Until the discovery of leptin in 1994 by the group led by Jeffrey Friedman 1 , white adipose tissue (WAT) was considered only an energy storage tissue. In the past dec- ade WAT has been recognized to be a very active tissue and an unexpected source of bioactive peptides, termed adipokines 2,3 . In addition to their metabolic activities, it is now well known that these adipose-derived factors represent a new family of compounds that are also syn- thesized in tissues other than WAT (such as placenta trophoblasts, amnion cells, cartilage or bone) 4 , and that could participate in several processes including inflammation and immunity 5–7 . Leptin is mainly produced by adipocytes and, in physiological conditions, its circulating levels correlate positively with WAT mass. Therefore, leptin is consid- ered a proinflammatory adipokine given that it seems to contribute to the so-called ‘low-grade inflammatory state’ in overweight and obese people 8 . Leptin is a 16 kDa non-glycosylated protein encoded by the LEP gene (the human homologue of murine Lep, also known as ob) 1 and exerts its biological actions by binding to its recep- tor (LEPR), which belongs to the class I cytokine recep- tor superfamily. There are several receptor isoforms: a soluble isoform, isoforms with short cytoplasmic domains, and a long isoform, which is found in almost all tissues and which seems to be the only isoform capable of transducing the leptin signal 9 . Similar to other class I cytokine receptors, the long form of LEPR transmits extracellular signals through the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) signalling pathway 10 (FIG. 1). Most immune cell types express LEPR at their surface, which suggests a role for leptin in immune responses 11 . Currently, leptin could be considered a link between the neuroendocrine and immune systems 12,13 . This hor- mone acts in the brain as an energy homeostasis reg- ulating factor that triggers a decrease in food intake and an increase in energy consumption by inducing anorexigenic factors and suppressing orexigenic factors 14 . Its own synthesis is mainly regulated by food intake and eating-related hormones, but also depends on energy status, sex hormones (leptin synthesis can be suppressed by testosterone and increased by oestrogen and proges- terone) 15 and a wide range of inflammatory mediators (increased or suppressed by proinflammatory cytokines depending on whether their action is acute or chronic) 16 . 1 SERGAS (Servizo Galego de Saude) and IDIS (Instituto de Investigación Sanitaria de Santiago), The NEIRID Group (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), Santiago University Clinical Hospital, Building C, Trav. Choupana, Santiago de Compostela 15706, Spain. Correspondence to O.G. oreste.gualillo@sergas.es doi:10.1038/nrrheum.2016.209 Published online 5 Jan 2017 Anorexigenic factors Mediators that reduce food intake by acting on hypothalamic receptors Orexigenic factors Mediators that induce appetite and stimulate food intake Leptin in the interplay of inflammation, metabolism and immune system disorders Vanessa Abella 1 , Morena Scotece 1 , Javier Conde 1 , Jesús Pino 2 , Miguel Angel Gonzalez-Gay 3 , Juan J. Gómez-Reino 4 , Antonio Mera 4 , Francisca Lago 5 , Rodolfo Gómez 1 and Oreste Gualillo 1 Abstract | Leptin is one of the most relevant factors secreted by adipose tissue and the forerunner of a class of molecules collectively called adipokines. Initially discovered in 1994, its crucial role as a central regulator in energy homeostasis has been largely described during the past 20 years. Once secreted into the circulation, leptin reaches the central and peripheral nervous systems and acts by binding and activating the long form of leptin receptor (LEPR), regulating appetite and food intake, bone mass, basal metabolism, reproductive function and insulin secretion, among other processes. Research on the regulation of different adipose tissues has provided important insights into the intricate network that links nutrition, metabolism and immune homeostasis. The neuroendocrine and immune systems communicate bi‑directionally through common ligands and receptors during stress responses and inflammation, and control cellular immune responses in several pathological situations including immune‑inflammatory rheumatic diseases. This Review discusses the latest findings regarding the role of leptin in the immune system and metabolism, with particular emphasis on its effect on autoimmune and/or inflammatory rheumatic diseases, such as rheumatoid arthritis and osteoarthritis. NATURE REVIEWS | RHEUMATOLOGY ADVANCE ONLINE PUBLICATION | 1 REVIEWS ©2017MacmillanPublishersLimited,partofSpringerNature.Allrightsreserved.