EMBO Reports, Journal Year: 2019, Volume and Issue: 20(9)

Published: Aug. 19, 2019

Review19 August 2019Open Access Inter-organ communication: a gatekeeper for metabolic health Judit Castillo-Armengol Center Integrative Genomics, University of Lausanne, Switzerland Search more papers by this author Lluis Fajas Corresponding Author [email protected] orcid.org/0000-0002-1283-9503 Isabel C Lopez-Mejia Information Castillo-Armengol1, *,1 and 1Center *Corresponding author. Tel: +41 21 692 41 11; E-mail: 4146; EMBO Reports (2019)20:e47903https://doi.org/10.15252/embr.201947903 See the Glossary abbreviations used in article. PDFDownload PDF article text main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract Multidirectional interactions between organs periphery central nervous system have evolved concomitantly with multicellular organisms maintain whole-body energy homeostasis ensure organism's adaptation external cues. These are altered pathological conditions such as obesity type 2 diabetes. Bioactive peptides proteins, hormones cytokines, produced both peripheral system, key messengers inter-organ communication. Despite early discovery first than 100 years ago, recent studies taking advantage novel technologies shed light on multiple ways cells body communicate balance. This review briefly summarizes well-established concepts focuses advances describing how specific proteins mediate crosstalk gut, brain, other order homeostasis. Additionally, outlines improved knowledge about these networks is helping us redefine therapeutic strategies an effort promote healthy living fight disorders diseases. ACC Acetyl-CoA Carboxylase ADBR3 β3-adrenergic receptor AdipoR1/2 Adiponectin receptors AgRP Agouti-related peptide AKT Protein kinase B (PKB), also known AMPK AMP-activated protein kinase. Anorexigenic Hormone(s) or compound(s) resulting decreased appetite. ARC Arcuate nucleus ATP Adenosine trisphosphate Autocrine signaling method which cell releases molecule that will bind exert its action same cell. BAs Bile acids BAT Brown adipose tissue BMP8b Bone morphogenetic 8b cAMP Cyclic adenosine monophosphate CCK Cholecystokinin CNS Central CSF Cerebrospinal fluid CTSB Cathepsin CX43 Connexin 43 CXCL14 C-X-C motif chemokine ligand-14 Cytokines class small can be broad variety act molecules. In circulation, cytokines usually found smaller concentration hormones. DIO2 Type iodothyronine deiodinase DIO Diet-induced DMH Dorsomedial hypothalamus Endocrine released into bloodstream before binding exerting distant cells. Exosomes extracellular vesicles from constitute intercellular communication transmission macromolecules may contain cargo molecules like lipids, DNA, mRNAs miRNAs. FBN1 Profibrillin gene. precursor asprosin. FGF19 Fibroblast growth factor 19 FGF21 FNDC5 Fibronectin III domain-containing 5. irisin. FoxO1 Forkhead box O1 GH Growth hormone GHSR secretagogue GIP Glucose-dependent insulinotropic GLP-1 Glucagon-like 1 GLP-1R GLUT2 Glucose transporter HFD High-fat diet Hormones secreted given trigger integrative responses stimuli. IL-1Ra Interleukin antagonist IL-6 Interleukine 6 IRS-2 Insulin substrate JAK2 Janus Lcn5 Lipocalin 5 LEAP2 Liver-expressed antimicrobial LepRb Leptin b LHA Lateral hypothalamic area MAPK Mitogen-activating MCP1 Monocyte chemotactic Metrnl Meteorin-like mTOR Mammalian target rapamycin NE Norepinephrine NPY Neuropeptide Y Orexigenic increased Paracrine nearby PGC1α Peroxisome proliferator-activated gamma coactivator 1-α PKA A PM20D1 Peptidase M20 POA Preoptic POMC Pro-opiomelanocortin PSNS Parasympathetic system—The part autonomic involved regulation numerous basic functions. It stimulates “feed breed” “rest digest” functions antagonistic SNS. RBP4 Retinol 4 RPA Raphe pallidus SctR Secretin SNS Sympathetic “fight flight” responses. rapid urgent reactions PSNS. STAT3 Signal transducer activator transcription 3 T2D diabetes T3, T4 Thyroid TCPTP T-cell tyrosine phosphatase TGFβ Transforming β TGR5 BA TG Triglycerides TNF-α Tumor necrosis factor-α TSH Thyroid-stimulating UCP1 Uncoupling VAN Vagal afferent neurons VMH Ventromedial WAT White Introduction adapt conditions, different tissues each via signals. Peripheral produce plethora bioactive molecules, including (from Greek horme means impulsion), autocrine, paracrine, endocrine manner (see Glossary). immune namely 1, participate Alternatively, coordinates metabolism not only production neurohormones locally, but direct innervation 2-5. Indeed, sympathetic parasympathetic fibers innervating express enzymes crucial biosynthesis transport (neurotransmitters neuropeptides) necessary tissue-specific response Early research 19th century, most notably Claude Bernard, suggested involving chemical ensures 6. The term “hormone” was 1905 British physiologist Ernest Stalling describe gut secretin, described just prior 7, 8. Carl Ferdinand Cori Gerty then cycle lactate anaerobic glycolysis muscles recycled liver converted glucose. turn, glucose returned muscle where it metabolized 9. “Cori cycle” one examples efficient organs, facilitate demands. Key hormones, pancreatic insulin glucagon, were successfully identified, synthesized, therapy course 20th century. identification has exponentially years, giving rise terms hepatokines 10, myokines 11, adipokines 12, batokines 13, liver, muscle, white (WAT), brown (BAT), respectively. secretion varies according status body. They respond instance fasting feeding cycles 14, circadian rhythm 15, cold exposure 16, exercise17, thus participating adaptive ensuring flexibility. pathologic example, related dysfunction, obesity. As such, alterations currently contribute spectrum obesity-associated pathologies. Therefore, pharmacological interventions modify hormones/cytokines, directly delivering recombinant being explored promising approaches treat wide obesity-related review, we summarize mechanisms focus highlighted importance WAT, BAT, pancreas, maintenance fitness. role been recently discussed elsewhere 18 review. further concludes citing additional actors mediators states our opinion future directions field. control fasting/feeding section, discuss organismal consumption food (Fig 1), followed compensatory engaged low state 2). Figure 1. under conditionsFood ingestion several GLP-1, secretin LEAP2. signal brain reduce intake. intestine reduces bile acid (BA) synthesis. stimulate (and glucagon) pancreas. glycogen uptake decrease increase lipogenesis circulating triglycerides (TGs) WAT. Leptin, adipocytes, repress Moreover, lipolysis liver. Download figure PowerPoint 2. conditionsGhrelin conditions. targets Pancreatic glucagon ghrelin, blood levels. Glucagon hepatic gluconeogenesis glycogenolysis, well lipolysis. Ghrelin adiposity increasing lipid synthesis reducing fatty (FA) oxidation. Fasting asprosin adiponectin through expenditure Asprosin gluconeogenesis, whereas increases FA Increased levels physiological meal initiates triggered presence nutrients. Enteroendocrine sense nutrients intestinal lumen cholecystokinin (CCK), incretins; glucose-dependent (GIP); glucagon-like (GLP-1) 19, 20. Gut play their acting circulation activating paracrine manner. major gut-derived vagal (VANs) 21. Endogenous acts VANs inhibit actions modulated fact (GLP-1R) internalized upon translocate plasma membrane after when ghrelin low. work synergistically potentiate glucose-stimulated β-cells inhibits α-cells. exocrine pancreas activity proper environment digestion absorption intake activation (SctR) sensory nerves melanocortin 22, 23. After postprandial initiated changes nutrients, mainly (TG), engage system. An sensed GLUT2. sensing leads β-cell ultimately 24. parallel, release α-cells 25, 26. insulin-sensitive induce utilization storage preventing hyperglycemia. By regulates behavior modifies tissues, cognitive 27-31. promotes metabolization hexokinases de novo lipogenesis, while decreasing production. Intact is, however, dispensable repression absence 32, 33, highlighting 34. triggers promoting externalization GLUT4 expression specifically glucose-derived glycerol serves building blocks TGs; TGs serve fuel stock scarcity. avoid excessive intake, adiposity, unnecessary storage, deleterious effects organism, capability hormone-producing organ. adipocytes proportionally stores 35-37. widely highly expresses long form leptin (LepRb). signals constant stock. suppresses adrenal corticosteroids 38, 39. activate oxidation AMPK-dependent 40. Whether process indirect remains unclear 41. (BAs) (Fgf15 mice) ileum. induces feedback 42. repressing 43, 44, independently insulin. Importantly, Fgf15 modulate 45 46. More recently, liver-expressed (LEAP2), initially liver-produced peptide, peptide. fed state, suppressed fasting. reported endogenous receptor, (GHSR). fully blunt (GH) 47. study adds growing list connect control. Thus far, body, state. Upon meal, aforementioned orchestrate coordinated substrates, initiating negative loop satiety “positive balance” 1). When low, lack stomach, glucose, replenish alternative substrates keep functioning. gastric epithelium stomach empty. Plasma concentrations high during 48. potent inducer 49, now GHSR. exerts orexigenic centrally arcuate (ARC) triggering agouti-related (AgRP) neuropeptide (NPY) However, exact mechanism plays unclear. To date, three hypotheses follows: (i) VANs, (ii) synthesized locally feeding, (iii) crosses blood–brain barrier activates 50. attenuates intracellular localization counteracting 51. secretion, carbohydrate use, stimulating synthesis, 50, 52. shown require intact 53. Adipokine modified rapidly reduction switch “fasted state” “fed 54. contrast leptin, at least cerebrospinal (CSF) 55, 56. Overall, inversely proportional correlate Numerous (adiponectin essentially ubiquitous). ARC, expenditure, suggesting anorexigenic sensitivity independent mechanisms: phosphorylation, AMPK-independent involves ceramide 57, IL-6-dependent upregulation (IRS-2) 58. 39 remain debated Asprosin, fasting-induced adipokine production, identified 59. C-terminal cleavage product profibrillin (FBN1 gene). encoded last two exons mice. release, without catecholamines, glucocorticoids. β-adrenergic (CNS) 60. (FGF21) hepatokine 61 62, 63. turn lipolysis, ketogenesis, availability brain. worth noting knockout mice exhibit lower glycemia fasted ketone bodies 64, 65. Fasting-induced hypoglycemia results stimulated glucagon. Hypoglycemia GLUT2-positive input 66. pathway mobilization (glycogenolysis) and, if prolonged, (gluconeogenesis), glycogenesis. preserve free glycerol. Glycerol transported oxidized gluconeogenesis. Albumin-bound tissues. promoted (SNS) innervation. norepinephrine (NE) similar tone could 67, 68. Notably, depots sparser 69. denser regions subcutaneous (or inguinal) 70, 71. cell-to-cell connexin (CX43) containing gap junctions essential disseminating adrenergic 72. situations deprivation counter regulatory maintains enough prevent function, energy-providing available all organs. accompanied overall energy. non-shivering thermogenesis temperature, developed homeotherms. Mammals specialized heat 73. especially abundant hibernating mammals 74, adult humans 75. stress summarized Fig 3. exposureCold stimuli, skin, thermoregulatory secrete orexin BMP8B thermogenesis. responsible local BAT. hypothalamic–pituitary–thyroid axis activated thyroid (T3 T4) Cold shivering myokine Irisin If sustained over time, undergoes browning process. addition, cold-dependent Finally, WAT; Cold-induced organ integrates CNS. terminals processed preoptic (POA), center 76. transduction regions, lateral (LHA), ventromedial (VMH), dorsomedial (DMH), (ARC). Orexin producing located LHA, named neurons, administration therefore 77. infusion firing 78. Both interact Hypothalamic bone (BMP8b) enhances projections 79. Interestingly, 80. Several linked cold. For stimulation thermogenic rats 81. Similarly, incretin 82. Outflow areas premotor stem region raphe (RPA). broadly present within parenchyma 83. hydroxylase, enzyme catecholamine 84. catecholamine-responsive tissue. constituted droplets number mitochondria. (ADBR3) cAMP/PKA pathway, uncoupling (UCP1). Free acids, activators uncouple mitochondrial respiration 73, 85. Apart 86. T3 synthetized gland pituitary thyroid-stimulating (TSH) 87. access transporters. active (DIO2) compensating gland-secreted 88.

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