receptor LstR on insulin-producing cells to decrease Dilp (Drosophila insulin-like peptide) secretion. JH is secreted from CA cells and acts through the receptor Met found in several organs to regulate growth and metabolism. Note that CC/CA cells are found close to the esophagus, proventriculus, and brain in adults and brain in larvae. Although JH and AKH have other target organs, selected organs and functions discussed in the text are shown for simplicity. Data from References , , , , , , , , , , , , and .

Figure 9

Muscle-derived Myo (myoglianin) may act through Babo or Wit receptors to decrease fat body nucleolar size and ribosomal RNA and increase life span. ImpL2 is secreted from muscle upon mild mitochondrial dysfunction. Injured imaginal discs secrete Dilp8 (Drosophila insulin-like peptide 8), which acts on Lgr3 (leucine rich repeat–containing G-protein–coupled receptor 3)-positive neurons to inhibit insulin and prothoracicotropic hormone (PTTH) signaling and developmental progression. Also, ImpL2 is secreted by malignant scrib and scrib Ras^V12 tumor-like larval imaginal discs transplanted to adults. Data from References , , , , , , , and .

Figure 10

Design of an organ-sensing screen in Drosophila. The Gal4-UAS system drives the tissue-specific expression of a transgene (RNA interference), cDNA, or Cas9, and the function of a distal organ is measured. Alternatively, secretion of a key systemic factor can be measured to address questions about the integration of pathways in interorgan communication.

Figure 11

Various interorgan communication factors are integrated to regulate insulin signaling (1, 3, 26, 27, 41, 48, 49, 58, 72, 74, 108, 118, 129, 147). Abbreviations: CCHa2, CCHamide2; Dilp, Drosophila insulin-like peptide; Egr, Eiger; GBP, growth-blocking peptide; Lst, limostatin; SDR, secreted decoy of insulin receptor; Upd2, unpaired-2.

Figure 12

Interorgan communication enabled and evolved as a result of specialization of organs (20, 37, 52, 71, 83, 99). Large organism size, overall efficiency of organ specialization, and codependency of specialized/differentiated organs stabilize organisms. This leads to increasingly differentiated organs, which results in interorgan communication. Interorgan communication (e.g., through insulin) enables regulation and coordination of organ functions and ensures organ dependency on the rest of the organism. In turn, interorgan communication leads to increasingly differentiated organs, which stabilize organisms.