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) (Martín-Romero et al., 2000). Accordingly, under Th2-polarizing conditions, the in vitro leptin treatment decreased IL-4-producing T cells and inhibited T cell proliferation (Batra et al., 2010). However, it was recently reported that in vivo leptin-deficiency attenuated allergic airway inflammation and that high leptin levels associated with obesity promoted proliferation and survival of Th2 lymphocytes, as well as the production of type 2 cytokines, altogether contributing to allergic responses (Zheng et al., 2016). Besides that, leptin was involved in thymus morphology and functions (Lamas et al., 2016), particularly in thymocyte differentiation of double positive CD4+CD8+ T cells into single positive CD4+ T cells (Kim et al., 2010).

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 (Yu et al., 2013; Fujita et al., 2014; Reis et al., 2015). In collagen-induced arthritis mouse model, articular injection of leptin (5 μg) increased the number of Th17 in the joint tissue, resulting in exacerbating joint inflammation, and consequently early onset of arthritis and increased disease severity (Deng et al., 2012). Leptin, in concentrations similar to that found in blood during pregnancy, promoted the differentiation of peripheral blood CD4+ cells to Th17 cells, but suppressed the formation of Treg cells in vitro (Orlova and Shirshev, 2014). CD4+ T cell-derived leptin, but not plasma leptin, were positively correlated with the percentage of Th17 cells or RORγt levels in chronic lymphocytic thyroiditis, an organ-specific autoimmune disease (Wang et al., 2013). Furthermore, Lepr-deficient CD4+ T cells verified a reduced capacity for Th17 differentiation, via down-regulation of STAT3 activation (Reis et al., 2015).

Leptin also regulated CD4+CD25+ Treg proliferation (Matarese et al., 2010). Treg lymphocytes play a critical role in controlling the inappropriate immune responses characteristic of autoimmune diseases and allergy. In humans, leptin negatively affected the proliferation of Foxp3+CD4+CD25+ Treg; in vitro leptin neutralization, during anti-CD3 and anti-CD28 stimulation, led to the proliferation of the isolated human Treg cell (De Rosa et al., 2007). Obese individuals presented a reduced number of CD4+CD25+CD127-Foxp3+ Treg cells, which was correlated with body weight, BMI, and plasma leptin levels (Wagner et al., 2013). Moreover, leptin-deficient mice presented an increased percentage of peripheral Treg, compared with wild-type mice, which is reversed after leptin administration (De Rosa et al., 2007). It was verified that leptin played an important role in Treg dysfunction in patients with pulmonary arterial hypertension (Huertas et al., 2016). Accordingly, Lepr-deficient rats developed less severe hypoxia-induced pulmonary hypertension and were protected against decreased Treg function after exposure to hypoxia (Huertas et al., 2016). In SLE, the disease-associated higher leptin serum levels were negatively correlated with disease severity and number of Treg cells (Ma et al., 2015; Margiotta et al., 2016; Wang et al., 2017), and fasting-induced hypoleptinaemia was related to Treg population recovery in lupus-prone mice (Liu et al., 2012). Leptin-deficient ob/ob mice and a mouse model of lupus with leptin deficiency demonstrated increased frequency of Tregs cells (Fujita et al., 2014; Lourenço et al., 2016). These data evidenced the potential of anti-leptin-based approaches for immune system-dysregulated pathologies associated with reduced Treg function, such as SLE, obesity, T2DM, and metabolic syndrome.

T cell metabolism is directly related to its function (MacIver et al., 2013); effector T cells, such as Th1 and Th17, demand a high glycolytic metabolism to fuel proliferation and function, while Treg cells require oxidative metabolism to fuel suppressive activity. Recently, leptin was found to directly promote T-cell glycolytic metabolism and consequently induce Th17 cell differentiation, being Treg cells unchanged, in a mouse model of experimental autoimmune encephalomyelitis (Gerriets et al., 2016). Leptin regulated glucose metabolism partly by up-regulation of glucose transporter Glut1 (Saucillo et al., 2014). Moreover, fasting led to decreased ability of T cells to secrete IL-2 and IFNγ, and inability to up-regulate glucose uptake and glycolytic flux (Saucillo et al., 2014), while Treg expansion was increased (Liu et al., 2012); leptin administration (1 μg/g body weight) rescued peripheral T cell function and metabolism in fasted mice (Saucillo et al., 2014). Likely, fasting was extensively reported to be associated with immune deficiency and increased susceptibility to infection (Gerriets and MacIver, 2014). Thus, leptin seems to provide a key link between nutritional status and inflammatory T cell responses (Gerriets et al., 2016; De Rosa et al., 2017).

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.

T2DM is the most significant obesity-associated metabolic disorder and their prevalence is increasing worldwide in parallel (Bhupathiraju and Hu, 2016). Leptin has been proposed as a therapeutic target of T2DM, for its impact on food intake and body weight as well as its potential to improve insulin action (Kalra, 2009). Interestingly, leptin-deficient mice (Pelleymounter et al., 1995) and human (Farooqi et al., 1999, 2002; Ozata et al., 1999) have diabetic features, which were reversed with leptin replacement. The anti-diabetic effect of leptin is mediated by activation of IRS-PI3K pathway that improved insulin sensitivity in peripheral tissues (Morton et al., 2005). Activation of JAK2/IRS/PI3K/Akt signaling pathway by leptin and insulin triggers the translocation of glucose transporter type 4 (GLUT4) from cytosol to cell surface, and glucose uptake (Benomar et al., 2006; Zhao and Keating, 2007). Moreover, in the liver, leptin deficiencies decrease AMPK activity (Namkoong et al., 2005), which is also involved in glucose homeostasis regulation (Schultze et al., 2012). Leptin has also been implicated in the regulation of insulin secretion by pancreatic β-cells (Kulkarni et al., 1997), as well as in peripheral insulin resistance (Silha et al., 2003; Yadav et al., 2011). However, clinical trials to evaluate the potential of leptin monotherapy in obese humans with T2DM failed to demonstrate therapeutic activity acutely or chronically, with no observation of important weight loss or metabolic improvements (insulin sensitization, amelioration of glucose and lipid metabolism) (Mittendorfer et al., 2011; Moon et al., 2011; Wolsk et al., 2011). In this context, unresponsiveness to leptin – leptin resistance, caused by hyperleptinemia observed in obese humans, should be considered (Frederich et al., 1995). Further understanding of leptin resistance mechanisms could enable new leptin targeted therapies for obesity and diabetes in specific subsets of patients. In fact, leptin therapy improved the diabetic condition in children (Farooqi et al., 1999, 2002) and adults (Licinio et al., 2004) with familial leptin deficiency, and in lipoatrophic diabetes (Oral et al., 2002).

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 (Donath, 2014), all promoted by obesity-associated inflammation in adipose tissue (Donath and Shoelson, 2011). Given the modulator action of leptin in innate and adaptive immune system (deeply described above), it is rational to see leptin as a linker of T2DM development, not only with metabolism but also with inflammation. Indeed, in patients with newly diagnosed T2DM, leptin levels were correlated with CRP, an inflammatory marker broadly evaluated for its association with risk factors for T2DM pathology (Morteza et al., 2013).

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 (Tiniakos et al., 2010). Given that NAFLD is increasing worldwide and it is associated with high-incident extra-hepatic complications such as obesity, T2DM, cardiovascular diseases and chronic kidney disease (Byrne and Targher, 2015; Polyzos et al., 2015), great efforts have been made in the last years to unravel the mechanisms underlying the disease pathophysiology and further development of effective NAFLD therapies.

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 (Arrese et al., 2016). Dysbiosis of the gut microbiota may also conduct to KC activation through PAMPs, which originate in the gut and reach liver via portal circulation due to altered intestinal permeability. Other immune cells have been implicated in the NAFLD pathophysiology, although its role is less clear (Arrese et al., 2016). NK cells were impaired in experimental NASH, while natural killer T cells (unique immune cell subtype that expresses NK cells surface markers as well as T-cell antigen receptor) are depleted in steatosis but increased later during disease progression likely leading to inflammation and fibrosis in NASH via the production of IL-4, osteopontin, and IFN-γ (Tajiri and Shimizu, 2012; Tian et al., 2013). Neutrophils exacerbate the ongoing inflammation through macrophage recruitment and cell damage via the release of myeloperoxidase, ROS, and elastase (Xu R. et al., 2014). The role of DCs in NASH is complex and somehow controversial. DCs rapidly infiltrate into the liver in experimental NASH exhibiting an activated immune phenotype, but its depletion exacerbates hepatic inflammation (Tacke and Yoneyama, 2013; Arrese et al., 2016). B- and T-cells also contributed to hepatic inflammation via secretion of pro-inflammatory cytokines that stimulated KC activation (Arrese et al., 2016).

Considering the strong metabolic and inflammatory components of NAFLD, leptin is regarded as a key regulator of NAFLD physiopathology (Polyzos et al., 2015). Leptin seems to feature a dual activity in NAFLD experimental models by exerting an early protective anti-steatosis effect in the initial stages of the disease, and a late pro-inflammatory and pro-fibrogenic action, when the disease persists or progress (Polyzos et al., 2015). In leptin-resistant Zucker fa/fa diabetic fatty rats, the expression of SREBP-1c (master regulator of glucose metabolism, and lipid and fatty acid production) is increased in liver (Kakuma et al., 2000), and infusion of adenovirus-leptin decreased hepatic triglyceride synthesis and β-oxidation via SREBP-1c down-regulation and PPARα up-regulation (Lee et al., 2002), thus preventing hepatic lipid accumulation.

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 (Polyzos et al., 2015). Activated HSCs were able to secrete leptin, thus establishing a vicious cycle that further promotes liver fibrosis (Polyzos et al., 2015). Moreover, leptin was reported as potent HSCs mitogen and to prevent HSCs apoptosis, hence promoting the pathogenesis of hepatic fibrosis. Leptin (200 nM) increased the expression of TGF-β1 in KCs and sinusoidal endothelial cells, and connective tissue growth factor in KCs (Ikejima et al., 2002), being KCs-HSCs cross-talk proposed for liver fibrosis (Wang et al., 2009). Additionally, leptin is involved in macrophage-mediated KCs activation via induction of oxidative stress in macrophages (Chatterjee et al., 2013). Compared to healthy subjects, NAFLD patients demonstrated an increased leptin-stimulated TNFα and ROS production in peripheral monocytes, as well as IFNγ production in circulating CD4+ cells (a marker of Th1 differentiation) (Inzaugarat et al., 2017). Altogether, these data elucidated the role of leptin in NAFLD by modulation of HSCs, KCs, and inflammatory cells response.

In ob/ob mice, the congenital absence of leptin abrogated the development of CCl₄-induced hepatic fibrosis comparing to lean littermates, which is reverted by leptin treatment (100 ng/ml) (Saxena et al., 2002). Likewise, xenobiotics- or thioacetamide-induced hepatic fibrosis was prevented in Zucker fa/fa rats, being involved the activation of HSCs and expression of procollagen-I and TGF-β1 (Ikejima et al., 2005). In humans, the role of leptin is controversial. Although leptin serum levels were initially related with hepatic steatosis but not with necroinflammation or fibrosis (Chitturi et al., 2002), later studies failed to demonstrate any significant association (Tsochatzis et al., 2009). Recombinant leptin has been successfully used in the treatment of insulin resistance and hepatic steatosis in patients with lipodystrophy and NASH (Oral et al., 2002; Petersen et al., 2002; Javor et al., 2005). However, large-scale and well-designed prospective cohort studies are necessary to deeply elucidate the role of leptin in hepatic lipid handling, inflammation, and fibrosis along with the identification of NAFLD patients subsets that may benefit from therapies directed to leptin system.

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) (Loeser et al., 2012). Leptin levels are increased in serum, infrapatellar fat pad (IPFP), synovial tissues, and cartilage of OA patients compared to healthy individuals (Dumond et al., 2003; de Boer et al., 2012; Conde et al., 2013). Accordingly, leptin-deficient or LepR-deficient mice developed extreme obese phenotype without increased incidence of knee OA, suggesting that leptin signaling is essential to the development and progression of obesity-associated OA (Griffin et al., 2009). Furthermore, long form of LEPR was found to be expressed in human cartilage cells – chondrocytes (Figenschau et al., 2001).

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 (Dumond et al., 2003). However, most of the studies reported a catabolic role of leptin underlying OA pathogenesis. A recent study determining the gene expression profile of leptin-induced articular rat cartilage by microarray analysis, associated the up-regulation of matrix metalloproteinases (MMPs), inflammatory factors, growth factors and osteogenic genes with leptin-induced OA phenotype (Fan et al., 2018). Our group demonstrated that leptin (400 or 800 nM), in synergy with IFNγ or IL-1β, activated type 2 nitric oxide synthase (NOS2) via JAK2, PI3K and MAPK (MEK1 and p38) pathways, in cultured human and murine chondrocytes (Otero et al., 2003, 2005, 2007). Nitric oxide (NO), is a well-known pro-inflammatory mediator which lead to joint degradation through induction of chondrocyte phenotype loss, apoptosis and metalloproteinase (MMP) activity (Rahmati et al., 2016). Leptin (800 nM), alone or in combination with IL-1β, also induced the expression of COX-2 and the production of PGE2, IL-6, and IL-8 in cartilage explants of OA patients and human primary chondrocytes (Vuolteenaho et al., 2009; Gomez et al., 2011), revealing that leptin contributed to the pro-inflammatory environment of OA cartilage. It was also demonstrated that leptin (500 ng/ml) enhanced IL-6 production, mediated by chondrocyte-synovial fibroblast cross-talk, in OA patients (Pearson et al., 2017). Moreover, leptin modulated the production of inflammatory mediators by immune cells. In particular, the production of IL-6, IL-8, and CCL3 were increased by leptin in CD4+ T cells from OA patients, but not from healthy subjects (Scotece et al., 2017); thus, demonstrating new insights into the role of leptin in the immune system and OA pathophysiology.

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 (Bao et al., 2010; Koskinen et al., 2011; Hui et al., 2012). MMP-2 (72 kDa type IV collagenase), MMP-9, and disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) 4 and ADAMTS5, were also increased by leptin, while fibroblast growth factor 2 and proteoglycan were down-regulated (Bao et al., 2010; Conde et al., 2011b). Leptin (800 nM) can perpetuate the cartilage-degradation processes due to induction of VCAM-1, an adhesion molecule responsible for leukocyte and monocyte chemotaxis and infiltration to inflamed joints, via JAK2 and PI3K pathways in chondrocytes (Conde et al., 2012; Vestweber, 2015). SOCS-3 was pointed as a regulator of leptin-induced expression of MMP-1, -3, and -13, and pro-inflammatory mediators IL-6, NO and COX-2 (Koskinen-kolasa et al., 2016). Additionally, leptin increased the production of other adipokines, namely lipocalin-2, by human cultured chondrocytes (Conde et al., 2011a).

MicroRNAs, small single-stranded non-coding segments of RNA, are increasingly recognized as regulatory molecules involved in disease processes, including OA, inflammation, and obesity (Marques-Rocha et al., 2015; Deiuliis, 2016; Nugent, 2016). miR-27 was found to be decreased in OA chondrocytes and to directly targeted the 3′-untranslated region of leptin (Zhou et al., 2017). Furthermore, the injection of OA rats with miR-27 lentiviral overexpression vector resulted in decreased levels of IL-6 and -8, as well as MMP-9 and -13, thus indicating the protective action of miR-27 in OA, possibly by targeting leptin.

Chondrogenic progenitor cells as cartilage seed cells are crucial to maintain cartilage homeostasis and replace damaged tissue (Seol et al., 2012). Leptin (50 ng/ml) can reduce CPCs migratory ability and their chondrogenic potential, and augment CPCs osteogenic transformation, hence changing CPC differentiation fate (Zhao et al., 2016). CPC cell cycle arrest and senescence are also induced by leptin (Zhao et al., 2016). Furthermore, leptin influenced the regulation of bone metabolism through induction of abnormal osteoblast function, which is associated to joint destruction in OA patients (Findlay and Atkins, 2014; Conde et al., 2015). The augmented production of leptin by OA subchondral osteoblasts is related with in vitro elevated levels of alkaline phosphatase, osteocalcin, collagen type 1, and TGF-β1, all being responsible for dysregulated osteoblast function (Mutabaruka et al., 2010). Additionally, bone morphogenic protein (BMP)-2 is increased in leptin-stimulated human primary chondrocytes (Chang et al., 2015). Leptin also suppressed bone formation in vivo (Ducy et al., 2000), but there are some discrepancies with in vitro results.

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 (McInnes, 2011; Smolen et al., 2016). Evidencing the crucial role of immune system in RA pathology, RA-associated synovitis comprises both innate immune cells (like monocytes, DCs, and mast cells) and adaptive immune cells (like Th1, Th17, and B cells) (McInnes, 2011; Smolen et al., 2016). As described above, leptin modulates neutrophils chemotaxis, activates proliferation and phagocytosis of monocytes and/or macrophages, regulates NK cytotoxicity, induces proliferation of naïve T cells, promotes Th1 cell immune response and down-regulates Th2 cell immune response. Moreover, leptin modulates the activity of Treg cells, which are potent inhibitors of autoimmunity, thus having a potential implication in RA pathophysiology (Toussirot et al., 2015).

Several studies have found a positive correlation between serum and synovial leptin levels and RA pathology (Otero et al., 2006; Targońska-Stępniak et al., 2008; Yoshino et al., 2011; Olama et al., 2012), but there are controversial results (Anders et al., 1999; Popa et al., 2005; Hizmetli et al., 2007; Oner et al., 2015). Differing results may be due to the relatively small sample size, inconsistency of the baseline characteristics of participants (age, race, disease duration, BMI, …), co-existence of other auto-immune diseases, employment of different methods to measure leptin levels in RA patients, or underlying patients treatments that intervene with the endocrine system. The present consensus is that leptin levels are elevated in RA patients, and serum and synovial fluid levels of leptin were associated with disease duration and parameters of RA activity (Olama et al., 2012; Lee and Bae, 2016), although large cohorts studies are necessary. Experimental animal models of arthritis had demonstrated the leptin action in joint inflammation. In particular, compared with control mice, leptin-deficient mice presented a less severe antigen-induced arthritis, decreased levels of TNF-α and IL-1β in knees synovium, and an impaired antigen-specific T cell proliferative response with lower IFN-γ and higher IL-10 production, which indicates a shift toward Th2 cell response (Busso et al., 2002). Accordingly, injection of leptin (5 μg) into the knee joint of collagen-immunized mice augmented arthritis severity, accompanied by elevated synovial hyperplasia and joint damage through enhancement of Th17 cell response (Deng et al., 2012). In fact, clinical trials using a humanized anti-IL-17 monoclonal antibody added to oral disease-modifying anti-rheumatic drugs, demonstrated improved signs and symptoms of RA, indicating the therapeutic potential of IL-17-directed strategies (Genovese et al., 2010).

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 (Fraser et al., 1999). Amidst the possible therapeutic approaches to antagonize leptin actions in RA, are leptin mutants with antagonist activity, and monoclonal antibodies against human LEPR or leptin itself (Tian et al., 2014). Interestingly, clinical studies evaluating the effect of drug modulators of insulin sensitivity (affected by leptin levels as described above), such as PPARγ agonists, are ongoing to provide new potential treatment to improve the inflammatory status and cardiovascular outcome in RA patients (Chimenti et al., 2015). Further understanding of leptin mechanisms would be of utmost importance for RA treatment.

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 (Gatto et al., 2013; Liu and La Cava, 2014).

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 (Li H.M. et al., 2016), recently, a meta-analysis of eighteen studies determined that serum/plasma leptin levels were significantly elevated in SLE patients (Lee and Song, 2018). Furthermore, leptin has been suggested as a player that affects the cardiovascular risk in SLE patients. Accordingly, leptin and HFD induced proinflammatory high-density lipoproteins and atherosclerosis in BWF1 lupus-prone mice, and leptin levels were correlated with BMI, disease activity index (SLEDAI), as well as insulin and CRP levels, all CVD risk factors, in SLE patients (Xu W.D. et al., 2014).

The role of leptin in SLE development has been investigated using leptin-deficient (ob/ob) mice treated with lupus-inducing agent (Lourenço et al., 2016). Leptin deficiency protected mice from the development of autoantibodies as well as renal disease, and elevated the levels of Treg cells, compared with wild-type controls. Moreover, in (NZBxNZW)F1 lupus-prone mice, leptin administration accelerated the development of autoantibodies and renal disease, while leptin antagonism delayed disease progression (Lourenço et al., 2016). At cellular level, leptin promoted Th1 responses in human CD4+ T cells and in lupus-prone mice via RORγ transcription, whereas leptin neutralization inhibited Th17 responses in autoimmune-prone mice (Yu et al., 2013). Additionally, fasting induced hypoleptinemia or leptin-deficient mice demonstrated decreased levels of Th17 and elevated levels of Treg cells (Liu et al., 2012). In SLE, apoptotic cells represent the major source of self antigens that promote and fuel autoimmune responses. Leptin promoted T cell survival and proliferation of autoreactive T cells in mice with an autoreactive T cell repertoire, including (NZBxNZW)F1 lupus-prone mice (Amarilyo et al., 2013). Leptin also promoted phagocytosis of apoptotic cells by macrophages in lupus-prone mice, which increase the availability of apoptotic-derived antigens to T cells and subsequent development of self-antigen-reactive T cells (Amarilyo et al., 2014).

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.