REVIEW published: 22 April 2020 doi: 10.3389/fphys.2020.00356 Edited by: Miles J. De Blasio, Monash University, Australia Reviewed by: Vicente Lahera, Complutense University of Madrid, Spain Joon (Kyungjoon) Lim, La Trobe University, Australia *Correspondence: Giovanni Messina giovanni.messina@unifg.it † These authors have contributed equally to this work Specialty section: This article was submitted to Integrative Physiology, a section of the journal Frontiers in Physiology Received: 03 September 2019 Accepted: 27 March 2020 Published: 22 April 2020 Citation: Polito R, Monda V, Nigro E, Messina A, Di Maio G, Giuliano MT, Orrù S, Imperlini E, Calcagno G, Mosca L, Mollica MP, Trinchese G, Scarinci A, Sessa F, Salerno M, Marsala G, Buono P, Mancini A, Monda M, Daniele A and Messina G (2020) The Important Role of Adiponectin and Orexin-A, Two Key Proteins Improving Healthy Status: Focus on Physical Activity. Front. Physiol. 11:356. doi: 10.3389/fphys.2020.00356 The Important Role of Adiponectin and Orexin-A, Two Key Proteins Improving Healthy Status: Focus on Physical Activity Rita Polito 1,2† , Vincenzo Monda 3† , Ersilia Nigro 1,4 , Antonietta Messina 3 , Girolamo Di Maio 3 , Maria Teresa Giuliano 3 , Stefania Orrù 5,6 , Esther Imperlini 6 , Giuseppe Calcagno 7 , Laura Mosca 8 , Maria Pina Mollica 8 , Giovanna Trinchese 8 , Alessia Scarinci 9 , Francesco Sessa 2 , Monica Salerno 10 , Gabriella Marsala 11 , Pasqualina Buono 4,5,6 , Annamaria Mancini 4,5 , Marcellino Monda 3 , Aurora Daniele 1,4† and Giovanni Messina 2 * 1 Dipartimento di Scienze e Tecnologie Ambientali Biologiche e Farmaceutiche, University of Campania “Luigi Vanvitelli”, Caserta, Italy, 2 Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy, 3 Dipartimento di Medicina Sperimentale, Sezione di Fisiologia Umana e Unità di Dietetica e Medicina dello Sport, Università degli Studi della Campania “Luigi Vanvitelli”, Naples, Italy, 4 Ceinge Biotecnologie Avanzate S. C. a R. L., Naples, Italy, 5 Dipartimento di Scienze Motorie e del Benessere, Università degli Studi di Napoli “Parthenope”, Naples, Italy, 6 IRCCS SDN, Naples, Italy, 7 Dipartimento di Medicina e Scienze della Salute “Vincenzo Tiberio”, Università degli Studi del Molise, Campobasso, Italy, 8 Dipartimento di Biologia, Universitá degli studi di Napoli Federico II, Naples, Italy, 9 Dipartimento di Scienze della Formazione, Psicologia, Comunicazione, Università degli Studi di Bari Aldo Moro, Bari, Italy, 10 Department of Medical, Surgery Sciences and Advanced Technologies “G.F. Ingrassia”, University of Catania, Catania, Italy, 11 Struttura Complessa di Farmacia, Azienda Ospedaliero Universitaria - Ospedali Riuniti, Foggia, Italy Exercise represents the most important integrative therapy in metabolic, immunologic and chronic diseases; it represents a valid strategy in the non-pharmacological intervention of lifestyle linked diseases. A large body of evidence indicates physical exercise as an effective measure against chronic non-communicable diseases. The worldwide general evidence for health benefits are both for all ages and skill levels. In a dysregulated lifestyle such as in the obesity, there is an imbalance in the production of different cytokines. In particular, we focused on Adiponectin, an adipokine producted by adipose tissue, and on Orexin-A, a neuropeptide synthesized in the lateral hypothalamus. The production of both Adiponectin and Orexin-A increases following regular and structured physical activity and both these hormones have similar actions. Indeed, they improve energy and glucose metabolism, and also modulate energy expenditure and thermogenesis. In addition, a relevant biological role of Adiponectin and Orexin A has been recently highlighted in the immune system, where they function as immune-suppressor factors. The strong connection between these two cytokines and healthy status is mediated by physical activity and candidates these hormones as potential biomarkers of the beneficial effects induced by physical activity. For these reasons, this review aims to underly the interconnections among Adiponectin, Orexin- A, physical activity and healthy status. Furthermore, it is analyzed the involvement of Adiponectin and Orexin-A in physical activity as physiological factors improving healthy status through physical exercise. Keywords: Adiponectin, physical exercise, Orexin-A, healthy status, obesity regulation Frontiers in Physiology | www.frontiersin.org 1 April 2020 | Volume 11 | Article 356