Edited by: Joaquin Garcia-Estañ, Universidad de Murcia, Spain
Reviewed by: Deanne Helena Hryciw, Griffith University, Australia; Antonio La Cava, University of California, Los Angeles, United States; Giuseppe Matarese, Università degli Studi di Napoli Federico II, Italy
†These authors have contributed equally to the realization of this work.
This article was submitted to Integrative Physiology, a section of the journal Frontiers in Physiology
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Obesity is an epidemic disease characterized by chronic low-grade inflammation associated with a dysfunctional fat mass. Adipose tissue is now considered an extremely active endocrine organ that secretes cytokine-like hormones, called adipokines, either pro- or anti-inflammatory factors bridging metabolism to the immune system. Leptin is historically one of most relevant adipokines, with important physiological roles in the central control of energy metabolism and in the regulation of metabolism-immune system interplay, being a cornerstone of the emerging field of immunometabolism. Indeed, leptin receptor is expressed throughout the immune system and leptin has been shown to regulate both innate and adaptive immune responses. This review discusses the latest data regarding the role of leptin as a mediator of immune system and metabolism, with particular emphasis on its effects on obesity-associated metabolic disorders and autoimmune and/or inflammatory rheumatic diseases.
Obesity, the greater public health problem in the western world, is associated with high-incident chronic autoimmune and inflammatory pathologies, such as T2DM, NAFLD, OA, and RA, thus having a huge social and economic impact (
Leptin was discovered in 1994 by the group of Jeffrey Friedman (
Leptin receptors and intracellular leptin signaling pathways. Leptin binds to its receptor (LEPR) isoforms: the soluble isoform (not shown), the short isoform and the long isoform. Binding of leptin to the long form of LEPR results in its dimerization and prompts Janus kinase 2 (JAK2) autophosphorylation, which phosphorylates cytoplasmatic domain of LEPR in tyrosine residues (Tyr974, Tyr985, Tyr1077, Tyr1138), each one functioning as docking sites for cytoplasmic adaptors. LEPR-phosphorylated Tyr1138 mediates the interaction with signaling transducer and activator of transcription 3 (STAT3), which dimerize and translocate to the nucleus to activate gene transcription of target genes, such as suppressor of cytokine signaling 3 (SOCS3) that acts as a negative feedback signaling. Additionally, leptin induces the activation of SHP2, which then recruits the adaptor protein Grb2 to prompt activation of Ras/Raf/MAPK signaling cascade. Leptin also mediated phosphatidylinositol-3-kinase (PI3K)/Akt activation via insulin receptor substrate 1/2 (IRS1/2) and protein tyrosine phosphatase 1B (PTP1B) acts as a negative regulator of leptin signaling through JAK2 dephosphorylation.
Pleiotropic nature of leptin. Since its discovery in 1994, several physiological functions have been attributed to leptin, such as modulation of vascular function, reproduction, bone metabolism, inflammation, infection, and immune responses, behind central regulation of food intake, energy expenditure and hormone regulation, via activation of leptin receptor (LEPR).
This review summarizes the latest data regarding the role of leptin as a mediator of innate and adaptive immune cells activity, and its effects on obesity-associated metabolic disorders, namely T2DM and NAFLD, and autoimmune and/or inflammatory rheumatic diseases, such as OA and RA.
The rising prevalence of obesity in western society is paralleled with a significant augment in autoimmune diseases. Accordingly, numerous association studies had demonstrated that overweight is implicated in a higher risk of developing multiple sclerosis (
Leptin, the forerunner of adipokine family, is a key sensor of energy metabolism and a cornerstone in the regulation of metabolism-immune system interplay. Malnutrition results in hypoleptinemia, while obesity leads to hyperleptinemia, both conditions affecting the immune response in an opposite manner. In particular, obese subjects demonstrated decreased levels of Treg (central players in the control of peripheral immune tolerance), which are inversely correlated with leptin levels and BMI (
Leptin effects on innate and adaptive immunity. Leptin regulates both innate and adaptive responses through modulation of immune cells survival and proliferation as well as its activity. In innate immunity, leptin increases the cytotoxicity of natural killer (NK) cells and promotes the activation of granulocytes, macrophages and DCs. Leptin also regulates the M1- or M2-phenotype polarization and modulates DCs, licensing them towards type 1 T helper cells (Th1) priming. In adaptive immunity, leptin increases the proliferation of naïve T cells and B cells while it reduces that of regulatory T cells (Treg). Leptin promotes the switch towards a pro-inflammatory Th1 (which secretes IFNγ) rather than anti-inflammatory Th2 (which secretes IL-4) phenotype, and facilitates Th17 responses. Finally, leptin activates B cells to secrete cytokines and modulates B cell development.
Human polymorphonuclear neutrophils express LEPR (
There is strong evidence for an effect of leptin on neutrophil chemotaxis and infiltration. Leptin (50 ng/ml) mediated the migration of human neutrophils
Alike neutrophils, both human eosinophils and basophils expressed LEPR on the cell surface (
In human basophils, leptin treatment (10 nM) induced a strong migratory response, promoted the secretion of type 2 cytokines IL-4 and IL-13, and up-regulated the cell surface expression of CD63, which may have an exacerbating action on allergic inflammation (
Altogether, these findings suggest leptin as a potent activator of neutrophils, eosinophils, and basophils through its positive action in cell survival, cytokines release and chemotaxis.
Both isoforms of LEPR are expressed in PBMCs, being lower in cells from obese individuals compared with lean subjects (
A dose-dependent effect of leptin as a trophic factor to prevent apoptosis was found in serum-deprived human monocytes, being this effect mediated by the p42/p44 MAPK pathways (
Leptin treatment (50 ng/ml) of human macrophages in culture, induced ‘alternatively activated’ or M2-phenotype surface markers, but they were able to secrete M1-typical cytokines (TNF-α, IL-6, IL-1β, IL-1ra, IL-10, MCP-1, and macrophage inflammatory protein 1-alpha (MIP-1α)), suggesting a role for leptin in the phenotype of macrophages found in adipose tissue (
Macrophages are indirectly regulated by leptin through mast cells (
Biologic drugs used for the treatment of psoriatic arthritis, namely adalimumab (an anti-TNF-α monoclonal antibody) and ustekinumab (a monoclonal antibody against the p40 subunit of IL-12 and IL-23), augmented LEPR expression in THP-1 human macrophages (
The role of leptin in regulating NK cell development and activation was first verified in obese
The above-mentioned results indicated that leptin signaling is required for normal NK cell immune function. However, there are some controversial findings concerning the time of leptin treatment
Overall, leptin signaling seems to be necessary for normal NK cell immune function, increasing the immune activity and cell proliferation, and reducing the apoptotic rate of NK cells. Long-term exposure to hyperleptinemia, observed in obesity, has been associated with decreased NK immune activity possibly due to the development of leptin resistance. Further studies are needed to better understand the correlation between leptin levels and NK cell development and function, as well as the potential implications in obesity.
Human DCs, both immature and mature DCs, present functional active LEPR with the capacity to signal STAT-3 phosphorylation (
Altogether, these data demonstrated the important role of leptin in DC activation, chemoattraction, and survival, with possible implications in DC maturation and migration. Given the ability of DCs to orchestrate immune response and promote potent immunogenic responses through activation of T cell immunity, DCs-based immunotherapies to elicit immunity against cancer and infectious diseases are currently being developed. In particular, DCs can be differentiated
The role of leptin in adaptive immunity has first evidenced working with
T lymphocytes expressed the long form of LEPR (higher in peripheral CD4+ than in CD8+ T cells) (
Leptin also promoted CD4+ T cell polarization toward a Th1 response (which secretes IFNγ and IL-2) rather than Th2 response (which secretes IL-4) (
IL-17-producing Th cells (Th17) have a crucial role in the promotion and maintenance of inflammatory and autoimmune pathologies. Leptin was demonstrated to increase Th17 population and responsiveness in SLE, via retinoic acid-related orphan receptor (ROR)γt (
Leptin also regulated CD4+CD25+ Treg proliferation (
T cell metabolism is directly related to its function (
Altogether, these data revealed the ability of leptin to increase immune activity by modulation of T cell number and function. Leptin can promote proliferation of naive T cells, as well as Th1 and Th17 proliferation and cytokine production. Moreover, leptin decreases Treg cell proliferation. Considering the regulatory effects of leptin on Th17 and Treg populations, revoking leptin signaling might be a potential therapeutic approach for inflammation and autoimmunity.
In contrast to macrophages and T cells, little is known about the role of leptin in the B lymphocytes development and function. B cells expressed the long form of the LEPR, suggesting a direct effect of leptin on B cell function (
Leptin can also modulate B cell development – decrease pro-B, pre-B and immature B cells and increase mature B cells- in bone marrow of fasted mice, characterized by low serum leptin levels (
In summary, leptin can increase B cell population by augmenting proliferation and reducing the apoptotic rate, activate B cell to secrete pro-, anti- and regulatory cytokines, and also modulate B cell development.
Obesity is associated with life-threatening co-morbidities, including insulin resistance, T2DM, NAFLD and steatohepatitis (NASH) (
T2DM is the most significant obesity-associated metabolic disorder and their prevalence is increasing worldwide in parallel (
Importantly, T2DM is associated with altered components of immune system, including modified levels of specific chemokines and cytokines, changed number and activation status of leukocytes populations and increased apoptosis and tissue fibrosis (
NAFLD, the major cause of chronic liver illness in developed countries, comprises a wide group of pathologies primary caused by a buildup of fat in the liver that spans from simple steatosis to NASH, liver fibrosis, cirrhosis, and hepatocellular carcinoma (
Hepatic inflammation and hepatocyte injury and death are hallmarks of NAFLD/NASH. Fat overload by hepatocytes causes lipotoxicity and the release of DAMPs which activated Kupfer cells (KC; specialized liver macrophages) and HSC promoting inflammation and fibrosis, respectively. KC activation plays a central role in NAFLD pathophysiology through the production of pro-inflammatory cytokines and chemokines such as TNF-α, IL-1β, IL-6, CCL2 and CCL5, that contributed to leukocyte infiltration and inflammatory necrosis of hepatocytes, and fibrogenesis (
Considering the strong metabolic and inflammatory components of NAFLD, leptin is regarded as a key regulator of NAFLD physiopathology (
Through anti-steatotic effect, leptin can ultimately lead to hepatic detrimental effects. Leptin activated HSCs, leading to up-regulation of pro-inflammatory and pro-angiogenic factors expression (like angiopoietin-1 and vascular endothelial growth factor), as well as collagen α1 and tissue inhibitor of metalloproteinase-1, ultimately acting as hepatic fibrogenesis inducer (
In
Leptin has been described as a key factor in the pathophysiology of rheumatic diseases due to its capability to modulate bone and cartilage metabolism and to influence innate and adaptive immune responses (
Effects of adipose tissue-derived leptin on osteoarthritis and rheumatoid arthritis. Body weight gain, accompanied by white adipose tissue expansion, lead to obesity and subsequent increase of mechanical load, resulting in cartilage degradation and osteoarthritis onset. Adipose tissue-derived leptin causes osteoblast dysregulation in subchondral bone, thus promoting joint destruction. Additionally, leptin induces pro-inflammatory cytokine release from innate and adaptive immune cells, generating an inflammatory environment that prompts cartilage damage and rheumatoid arthritis.
Osteoarthritis, the most common joint disease, is a painful and debilitating illness characterized by progressive degeneration of articular joints. Initially seen as simply “wear and tear” disease, OA is currently considered a complex and multifactorial pathology triggered by inflammatory and metabolic imbalances that affect the entire joint structure (articular cartilage, meniscus, ligaments, bone, and synovium) (
Some initial findings suggested an anabolic role of leptin in cartilage. In particular, exogenous leptin administration (30 μg) stimulated proteoglycan and growth factors (insulin-like growth factor-1 and TGF-β) synthesis in rat knee-joint cartilage (
Leptin can directly induce the expression of MMPs that are involved in OA-related joint destruction, like MMP-1 (also known as interstitial collagenase), MMP-3 (also known as stromelysin), and MMP-13 (also known as collagenase), via NF-κB, PKC, and MAPK pathways (
MicroRNAs, small single-stranded non-coding segments of RNA, are increasingly recognized as regulatory molecules involved in disease processes, including OA, inflammation, and obesity (
Chondrogenic progenitor cells as cartilage seed cells are crucial to maintain cartilage homeostasis and replace damaged tissue (
Taking together, this evidence indicated a key role of leptin in OA pathophysiology by influencing pro-inflammatory status, cartilage catabolic activity, as well as cartilage and bone remodeling. However, studies in a large cohort of patients are needed to better clarify the leptin significance in the development and progression of OA.
Rheumatoid arthritis is a chronic inflammatory joint illness characterized by synovial membrane inflammation and hyperplasia (“swelling”), production of autoantibodies, namely rheumatoid factor and anti-citrullinated protein antibody – autoimmune disease, destruction of cartilage and bone (“deformity”), and systemic features including skeletal, cardiovascular, pulmonary, and psychological complications (
Several studies have found a positive correlation between serum and synovial leptin levels and RA pathology (
Since leptin modulates the immune system, as well as insulin resistance and metabolic disorders like metabolic syndrome and obesity, all RA-associated conditions, this adipokine represents an attractive therapeutic target for RA. Accordingly, reducing leptin levels in RA patients by fasting improved the clinical symptoms of the disease (
Hence, leptin can be pointed as a link between immune tolerance, metabolic function, and autoimmunity, and leptin signaling-directed strategies could provide future innovative therapies for autoimmune disorders like RA.
Systemic lupus erythematosus is a chronic autoimmune disorder of unclear etiology characterized by hyperactive T and B cells, autoantibody production, deposition of immune complex, elevated blood levels of pro-inflammatory cytokines and multisystem organ damage, encompassing from mild manifestations (non-erosive arthritis or skin rash) to life-threatening complications (lupus nephritis, neuropsychiatric disorders, cardiovascular disorders, and metabolic syndrome). Although the pathogenesis of SLE is poorly understood, genetic, hormonal and environmental factors have been implicated in the onset of this heterogeneous disease, which predominantly affects women of childbearing age (
Several studies suggest the implication of adipokines, namely leptin, in the pathogenesis of SLE. Although some reports found no statistical association between disease activity and leptin levels (
The role of leptin in SLE development has been investigated using leptin-deficient (ob/ob) mice treated with lupus-inducing agent (
Altogether, these data support the involvement of leptin in the development of SLE. However, further investigations are needed to fully understand the role of leptin in SLE and thus, explore this adipokine as potential therapeutic target of SLE.
Obesity and its comorbidities, such as T2DM, non-alcoholic fatty acid liver disease, OA and RA, reached epidemic proportions and are still rising in developing countries. Anti-obesity therapeutic options have provided only a limited long-term efficacy (lifestyle changes, physical activity, diet, and pharmacotherapies) or are not completely safe (bariatric surgery) (
The adipose tissue-derived factor leptin has been emerged as a key regulator of nutritional state and metabolism, as well as a modulator of immune system activation and innate-adaptive frontier; thus bridging obesity with metabolic disorders (T2DM and NAFLD) and inflammatory pathologies that affect bones and joints (OA and RA). Consequently, plasma leptin concentration could be a biological marker of the inflammatory status and the onset and evolution of pathologies associated with dysregulation of the immune system, and hereafter evaluations will be essential to establish leptin as clinical biomarker. Moreover, control of bioactive leptin levels by high-affinity leptin-binding molecules, miRNAs targeting leptin, LEPRs antagonists or monoclonal humanized antibodies against LEPR are likely to be feasible therapeutic approaches (
VF and JP have made a substantial contribution to acquisition and analysis of data and critically revised it. VC-C, CR-F, AM, MG-G, and RG have been involved in drafting the manuscript and revising it critically for important intellectual content. OG made a substantial contribution to conception and design of the review article, drafting the manuscript, and critically revising it. All authors approved the final version to be published.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
a disintegrin and metalloproteinase with thrombospondin motifs
adenosine monophosphate-activated protein kinase
arginase-1
bone marrow-derived macrophages
body mass index
cyclic adenosine monophosphate
CC-chemokine ligand
cluster of differentiation
cyclooxygenase-2
chondrogenic progenitor cells
C-reactive protein
damage-associated molecular patterns
dendritic cells
extracellular signal-regulated kinase
glucose transporter
high-fat diet
human leukocyte antigen-antigen D related
hepatic stellate cell
intercellular adhesion molecule
interferon γ
interleukin
inducible nitric oxide synthase
intrapatellar fat pad
insulin receptor substrate
Janus kinase
c-jun N-terminal kinase
kupffer cells
leptin receptor
lipoprotein lipase
lipopolysaccharide
mitogen-activated protein kinase
monocyte chemoattractant protein 1
mitogen-activated protein kinase kinase
macrophage inflammatory protein-1 alpha
microRNA
matrix metalloproteinases
non-alcoholic liver disease
non-alcoholic steatohepatitis
nuclear factor- κB
nitric oxide
nitric oxide synthase 2
osteoarthritis
pathogen-associated molecular patterns
prostaglandin E2
phosphoinositide 3-kinase
protein kinase C
phorbol myristate acetate
human polymorphonuclear neutrophils
peroxisome proliferator-activated receptor alpha
rheumatoid arthritis
retinoic acid-related orphan receptor gamma t
reactive oxygen species
systemic lupus erythematosus
sterol regulatory element-binding protein-1c
signal transducer and activator of transcription
type 2 diabetes mellitus
transforming growth factor
T helper cells
toll-like receptor
tumour necrosis factor-α
T regulatory cells
visceral adipose tissue
vascular cell adhesion molecule
white adipose tissue