REVIEW
published: 01 June 2018
doi: 10.3389/fphys.2018.00640
Obesity, Fat Mass and Immune
System: Role for Leptin
Vera Francisco 1* † , Jesús Pino 1† , Victor Campos-Cabaleiro 1 , Clara Ruiz-Fernández 1 ,
Antonio Mera 2 , Miguel A. Gonzalez-Gay 3 , Rodolfo Gómez 4 and Oreste Gualillo 1
1
The NEIRID Group (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), Servizo Galego de Saude
and Instituto de Investigación Sanitaria de Santiago, Santiago University Clinical Hospital, Santiago de Compostela, Spain,
2
Servizo Galego de Saude, Division of Rheumatology, Santiago University Clinical Hospital, Santiago de Compostela, Spain,
3
Epidemiology, Genetics and Atherosclerosis Research Group on Systemic Inflammatory Diseases, Hospital Universitario
Marqués de Valdecilla, Universidad de Cantabria and IDIVAL, Santander, Spain, 4 Musculoskeletal Pathology Group, Servizo
Galego de Saude and Instituto de Investigación Sanitaria de Santiago, Santiago University Clinical Hospital, Santiago de
Compostela, Spain
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
*Correspondence:
Vera Francisco
vlgfrancisco@gmail.com
† These authors have contributed
equally to the realization of this work.
Specialty section:
This article was submitted to
Integrative Physiology,
a section of the journal
Frontiers in Physiology
Received: 18 December 2017
Accepted: 11 May 2018
Published: 01 June 2018
Citation:
Francisco V, Pino J,
Campos-Cabaleiro V,
Ruiz-Fernández C, Mera A,
Gonzalez-Gay MA, Gómez R and
Gualillo O (2018) Obesity, Fat Mass
and Immune System: Role for Leptin.
Front. Physiol. 9:640.
doi: 10.3389/fphys.2018.00640
Frontiers in Physiology | www.frontiersin.org
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.
Keywords: adipokines, adipose tissue, immunometabolism, leptin, metabolism, rheumatic diseases, rheumatoid
arthritis, Type 2 diabetes mellitus (T2DM)
Abbreviations: ADAMTS, a disintegrin and metalloproteinase with thrombospondin motifs; AMPK, adenosine
monophosphate-activated protein kinase; Arg-1, arginase-1; BMDM, bone marrow-derived macrophages; BMI, body
mass index; cAMP, cyclic adenosine monophosphate; CCL, CC-chemokine ligand; CD, cluster of differentiation; COX-2,
cyclooxygenase-2; CPCs, chondrogenic progenitor cells; CRP, C-reactive protein; DAMPs, damage-associated molecular
patterns; DCs, dendritic cells; ERK, extracellular signal-regulated kinase; GLUT, glucose transporter; HFD, high-fat diet;
HLA-DR, human leukocyte antigen-antigen D related; HSC, hepatic stellate cell; ICAM, intercellular adhesion molecule;
IFNγ, interferon γ; IL, interleukin; iNOS, inducible nitric oxide synthase; IPFP, intrapatellar fat pad; IRS, insulin receptor
substrate; JAK, Janus kinase; JNK, c-jun N-terminal kinase; KC, kupffer cells; LEPR, leptin receptor; LPL, lipoprotein lipase;
LPS, lipopolysaccharide; MAPK, mitogen-activated protein kinase; MCP-1, monocyte chemoattractant protein 1; MEK,
mitogen-activated protein kinase kinase; MIP-1α, macrophage inflammatory protein-1 alpha; miRNA, microRNA; MMPs,
matrix metalloproteinases; NAFLD, non-alcoholic liver disease; NASH, non-alcoholic steatohepatitis; NF-κB, nuclear factorκB; NO, nitric oxide; NOS2, nitric oxide synthase 2; OA, osteoarthritis; PAMPs, pathogen-associated molecular patterns;
PGE2, prostaglandin E2; PI3K, phosphoinositide 3-kinase; PKC, protein kinase C; PMA, phorbol myristate acetate; PMNs,
human polymorphonuclear neutrophils; PPARα, peroxisome proliferator-activated receptor alpha; RA, rheumatoid arthritis;
RORγt, retinoic acid-related orphan receptor gamma t; ROS, reactive oxygen species; SLE, systemic lupus erythematosus;
SREBP-1c, sterol regulatory element-binding protein-1c; STAT, signal transducer and activator of transcription; T2DM, type
2 diabetes mellitus; TGF-β, transforming growth factor; Th, T helper cells; TLR, toll-like receptor; TNF-α, tumour necrosis
factor-α; Treg, T regulatory cells; VAT, visceral adipose tissue; VCAM, vascular cell adhesion molecule; WAT, white adipose
tissue.
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Leptin in Immune System Disorders
system, evoking leptin as a crucial linker of neuroendocrine and
immune systems (Carlton et al., 2012; Procaccini et al., 2017).
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.
INTRODUCTION
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 (Zhang et al.,
2014). Adipose tissue, initially considered as a simple energy
storage tissue, is now recognized as an active endocrine organ and
a bona fide immune organ, constituted not only by adipocytes
but also by fibroblasts, endothelial cells and a wide array of
immune cells (adipose tissue macrophages, neutrophils, mast
cells, eosinophils, T and B cells that maintains tissue homeostasis
in lean individuals (Huh et al., 2014; Vieira-Potter, 2014). The
adipocyte expansion caused by positive energy balance leads to
adipocyte hypoxia, apoptosis, and cell stress, ultimately resulting
in the expression of chemoattractant molecules and infiltration
of inflammatory cells (Vieira-Potter, 2014). The obese adipose
tissue is also characterized by a markedly deregulated production
of adipose tissue-derived factors, i.e., adipokines, a growing
family of low molecular weight, biologically active proteins
with pleiotropic functions (Al-Suhaimi and Shehzad, 2013).
Adipokines are crucial players not only in energy metabolism
but also in inflammation and immunity, most of them being
increased in obesity and contributing to the associated ‘low-grade
inflammatory state’ (Tilg and Moschen, 2006).
Leptin was discovered in 1994 by the group of Jeffrey
Friedman (Zhang et al., 1994) and is the best-characterized
member of adipokine family. Encoded by LEP gene (the human
homolog of murine ob gene), leptin is a 16 kDa non-glycosylated
protein mainly produced by adipocytes, but also by skeletal
muscle, intestine, brain, joint tissues and bone (Scotece et al.,
2014). This adipokine exerts its physiological activity through
its receptor (LEPR or Ob-R), a class I cytokine receptor family
from diabetes (db) gene (Münzberg and Morrison, 2015). There
are at least six LEPR isoforms that differ in the length of the
cytoplasmic domain: a soluble isoform, four short isoforms, and
a long isoform, which has the full intracellular domain that allows
the transduction of leptin signal via JAK and STAT signaling
pathways (Frühbeck, 2006). Alternatively to canonical JAK/STAT
pathway, LEPR could activate ERK 1/2, p38 MAPK, JNK, PKC,
and PI3K/Akt pathways (Zhou and Rui, 2014) (Figure 1).
This hormone, together with other regulatory molecules, has
a central role in appetite and body weight homeostasis
by inducing anorexigenic factors (as cocaine-amphetaminerelated transcript) and suppressing orexigenic neuropeptides (as
neuropeptide Y) on hypothalamus (Al-Suhaimi and Shehzad,
2013; Rosenbaum and Leibel, 2014). Therefore, central leptin
resistance, caused by impairment of leptin transportation, leptin
signaling and leptin target neural circuits, is considered the
main risk factor for the obesity pathogenesis.(Al-Suhaimi and
Shehzad, 2013; Rosenbaum and Leibel, 2014). Interestingly,
leptin release is modulated in a circadian rhythm manner, which
has been correlated with sweet taste recognition (Nakamura et al.,
2008). Moreover, leptin also affects other physiological functions,
namely bone metabolism, inflammation, infection and immune
responses (Scotece et al., 2014) (Figure 2). Accordingly, LEPR
is expressed in across the cells of innate and adaptive immune
Frontiers in Physiology | www.frontiersin.org
LEPTIN AND IMMUNOMETABOLISM
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
(Kavak et al., 2015), RA (Ajeganova et al., 2013), and psoriasis
(Duarte et al., 2013). On the other hand, malnutrition/starvation
has been long related to increased susceptibility to infectious
diseases (Taylor et al., 2013; Jones et al., 2014). These observations
bring out immune response as a highly energy-dependent
biological process that is dependent on an adequate food
intake and metabolism. In fact, a recent article critically discuss
the correlation between autoimmunity and overnutrition or
metabolic pressure (De Rosa et al., 2017). At the interface of
the historically distinct fields of immunology and metabolism,
immunometabolism has emerged as a new research discipline
(Mathis and Shoelson, 2011). In the last years, it has been
evidenced that metabolic status of immune cells directly
determines their function and differentiation, thus affecting
immunity and tolerance, as well as the failure of the immune
response in autoimmune pathologies (Gaber et al., 2017).
In fact, innate and adaptive immune cells adapt to altered
tissue microenvironment, characterized by hypoxia and nutrient
competition, by reprogramming their metabolism (Gaber et al.,
2017), and failure in this metabolic reconfiguration ultimately
leads to a deregulated immune response and pathology (Gaber
et al., 2017).
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 (Matarese et al., 2010). In malnutrition, altered T cell
function and metabolism was associated with decreased leptin
levels (Cohen et al., 2017). Leptin and LepR-deficient mouse
models presented augmented number and activity of Treg cells
together with a resistance to autoimmune diseases, and leptin
replacement rescues Treg cell levels to wild-type mice values
(Matarese et al., 2010). Accordingly, human T cell activation and
production of cytokines can be induced after incubation with
10 ng/mL exogenous leptin following nutritional rehabilitation
(Rodríguez et al., 2007). Furthermore, the central effect of leptin
on the hypothalamus is mediated, at least in part, by inhibition
of hypothalamic-pituitary-adrenal axis and activation of the
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Leptin in Immune System Disorders
FIGURE 1 | 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.
sympatho-adrenal axis, having the sympathetic nervous system
a function in the central control of the immune system (PérezPérez et al., 2017). Moreover, most immune cells express LEPR
at their surface, which evokes a straight action of leptin in the
modulation of the immune response (Procaccini et al., 2017).
cytokine for neutrophils. At 500 nM, leptin delayed the cleavage
of Bid and Bax, mitochondrial release of cytochrome C and
second mitochondria-derived activator of caspase, as well as the
activation of caspase-3 and caspase-8 (Bruno et al., 2005). PI3K,
NF-κB, and MAPK pathways were involved in the anti-apoptotic
activity of leptin in human neutrophils in vitro (Bruno et al., 2005;
Sun et al., 2013). Additionally, leptin (250 ng/ml) stimulated
the release of oxygen radicals, such as superoxide anion and
hydrogen peroxide, by PMNs (Caldefie-Chezet et al., 2001, 2003).
There is strong evidence for an effect of leptin on neutrophil
chemotaxis and infiltration. Leptin (50 ng/ml) mediated the
migration of human neutrophils in vitro, through activation of
p38 MAPK and Src kinases (Montecucco et al., 2006), and by
indirect mechanisms via TNF-α released by monocytes (CaldefieChezet et al., 2001; Zarkesh-Esfahani et al., 2004), having no
secretagogue properties (no detectable [Ca2+ ]i mobilization,
oxidant production, or β2-integrin upregulation) (Montecucco
et al., 2006). Otherwise, leptin inhibits neutrophil chemotaxis to
classical chemoattractants, like interleukin (IL)-8 (Montecucco
et al., 2006). Murine neutrophils with Q223R LEPR mutation
had reduced chemotaxis toward leptin (Naylor et al., 2014), while
LEPTIN AND INNATE IMMUNITY
(FIGURE 3)
Granulocytes (Neutrophils, Eosinophils,
and Basophils)
Human polymorphonuclear neutrophils express LEPR (CaldefieChezet et al., 2001), but only the short-form (Ob-Ra) was been
detected (Zarkesh-Esfahani et al., 2004). Although the short-form
of LEPR lacks most of the intracellular domain of the receptor,
it is enough to signal through MAPK pathways, enhancing CD
11b expression and preventing apoptosis, but not through JAKSTAT pathways as long-form of LEPR (Bjorbaek et al., 1997;
Zarkesh-Esfahani et al., 2004). Leptin is likely to act as a survival
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FIGURE 2 | 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).
neutrophils from human volunteers and wild-type C57BL/6 mice
migrated toward leptin in a dose-dependent manner, requiring
JAK2/PI3K signaling (Ubags et al., 2014). Nevertheless, one study
found that physiological concentrations of leptin (1–100 ng/ml)
do not affect human neutrophils, and high leptin concentrations
induced survival and changes in neutrophils proteome, but
no effect on chemotaxis was observed (Kamp et al., 2013).
In vivo studies clarified the effect of leptin in neutrophils. It was
observed that neutrophil populations were enhanced in rats with
high-fat-diet induced obesity, compared with control diet rats
(do Carmo et al., 2013), and neutrophils from obese subjects
displayed elevated superoxide release and chemotactic activity
(Brotfain et al., 2015). Furthermore, leptin administration (50 µg)
increased pulmonary neutrophilia in Escherichia coli pneumonia
murine model as well as in healthy mice (Ubags et al., 2014).
Alike neutrophils, both human eosinophils and basophils
expressed LEPR on the cell surface (Bruno et al., 2005; Suzukawa
et al., 2011). In eosinophils, leptin (50 ng/ml) enhanced the
release of pro-inflammatory cytokines IL-1β and IL-6, and
chemokines IL-8, growth-related oncogene-α and MCP-1 (Wong
et al., 2007). It also modulated the surface expression of adhesion
molecules; in particular, up-regulates ICAM-1 and CD18, and
suppress ICAM-3 and L-selectin (Wong et al., 2007). Treatment
of human eosinophils with recombinant leptin in vitro delayed
Frontiers in Physiology | www.frontiersin.org
apoptosis via JAK, NF-κB, and p38 MAPK signaling pathways,
suggesting leptin as a survival cytokine (Wong et al., 2007),
similar to neutrophils (Bruno et al., 2005). Furthermore, leptin
also stimulated chemokinesis (Wong et al., 2007) and enhanced
chemotactic migration of eosinophils isolated from human
peripheral blood, in a dose-dependent manner, however, the
underlying mechanisms remain unclear (Kato et al., 2011). In
obese individuals, eosinophils demonstrated greater adhesion
and chemotaxis toward eotaxin and RANTES (CCL5), compared
with non-obese healthy volunteers (Grotta et al., 2013).
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 (Suzukawa et al., 2011). Moreover,
leptin is a survival-enhancing factor of human basophils, as
aforementioned for eosinophils and neutrophils. Although leptin
was a weak effect on direct induction of basophil degranulation,
it potently primed basophils for enhanced degranulation in
response to aggregation of IgE or its high-affinity receptor FcεRI
(Suzukawa et al., 2011).
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.
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Leptin in Immune System Disorders
FIGURE 3 | 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.
Monocytes and Macrophages
oxide (Dixit et al., 2003), and pro-inflammatory cytokines,
namely TNF-α, IL-6, IL-1β, and resistin (Tsiotra et al., 2013;
Scotece et al., 2014; Inzaugarat et al., 2017). By contrast, it was
reported that 1 µg/ml leptin had no effect on IL-1β secretion
but enhanced IL-18 in the THP-1 murine monocytic cell line.
These apparent discrepancies could be species-specific (human
vs. murine cells) and/or leptin treatment-dependent (1 µg/ml
for 24 h vs. 1 µg/ml for 3 h). Additionally, recombinant leptin
increased the expression of TLR2, but not TLR4, in human
monocytes (Jaedicke et al., 2013).
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 (Najib and Sánchez-Margalet, 2002). Leptin (2 nM)
stimulated the oxidative burst in monocytes (Sánchez-Pozo
et al., 2003), and increased LPL expression through oxidative
stress- and PKC-dependent pathways (Maingrette and Renier,
2003). Moreover, leptin promoted the phagocytosis of apoptotic
cells by macrophages from lupus mice, via modulation of
cAMP levels (Amarilyo et al., 2014). Leptin also promoted a
Both isoforms of LEPR are expressed in PBMCs, being lower
in cells from obese individuals compared with lean subjects
(Tsiotra et al., 2000). Functional LEPR was also expressed in
macrophages (O’Rourke et al., 2001). The effect of leptin on
monocytes and macrophages has been well-established since its
first evidence in Santos-Alvarez et al. (1999). Leptin promoted
the proliferation of human circulating monocytes in vitro as
well as its activation through induction of TNF-α and IL-6
production, and stimulation of surface markers, namely CD25,
HLA-DR, CD38, CD71, CD11b, CD11c, and CD16 (SantosAlvarez et al., 1999; Cannon et al., 2014). Moreover, leptin
potentiated the stimulatory effect of LPS or PMA on human
monocytes (Santos-Alvarez et al., 1999), and increased CCLs
in cultured murine macrophages, being JAK2-STAT3 signaling
pathway involved (Kiguchi et al., 2009). Leptin (625 nM) also
augmented the production of several inflammatory mediators
in monocytes/macrophages, such as interleukin 1 receptor
antagonist (IL-1Ra) (Gabay et al., 2001), interferon-c-inducible
protein (Meier et al., 2003), leukotrienes (Mancuso, 2004), nitric
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Leptin in Immune System Disorders
of leptin, suggesting a novel mechanism for this biological
drug. Further mechanistic studies focused on the leptin
pathway could have potential therapeutic action in common
obesity-related complications of psoriasis (Voloshyna et al.,
2016). The establishment of LepR-deficient macrophage cell
line DB-1, derived from differentiated bone marrow cells
of Lepr-knockout mice, provide a powerful tool to study
the role of leptin and its receptor in obesity-associated
inflammation and immune system deregulation (Dib et al.,
2016).
defensive environment against Leishmania donovani infection by
induction of macrophage phagocytic activity and intracellular
ROS generation (Dayakar et al., 2016). Accordingly, macrophages
from knocked-out LepR Tyr 985 mice presented reduced
phagocytosis and killing activity of Klebsiella pneumoniae that
was associated with diminished ROS production (Mancuso et al.,
2012). It has been demonstrated that leptin-mediated protein
radical formation, tyrosine nitration and activation of KCs are
caused by peroxynitrite formation, which exacerbated NASH in
diet-induced obese mice (Chatterjee et al., 2013). Concerning
to chemoattractive activity, it was verified that leptin induced
in vitro chemotactic responses for monocytes and macrophages
(Curat et al., 2004; Gruen et al., 2007), via intracellular calcium
influx, JAK/STAT, MAPK and PI3K pathways (Gruen et al.,
2007). However, it has been reported that hematopoietic LEPR
deficiency in mice did not change macrophage accumulation in
WAT after diet-induced obesity versus wild-type mice (Gutierrez
and Hasty, 2012). Likely, compensatory in vivo effects of
other cytokines (like IL-1 or TNF-α) present in WAT could
occur in obese individuals and which are absent in in vitro
assays.
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 (Acedo et al., 2013).In macrophages,
leptin also triggered catecholamine-dependent increases
in cAMP-histone deacetylase 4 signaling pathway, that
reduced inflammation in adipose tissue (Luan et al., 2014).
Additionally, leptin increased the expression of LEPR in M2
macrophages and stimulated IL-8 expression via p38 and ERK
signaling pathways (Cao et al., 2016). In tumor-associated
macrophages, leptin induced the expression of IL-18 via
NF-kB, possible contributing to tumor progression (Li K. et al.,
2016).
Macrophages are indirectly regulated by leptin through
mast cells (Zhou et al., 2015). In particular, leptin expression
was reduced in both human and mouse mast cells from
lean adipose tissue compared with obese individuals. Leptin
deficiency led to the anti-inflammatory activity of mast cells
and, consequently, to a shift in macrophage polarization from
M1 to M2; in vitro co-cultures of mast cells with BMDM
increased IL-4-mediated arginase-1 and IL-10 expression,
and suppressed LPS-mediated iNOS and IL-6 expression
(Zhou et al., 2015). Furthermore, reduction of mast cells in
leptin-deficient ob/ob mice exacerbated obesity and diabetes,
indicating an important role of mast cells in obesity-related
inflammation through its reactivity to leptin levels (Zhou et al.,
2015).
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 (Voloshyna et al., 2016).
However, only ustekinumab was able to increase the expression
Frontiers in Physiology | www.frontiersin.org
NK Cells
The role of leptin in regulating NK cell development and
activation was first verified in obese Lepr-deficient (db/db)
mice, which showed decreased NK cell function (Tian et al.,
2002). In this animal model, the population of NK cells in
bone marrow was impaired through an increase in apoptotic
rate, and recombinant leptin (200 ng/ml) significantly enhanced
the survival of immature NK cells from wild-type mice via
modulation of Bcl-2 and Bax gene expression (Lo et al.,
2009). Furthermore, leptin administration (500 µg/kg) led to
a higher activity of NK cells in lean animals (Nave et al.,
2008). Consistently, human NK cells expressed functional
long- and short-form of LEPR that influenced NK cell
cytotoxicity through STAT3 activation and, consequently,
transcription of genes encoding IL-2 and perforin (Zhao et al.,
2003).
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 in vitro. Short-term stimulation of
human NK cells with leptin (50 nM) raised the secretion
of IFNγ and cytotoxicity (Wrann et al., 2012; Laue et al.,
2015). By contrast, long-term exposure to leptin decreased
NK cell proliferation and immune function (Wrann et al.,
2012). Obesity is partially characterized by a state of
long-term, highly elevated leptin exposure, and NK cells
from obese animals were significantly resistant to leptin
stimulation (Nave et al., 2008), which could explain the
functional desensitization of NK cells after long-term
exposure. Accordingly, exposure of NK-92 human cell
line to hyperleptinemia (similar to that observed in obese
individuals) led to metabolic activation of NK-92 cells after
24 h, but there is a reduction of cell metabolism after 96 h
(Lamas et al., 2013). Furthermore, obese individuals have
lower NK function compared to lean individuals (Laue et al.,
2015) and, after weight loss, the decrease of plasma leptin
levels is accompanied by a restoration of IFNγ production
by NK cell (Jahn et al., 2015; Bähr et al., 2017; Favreau et al.,
2017).
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
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Leptin in Immune System Disorders
immunopotentiator in vaccination protocols employing ex vivo
generated autologous DCs.
and NK cell development and function, as well as the potential
implications in obesity.
Dendritic Cells
LEPTIN AND ADAPTIVE IMMUNITY
(FIGURE 3)
Human DCs, both immature and mature DCs, present functional
active LEPR with the capacity to signal STAT-3 phosphorylation
(Mattioli et al., 2009). Leptin (10 nM) acted as an activator of
human DCs, evidenced by up-regulation of IL-1β, IL-6, IL-12,
TNF-α and MIP-1α production, improvement of immature DCs
migration (Mattioli et al., 2008; Al-Hassi et al., 2013) and their
chemotactic responsiveness, licensing them toward Th1 priming
(Mattioli et al., 2008). Moreover, leptin treatment promoted DC
survival through decreased apoptosis via activation of NF-κB and
PI3K-Akt signaling pathways, with a parallel increase of bcl-2 and
bcl-xL gene expression (Lam et al., 2006; Mattioli et al., 2009).
Lepr-deficient db/db mouse bone marrow culture displayed
a reduced number of DCs, attributable to dysregulation of Bcl2 genes and a consequent increase of apoptosis (Lam et al.,
2006). Moreover, DCs from db/db mice possessed markedly
reduced expression of co-stimulatory molecules and a Th
2-type cytokine profile, with a poor capacity to stimulate
allogeneic T cell proliferation (Lam et al., 2006). Consistently,
db/db DCs demonstrated down-regulation of PI3K/Akt and
STAT-3 pathways (Lam et al., 2006). Lep-deficient ob/ob mice
presented a reduced expression of DC maturation markers
(CD40, CD80, and CD86), decreased production of inflammatory
cytokines (IL-12, TNF-α, and IL-6), and augmented TGF-β
production, but ob/ob mice-derived DCs were more efficient in
inducing Treg or Th17 cells than wild-type animals (MoraesVieira et al., 2014). In DCs from ob/ob mice, leptin deficiency
resulted in defective antigen presentation function toward
Leishmania donovani, which was not reversed by leptin treatment
(Maurya et al., 2016). Conversely, one report verified no
changes in the phenotype, activation, antigen processing or
presentation of DCs from leptin-knockout mice, but these cells
showed an enhanced ability to activate T cells, suggesting that
leptin may dampen T-cell responsiveness in the physiological
context (Ramirez and Garza, 2014). Diet-induced obesity in
mice fed with HFD results in an elevation of serum leptin
levels and splenic CD11c+ DCs, with diminished DC cell
stimulatory capacity, being these effects distinct from that
caused by HFD alone in obese-resistant mice (Boi et al.,
2016).
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 ex vivo,
exposed to antigens and induced to mature in the presence of
adjuvants. Then, the mature DCs are injected into the patient
and migrate to the lymph nodes to present antigens to T cells.
Thus, the modulation of DCs maturation and activity by leptin
is of most importance considering a potential application of
leptin in immunotherapeutic approaches and as novel adjuvant
Frontiers in Physiology | www.frontiersin.org
The role of leptin in adaptive immunity has first evidenced
working with ob/ob and db/db mice, which showed thymus
atrophy, T-cell lymphopenia, and impaired delayed-type
hypersensibility (Lord et al., 1998; Howard et al., 1999; Matarese,
2000). Moreover, chronic leptin administration (1 µg/g body
weight) reversed immunosuppressive status and thymic atrophy
of ob/ob mice (Lord et al., 1998, Nature; Howard et al., 1999,
J. Clin. Inv.). Since then, the role of leptin in T and B cell
populations have been extensively studied.
T Cells
T lymphocytes expressed the long form of LEPR (higher
in peripheral CD4+ than in CD8+ T cells) (Lord et al.,
1998; Kim et al., 2010), with signaling capacity to activate
JAK-STAT pathway (Sanchez-Margalet and Martin-Romero,
2001). Consequently, leptin modulated cell proliferation,
responsiveness, and polarization of T cells. Leptin dosedependently promoted the proliferation of human naïve
(CD45RA+) CD4+ T cells, whereas it minimally affected
memory (CD45RO+) CD4+ T cells proliferation (Lord et al.,
1998, 2002). Additionally, morbidly obese children, who were
congenitally deficient in leptin, presented a decreased number of
circulating CD4+ T cells, as well as impaired T cell proliferation
and cytokine release, which were reversed by administration
of recombinant human leptin (Farooqi et al., 2002). Moreover,
leptin inhibited autophagy in human CD4+CD25− conventional
T cells via mTOR pathway (Cassano et al., 2014), which emerged
as the potential link between immunity and nutritional status
(Procaccini et al., 2012).
T Helper 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) (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
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Leptin in Immune System Disorders
2016). Leptin regulated glucose metabolism partly by upregulation 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.
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).
T Regulatory Cells (Treg)
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 hypoxiainduced 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.,
Frontiers in Physiology | www.frontiersin.org
B Cells
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 (Busso et al., 2002).
Accordingly, db/db and ob/ob presented a reduced number of
peripheral blood and bone marrow B lymphocytes, which was
recovered after leptin treatment (Bennett et al., 1996; Claycombe
et al., 2008). Conversely, db/db mice presented an increased
absolute number of B cells in the peritoneal cavity (Jennbacken
et al., 2013), and the increase of leptin was correlated with a
decrease in B cells of mice with unbalanced diets (carbohydraterich and fat-rich) (Martínez-Carrillo et al., 2015). Thus, further
investigation is needed to better clarify the role of leptin in
lymphopoiesis. Leptin promoted B cell homeostasis through
inhibition of apoptosis and induction of cell cycle entry via Bcl-2
and cyclin D1 activation (Lam et al., 2010). Furthermore, leptin
dose-dependently activated human peripheral blood B cells,
inducing the secretion of pro-inflammatory cytokines, namely
TNF-α and IL-6, and the anti-inflammatory cytokine IL-10, via
JAK-STAT and p38MAPK-ERK1/2 signaling pathways (Agrawal
et al., 2011). Likewise, leptin (50 ng/ml) activated and induced
the production of higher amounts of TNF-α, IL-6, and IL-10 by B
cells from aged subjects compared to young individuals (Gupta
et al., 2013), which is associated with leptin-mediated STAT3
phosphorylation (Gupta et al., 2013; Frasca et al., 2016).
Leptin can also modulate B cell development – decrease proB, pre-B and immature B cells and increase mature B cellsin bone marrow of fasted mice, characterized by low serum
leptin levels (Tanaka et al., 2011). Leptin administration reversed
the starvation-induced lymphopenia of bone marrow B cells,
indicating an important role of central leptin in the immune
system (Tanaka et al., 2011; Fujita et al., 2012). Moreover, leptin
might regulate B cell activity in obesity (Nikolajczyk, 2010;
Frasca et al., 2016). In particular, B cells were described to
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Leptin in Immune System Disorders
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).
accumulate in murine VAT and to critically regulate T2DMassociated inflammation through activation of CD8+ and Th1
cells and release of pathogenic antibodies (Winer et al., 2011;
DeFuria et al., 2013).
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.
LEPTIN AND IMMUNE-METABOLIC
PATHOLOGIES
Leptin and Obesity-Associated
Metabolic Disorders
Obesity is associated with life-threatening co-morbidities,
including insulin resistance, T2DM, NAFLD and steatohepatitis
(NASH) (Lebovitz, 2003; Kamada et al., 2008; Klöting and
Blüher, 2014; Fasshauer and Blüher, 2015). Adipokines, in
particular leptin, mediate the crosstalk between adipose tissue
and metabolic organs (especially liver, muscle, pancreas and
central nervous system) (Cao, 2014). Thus, leptin has emerged
as a significant pathological component in the development of
metabolic disorders (DePaoli, 2014).
Non-alcoholic Fatty Liver Disease
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
Type 2 Diabetes Mellitus
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
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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.
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 thioacetamideinduced hepatic fibrosis was prevented in Zucker fa/fa rats, being
involved the activation of HSCs and expression of procollagenI 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
Frontiers in Physiology | www.frontiersin.org
Leptin in Rheumatic Diseases
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 (Figure 4).
Osteoarthritis
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 upregulation 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
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Leptin in Immune System Disorders
FIGURE 4 | 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.
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 miR27 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
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 NFκB, 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 cartilagedegradation 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
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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 collagenimmunized 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.
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
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-Ste˛pniak 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
Frontiers in Physiology | www.frontiersin.org
Systemic Lupus Erythematosus
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 lifethreatening 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
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Francisco et al.
Leptin in Immune System Disorders
therapeutic approaches (Otvos et al., 2011). Recombinant leptin
is already available for use in patients with leptin congenital
deficiency while the synthetic leptin analog metreleptin has been
approved for lipodystrophy treatment (Tchang et al., 2015).
Importantly, the development of antibodies that could crossreact with endogenous leptin and cause an effective leptindeficient state responsible for the loss of efficacy and infection
has become a significant concern (DePaoli, 2014). However,
given the pleiotropic action of leptin, a systematic approach
to modulate their levels and thus prevent obesity-associated
disorders might be, for the moment, unavailable. Instead,
strategies targeting leptin’s actions precisely and in specific
immune cell subpopulations, or targeting of specific receptor
isoforms, could be a potential viable option to add novel
therapeutic agents against immune-metabolic pathologies. It is
now clear that leptin is an important regulator of metabolic
status and influence inflammatory and immune responses in
several diseases. Nonetheless, leptin network is complex and
a lack of a full understanding of leptin’s immunomodulatory
mechanisms in almost all of the cells of immune system
and its potential side effects are still problems that need to
be figured out in drug discovery. Further insights into the
pathophysiological role of leptin in the immune system and
in obesity-associated disorders will be of great importance for
the development of novel therapeutic approaches for these
diseases.
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 lupusprone mice via RORγ transcription, whereas leptin neutralization
inhibited Th17 responses in autoimmune-prone mice (Yu et al.,
2013). Additionally, fasting induced hypoleptinemia or leptindeficient 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.
AUTHOR CONTRIBUTIONS
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.
CONCLUSION AND FUTURE OUTLOOK
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) (Zhang et al.,
2014). Therefore, it has become increasingly relevant to
disclose new clinical biomarkers and to develop innovative
therapeutic strategies for obesity-associated pathologies and
chronic inflammation.
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
Frontiers in Physiology | www.frontiersin.org
FUNDING
OG is Staff Personnel of Xunta de Galicia (Servizo Galego de
Saude, SERGAS) through a research-staff stabilization contract
(ISCIII/SERGAS). VF is a “Sara Borrell” Researcher funded by
ISCIII and FEDER. RG is a “Miguel Servet” Researcher funded
by Instituto de Salud Carlos III (ISCIII) and FEDER. OG, MG-G,
and RG are members of RETICS Program, RD16/0012/0014
(RIER: Red de Investigación en Inflamación y Enfermedades
Reumáticas) via Instituto de Salud Carlos III (ISCIII) and
FEDER. The work of OG and JP (PIE13/00024 and PI14/00016,
PI17/00409), and RG (PI16/01870 and CP15/00007) was funded
by Instituto de Salud Carlos III and FEDER. OG is a beneficiary of
a project funded by Research Executive Agency of the European
Union in the framework of MSCA-RISE Action of the H2020
Program (Project No. 734899). The funders had no role in study
design, data collection, and analysis, decision to publish, or
preparation of the manuscript.
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Leptin in Immune System Disorders
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Conflict of Interest Statement: The authors declare that the research was
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be construed as a potential conflict of interest.
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