Review Inter-organ communication: a gatekeeper for metabolic health Judit Castillo-Armengol, Lluis Fajas* & Isabel C Lopez-Mejia** Abstract communication. Alternatively, the nervous system coordinates whole-body metabolism not only by the production of neurohor- Multidirectional interactions between metabolic organs in the mones that act locally, but also by direct innervation of the target periphery and the central nervous system have evolved concomi- tissues [2–5]. Indeed, sympathetic and parasympathetic fibers inner- tantly with multicellular organisms to maintain whole-body energy vating peripheral tissues express enzymes crucial for the biosynthesis homeostasis and ensure the organism’s adaptation to external cues. and transport of specific molecules (neurotransmitters and neuropep- These interactions are altered in pathological conditions such as tides) necessary for the tissue-specific response to external cues. obesity and type 2 diabetes. Bioactive peptides and proteins, such Early research from the 19th century, most notably from Claude as hormones and cytokines, produced by both peripheral organs Bernard, first suggested that a system involving chemical messengers and the central nervous system, are key messengers in this inter- ensures the communication between the different organs of the body organ communication. Despite the early discovery of the first [6]. The term “hormone” was first used in 1905 by the British physiolo- hormones more than 100 years ago, recent studies taking advan- gist Ernest Stalling to describe the gut hormone secretin, first described tage of novel technologies have shed light on the multiple ways just 3 years prior [7,8]. Carl Ferdinand Cori and Gerty Cori then used by cells in the body to communicate and maintain energy described the cycle in which lactate produced by anaerobic glycolysis balance. This review briefly summarizes well-established concepts in muscles can be recycled by the liver and converted to glucose. In and focuses on recent advances describing how specific proteins turn, this glucose is returned to the muscle where it is metabolized to and peptides mediate the crosstalk between gut, brain, and other lactate [9]. This “Cori cycle” was one of the first described examples of peripheral metabolic organs in order to maintain energy homeosta- an efficient communication system between organs, which functions sis. Additionally, this review outlines how the improved knowledge to facilitate the metabolic adaptation to energy demands. about these inter-organ networks is helping us to redefine thera- Key metabolic hormones, like pancreatic insulin and glucagon, peutic strategies in an effort to promote healthy living and fight were successfully identified, synthesized, and used for therapy in the metabolic disorders and other diseases. course of the 20th century. The identification of signaling molecules produced by metabolic organs has increased exponentially in recent Keywords energy homeostasis; inter-organ communication; metabolism; years, giving rise to the terms hepatokines [10], myokines [11], obesity adipokines [12], and batokines [13], to describe the hormones DOI 10.15252/embr.201947903 | Received 11 February 2019 | Revised 21 May produced by liver, muscle, white adipose tissue (WAT), and brown 2019 | Accepted 24 May 2019 | Published online 19 August 2019 adipose tissue (BAT), respectively. The secretion of these signaling EMBO Reports (2019) 20:e47903 molecules varies according to the metabolic status of the body. They respond for instance to fasting and feeding cycles [14], to the circa- See the Glossary for abbreviations used in this article. dian rhythm [15], to cold exposure [16], and to exercise[17], thus participating in the organism’s adaptive response and ensuring meta- bolic flexibility. Inter-organ communication is altered in different Introduction pathologic conditions, for example, in conditions related to adipose tissue dysfunction, like obesity. As such, alterations in hormones and In order to maintain homeostasis and adapt to external conditions, cytokines are currently known to notably contribute to the spectrum the different tissues of multicellular organisms communicate with of obesity-associated pathologies. Therefore, pharmacological inter- each other via multiple signals. Peripheral organs produce a plethora ventions to modify the production of hormones/cytokines, or directly of bioactive molecules, including hormones (from the Greek horme delivering recombinant hormones/cytokines, are currently being that means impulsion), that ensure intercellular signaling in an auto- explored as promising approaches to treat a wide variety of obesity- crine, paracrine, or endocrine manner (see Glossary). Peripheral related endocrine diseases. In this review, we summarize well-estab- organs and immune cells can also produce smaller bioactive proteins, lished mechanisms of inter-organ communication and focus on how namely cytokines [1], that also participate in inter-organ recent research has highlighted the importance of the crosstalk Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland *Corresponding author. Tel: +41 21 692 41 11; E-mail: [email protected] **Corresponding author. Tel: +41 21 692 4146; E-mail: [email protected] ª 2019 The Authors. Published under the terms of the CC BY 4.0 license EMBO reports 20:e47903 | 2019 1 of 16 EMBO reports Judit Castillo-Armengol et al Glossary ACC Acetyl-CoA Carboxylase Hormones class of proteins that act as signaling ADBR3 b3-adrenergic receptor molecules. Hormones are secreted by a given AdipoR1/2 Adiponectin receptors tissue and are used to communicate between AgRP Agouti-related peptide organs in order to trigger integrative responses AKT Protein kinase B (PKB), also known as AKT to specific stimuli. AMPK AMP-activated protein kinase. IL-1Ra Interleukin 1 receptor antagonist Anorexigenic Hormone(s) or compound(s) resulting in IL-6 Interleukine 6 decreased appetite. IRS-2 Insulin receptor substrate 2 ARC Arcuate nucleus JAK2 Janus kinase 2 ATP Adenosine trisphosphate Lcn5 Lipocalin 5 Autocrine signaling signaling method in which a cell releases a LEAP2 Liver-expressed antimicrobial peptide 2 signaling molecule that will bind to receptors LepRb Leptin receptor b and exert its action in the same cell. LHA Lateral hypothalamic area BAs Bile acids MAPK Mitogen-activating protein kinase BAT Brown adipose tissue MCP1 Monocyte chemotactic protein 1 BMP8b Bone morphogenetic protein 8b Metrnl Meteorin-like cAMP Cyclic adenosine monophosphate mTOR Mammalian target of rapamycin CCK Cholecystokinin NE Norepinephrine CNS Central nervous system NPY Neuropeptide Y CSF Cerebrospinal fluid Orexigenic Hormone(s) or compound(s) resulting in CTSB Cathepsin B increased appetite. CX43 Connexin 43 Paracrine signaling signaling method in which a cell releases a CXCL14 C-X-C motif chemokine ligand-14 signaling molecule that will bind to receptors Cytokines class of small proteins that can be produced and exert its action in nearby cells. by a broad variety of cells and act as PGC1a Peroxisome proliferator-activated receptor signaling molecules. In circulation, cytokines gamma coactivator 1-a are usually found in smaller concentration PKA Protein kinase A than hormones. PM20D1 Peptidase M20 domain-containing 1 DIO2 Type 2 iodothyronine deiodinase POA Preoptic area DIO Diet-induced obesity POMC Pro-opiomelanocortin DMH Dorsomedial hypothalamus PSNS Parasympathetic nervous system—The PSNS is Endocrine signaling method in which a cell releases a part of the autonomic nervous system involved signaling molecule that will be released into in the regulation of numerous basic body the bloodstream before binding to receptors functions. It stimulates “feed and breed” and and exerting its action in distant cells. “rest and digest” functions and is antagonistic Exosomes extracellular vesicles that are released from to the SNS. cells. Exosomes constitute a system for RBP4 Retinol binding protein 4 intercellular communication and for the RPA Raphe pallidus transmission of macromolecules between cells. SctR Secretin receptor Exosomes may contain a broad variety of cargo SNS Sympathetic nervous system—The SNS is part of molecules like proteins, lipids, DNA, mRNAs and the autonomic nervous system involved in “fight miRNAs. or flight” responses. It stimulates rapid and FBN1 Profibrillin gene. Profibrillin is the precursor of urgent reactions and is antagonistic to the PSNS. asprosin. STAT3 Signal transducer and activator of transcription 3 FGF19 Fibroblast growth factor 19 T2D Type 2 diabetes FGF21 Fibroblast growth factor 21 T3, T4 Thyroid hormones FNDC5 Fibronectin type III domain-containing protein TCPTP T-cell protein tyrosine phosphatase 5. FNDC5 is the precursor of irisin. TGFb Transforming growth factor b FoxO1 Forkhead box protein O1 TGR5 BA receptor GH Growth hormone TG Triglycerides GHSR Growth hormone secretagogue receptor TNF-a Tumor necrosis factor-a GIP Glucose-dependent insulinotropic peptide TSH Thyroid-stimulating hormone GLP-1 Glucagon-like peptide 1 UCP1 Uncoupling protein 1 GLP-1R GLP-1 receptors VAN Vagal afferent neurons GLUT2 Glucose transporter 2 VMH Ventromedial hypothalamus HFD High-fat diet WAT White adipose tissue between gut, brain, and other specific peripheral metabolic organs, Inter-organ communication in the control of fasting/ namely liver, muscle, WAT, BAT, and pancreas, in the maintenance feeding cycles of metabolic fitness. The role of the immune system in energy home- ostasis has