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BRIEF REVIEWS |
* Gruppo di ImmunoEndocrinologia, Istituto di Endocrinologia e Oncologia Sperimenttale, Consiglio Nazionale delle Ricerche (IEOS-CNR), Napoli, Italy;
Department of Medicine, Division of Hematology/Oncology, Pittsburgh Cancer Institute, Pittsburgh, PA 15232; and
Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215
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Abstract |
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 Top Abstract IntroductionLeptin and leptin signaling...The role of leptin...Leptin and states of...Leptin, inflammation, and...Future directionsDisclosuresReferences |
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Introduction |
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TopAbstractIntroductionLeptin and leptin signaling...The role of leptin...Leptin and states of...Leptin, inflammation, and...Future directionsDisclosuresReferences |
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Immunity requires adequate and balanced energy supply for optimal function (2). Although the risk of infection and death is highest when energy reserves are not sufficient (3), obesity, a state of energy excess, has also been associated with increased susceptibility to infection, bacteremia, and poor wound healing (4).
The discovery of the adipocyte-derived hormone leptin, the levels of which reflect the amount of energy stored in the adipose tissue and are altered by conditions such as fasting and overfeeding, has proved to be fundamental to our understanding of the concept of energy availability influencing several physiological systems. More specifically, leptin has been shown to play an important role in the regulation of neuroendocrine function and energy homeostasis (5) and other energy-demanding physiological processes, such as reproduction (6), hemopoiesis (7), and angiogenesis (8). We review herein accumulating evidence that leptin may also be playing an important role in the regulation of the immune system in energy- or leptin-deficient states.
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Leptin and leptin signaling in immune cells |
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TopAbstractIntroductionLeptin and leptin signaling...The role of leptin...Leptin and states of...Leptin, inflammation, and...Future directionsDisclosuresReferences |
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helix bundle motif which is common to the IL-6
family of cytokines (11). Leptin receptor (ObR), is also a
member of the class I cytokine receptor superfamily and has at least
six isoforms as a result of alternative splicing. All isoforms share an
identical extracellular ligand-binding domain (12).
Leptin’s functional receptor (ObRb) is expressed not only in the
hypothalamus where it regulates energy homeostasis and neuroendocrine
function, but also in all cell types of innate and adaptive immunity
(13, 14, 15, 16). The full-length b isoform (ObRb)
lacks intrinsic tyrosine kinase activity, is involved in several
downstream signal transduction pathways, and has been identified in
immune cells of both animals and humans (13) (Fig. 1). Leptin binding to its functional
receptor recruits Janus tyrosine kinases and activates the receptor,
which then serves as a docking site for cytoplasmic adaptors such as
STAT (17). STATs translocate to the nucleus and induce
expression of other genes, including negative regulators, such as the
suppressor of cytokine signaling 3 (18) and the protein
tyrosine phosphatase 1B (19). A number of studies in human
PBMCs have shown that, in addition to the JAK-2-STAT-3 pathway,
which is an important pathway mediating leptin’s effect on immune
cells, other pathways are also involved. The MAPK, the insulin receptor
substrate 1, and the phosphatidylinositol 3'-kinase
(PI3'K)4 pathways
(20) are also important pathways that mediate leptin’s
action on immune T cells (21). Moreover, in PBMCs the MAPK
pathway seems to mediate antiapoptotic effects (22),
whereas the PI3'K pathway may be important in regulating glucose uptake
(23). Src associated in mitosis protein (Sam68), an
RNA-binding protein, regulator of RNA metabolism and effector of the
PI3'K is currently thought to function as an adaptor protein by binding
to activated STAT-3 and to the p85 subunit of PI3'K (20)
(Fig. 1).
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The role of leptin in innate and adaptive immunity |
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TopAbstractIntroductionLeptin and leptin signaling...The role of leptin...Leptin and states of...Leptin, inflammation, and...Future directionsDisclosuresReferences |
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Leptin has a well-established role in all cells involved in innate
immunity, which "inflexibly" senses either specific
pathogen-associated molecular patterns, formally not expressed by host
tissues, or endogenous molecules released from "stressed" cells. In
macrophages/monocytes, leptin up-regulates phagocytic
function (30) via phospholipase activation
(31) as well as proinflammatory cytokine secretion, such
as TNF- (early), IL-6 (late), and IL-12 (32, 33).
Leptin stimulates the proliferation of human circulating monocytes in
vitro and up-regulates expression of activation markers, such as CD25
(-chain of IL-2 receptor), CD71 (transferring receptor), CD69, and
CD38, while it further increases the expression of other activation
markers already present at high levels on the surface of resting
monocytes, such as HLA-DR, CD11b, and CD11c (28). In
polymorphonuclear cells of healthy subjects, leptin stimulates reactive
oxygen species production (16) and chemotaxis
(34) via a mechanism that may involve interaction with
monocytes (35). In NK cells, leptin is involved in all
processes of cell development, differentiation, proliferation,
activation, and cytotoxicity (36). The effect is mediated
at least via STAT-3 activation and up-regulated expression of perforin
and IL-2 genes (14).
The effect of leptin in adaptive immunity, which is mediated by lymphocytes that predominantly recognize peptide-MHC complexes and provides a broad range of immune responses against molecular structures other than carbohydrates in mice, is also well studied. Leptin may induce lymphopoiesis in mice (7), and leptin also provides a survival signal for the double-positive CD4+CD8+ and the single-positive CD4+CD8– thymocytes during T lymphocyte maturation (37).
Studies in humans have further delineated the role of leptin in
activation of lymphocytes. In contrast to macrophages/monocytes, leptin
alone is unable to induce proliferation and activation of mature human
peripheral blood lymphocytes unless it is coadministered with other
nonspecific immunostimulants, in which case leptin results in induction
of early (CD69) and late activation markers (CD25, CD71) in both
CD4+ and CD8+ lymphocytes (38).
The proliferative effect of leptin seems to be specific only for
distinct lymphocyte subpopulations, however. More specifically, leptin
induces proliferation of the naive CD4+CD45RA+
T cells, but inhibits proliferation of the
CD4+CD45RO+ T cells (39). At the
functional level, leptin polarizes Th cytokine production toward a
proinflammatory (Th1, IFN-
± IL-2) rather than
anti-inflammatory phenotype (Th2, IL-4) (13, 38).
These effects may be mediated by promoting T lymphocyte survival by
up-regulating expression of antiapoptotic proteins, such as
Bcl-xL (40) and T-bet (39), and
synergize with other cytokines in lymphocyte proliferation and
activation possibly via STAT3 (41, 42).
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Leptin and states of immune dysfunction: energy deficiency and energy excess |
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TopAbstractIntroductionLeptin and leptin signaling...The role of leptin...Leptin and states of...Leptin, inflammation, and...Future directionsDisclosuresReferences |
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In this context, we have recently shown that leptin administration to women with exercise-induced relative energy and leptin deficiency improves not only neuroendocrine but also immune function in the Th1 direction (46). Whether administration of leptin will be effective in enhancing Th1 responses or morbidity/mortality from other conditions that have long been associated with protein calorie malnutrition, such as tuberculosis, remains to be studied.
The role of leptin in regulating the immune system of obese subjects
who have a higher incidence of infections remains less well defined.
Leptin levels are increased and mRNA expression of the ObRb
receptor isoform may be decreased in diet-induced obese vs control
rats, indicating a state of leptin resistance (43). In
rodent models of diet-induced obesity, thymic lymphopenia, lower
mitogenic response of splenocytes, and suppressed NK cytotoxic
activity have been observed (47). Similarly, in obese
subjects, T lymphocyte subpopulations (CD3+,
CD4+CD45RO+, CD8+) and their
proliferative response to polyclonal mitogens are also suppressed
(48). These immune abnormalities are reversed with energy
restriction (which decreases leptin levels) in both humans and animals
(43). Although the exact mechanism for these immune
defects in obesity remains largely unknown, leptin levels are
correlated not only with the organism’s energy status but also with
serum TNF- levels which are also elevated in obesity and have a
suppressive effect on lymphocyte function (48, 49). We
have recently completed the first interventional studies
involving leptin administration to subjects with leptin sufficiency or
excess (obesity). Our data indicate that although STAT-3 (but not MAPK)
was activated after exogenous leptin administration in obese subjects
(46), no direct link between leptin and any alterations of
the immune system associated with obesity could be established
(50). More work is thus needed to fully elucidate the role
of leptin in the immune system of the obese and to further delineate
the signaling pathways activated by leptin in lean and obese subjects
in health and disease.
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Leptin, inflammation, and enhanced anti-self-immune responses |
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TopAbstractIntroductionLeptin and leptin signaling...The role of leptin...Leptin and states of...Leptin, inflammation, and...Future directionsDisclosuresReferences |
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(53), zymosan-induced
arthritis (54)). The mechanism for this presumed
anti-inflammatory effect of leptin deficiency is unknown, but an
imbalance between proinflammatory (unchanged) and anti-inflammatory
cytokines (IL-10 and IL-1R antagonist are reduced) has been noted
(51), raising the hypothesis that leptin may alter the
production of anti-inflammatory cytokines by monocytes/macrophages
via STAT-3 activation (55). In animals with adaptive
immunity-mediated inflammation (lymphocytes) (Con A-induced hepatitis
(56, 57), Clostridium difficile toxin
A-induced enteritis (58), Ag-induced arthritis
(59), or other autoimmune disease, see below), leptin
deficiency has a protective effect by resulting in reduced production
of proinflammatory Th1 cytokines (57) and a shift toward a
Th2 response (59). Importantly, inflammatory cells may
themselves express and secrete leptin which may further foster the
inflammatory process (60, 61).
Several groups have investigated the susceptibility of
ob/ob and db/db mice to experimentally
induced autoimmune diseases (56, 57, 58, 59, 61, 62, 63, 64, 65).
Ob/ob mice are resistant to both actively and passively
induced experimental autoimmune encephalomyelitis (EAE), a model of
multiple sclerosis but, consistent with leptin’s Th1-promoting
activities, these mice become susceptible to the disease after leptin
administration (63). Resistance to EAE in
ob/ob mice is associated with a reduced proliferative
response to myelin Ags and with an increased IL-4 response, whereas
leptin replacement converted the Th2 toward a Th1-type cytokine
response, leading to secretion of IFN- and to an IgG1-to-IgG2a
isotype shift switch. Leptin administration to susceptible wild-type
mice also worsened the disease by increasing both proinflammatory
cytokine levels and IgG2a production. Furthermore, infiltrating T cells
and macrophages in the CNS lesions stain positive for production of
immunoreactive leptin, suggesting that leptin is also produced by
immune cells during acute EAE (Fig. 2A).
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The role of leptin has also been investigated in spontaneous models of
autoimmunity, such as type 1 diabetes, and NOD (NOD/LtJ) mice as well
as in relation to the gender-related difference in susceptibility to
autoimmune diseases. More specifically, leptin administration
significantly increases inflammatory infiltrates in pancreatic islets,
increases IFN- production by T cells, anticipates the onset of type
1 diabetes, increases mortality, and increases inflammatory infiltrates
in pancreatic islets (65). Mouse strains spontaneously
developing autoimmune diseases, such as the NOD/LtJ and the
IL-2-deficient mice, have increased basal serum leptin before the
development of disease onset (45, 65, 67) and reduced
numbers of circulating regulatory T cells (68). In humans,
the prevalence of autoimmune diseases (i.e., multiple sclerosis,
rheumatoid arthritis, thyroiditis, and systemic lupus erythematosus) is
increased in females (69), as are serum leptin levels.
Recent clinical reports on patients with autoimmune diseases
demonstrate that high serum leptin levels may be either a contributing
factor (70, 71, 72) or a marker of disease activity
(73, 74, 75), and hypocaloric diets, which decrease serum
leptin levels, may have a beneficial role in the control of
autoimmunity in humans (70), but whether these
associations are causal has not yet been tested.
Obesity, a hyperleptinemic state, is increasingly being considered a
chronic proinflammatory state associated with progressive adipose
tissue infiltration by macrophages (60, 76) (Fig. 2B and Fig. 3) that
secrete proinflammatory cytokines (TNF-, IL-1
, and IL-6), which
in turn stimulate adipocytes to further secrete leptin and
proinflammatory cytokines such as TNF-; leptin levels are thus
associated with several proinflammatory cytokines
(77, 78, 79). To prove or disprove whether the above
associations reflect a causal role for leptin, we have recently
performed interventional studies involving rmetHuLeptin
administration to normal and obese humans. We demonstrated that
rmetHuLeptin administration to increase circulating leptin levels to
high physiological or pharmacological levels does not materially alter
proinflammatory cytokine levels or immune function in subjects with
leptin sufficiency or excess (obesity) (50). Thus, similar
to neuroendocrine function, the main role of leptin may be to regulate
immune function in leptin-deficient and not leptin-sufficient states in
humans.
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Future directions |
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TopAbstractIntroductionLeptin and leptin signaling...The role of leptin...Leptin and states of...Leptin, inflammation, and...Future directionsDisclosuresReferences |
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What is the effect of leptin on the function of the immune system in
obesity or other leptin-resistant states? In vitro studies in
diet-induced obese mice have shown that LPS stimulates proliferation of
cultured splenocytes and that PHA stimulated production of certain
cytokines (IFN- and IL-10), but not all (IL-2) (80). In
vivo studies in fasting diet-induced obese mice showed that leptin
administration prevents pre- and poststarvation reduction in spleen
weight compared with lean controls, but does not affect cytokine
production (IL-2, IL-10, IFN-) in these mice, implying that the
effect of leptin on immune cells in the obese state may be
insignificant (81). Although our initial studies in humans
(see above) are consistent with these findings in mice, it remains to
be fully examined to which extent leptin influences the immune system
and/or contributes to infections more frequently seen in patients with
obesity. Thus, carefully designed studies in obese humans are
needed.
Can exogenous leptin administration potentiate the immune system in energy-deficient states and, if yes, under which conditions and in which population of subjects? Exogenous leptin administration in subjects with congenital leptin deficiency restored CD4+ counts and proliferative responses, and we have shown that exogenously administered rmetHuLeptin to subjects with acquired leptin deficiency (exercise-induced energy deficiency of several years duration) improves their circulating cytokine levels. Energy and thus leptin deficiency models, such as anorexia nervosa, eating disorders, or exercise-induced energy deficiency, can be useful models to address the impact of chronic caloric deprivation and associated reduction of serum leptin levels on the immune function. Therefore, it would be very interesting to study in detail the immune function of the above groups of subjects and the impact of leptin on their immune system (46). Would exogenous rmetHuLeptin administration improve lymphocyte subpopulations, proliferation, or immune function assessed by other detailed methods in this model of chronic leptin deficiency? Would rmetHuLeptin administration induce or exacerbate inflammation, based on clinical or laboratory grounds, in subjects with normal or low leptin levels at a steady state? Only detailed, interventional studies utilizing rmetHuLeptin administration to humans can answer these questions. Finally, what is the role of leptin in other models of energy/leptin deficiency such as HIV-lipoatrophy or advanced cancer? Such patients exhibit a poorly functioning immune system, a higher percentage of apoptotic PBMCs, and lower levels of leptin and IL-2, probably as a result of cachexia (82) which has been correlated with both severity of disease and poor survival. What would be the effect of rmetHuLeptin administration in the immune system preservation and/or effect in overall survival? Carefully designed studies in humans are expected to answer all of these clinically important questions in the near future.
If leptin’s role is fundamental in Th1-mediated autoimmune diseases or inflammatory diseases, such as inflammatory bowel syndrome, would any therapeutic effect be anticipated by blocking peripheral leptin action (83)? Moreover, what would be the effect, immunosuppressive or other, of antileptin therapy in the innate vs the adaptive arms of immunity? Is there a role for anti-leptin blocking Abs in the treatment of disease states such as intestinal inflammation in humans?
Great progress has been achieved in understanding leptin’s role in vitro or in studies in animals. Although several observational studies in humans have raised important hypotheses, it is only through well-designed interventional studies in humans that any causal role for leptin in the physiology and pathophysiology of the immune system in humans can be elucidated. Similarly interventional studies in humans are also needed to clearly define whether rmetHuLeptin will eventually find a position in our therapeutic armamentarium for the treatment of immune diseases.
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Disclosures |
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TopAbstractIntroductionLeptin and leptin signaling...The role of leptin...Leptin and states of...Leptin, inflammation, and...Future directionsDisclosuresReferences |
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Footnotes |
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1 G.M. is partly supported by grants from Fondazione Italiana Sclerosi Multipla and Fondo per lo Studio del Lupus "Giacinta Magaldi." C.S.M. is supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant R01-57875. 
2 G.M. and S.M. contributed equally.
3 Address correspondence and reprint requests to Dr. Christos S. Mantzoros, Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Stoneman 816, Boston, MA 02215. E-mail address: cmantzor{at}bidmc.harvard.edu and Dr. Giuseppe Matarese, Gruppo di ImmunoEndocrinologia, Istituto di Endocrinologia e Oncologia Sperimenttale, Consiglio Nazionale delle Richerche (IEOS-CNR), Napoli, Italy. E-mail address: gmatarese{at}napoli.com
4 Abbreviations used in this paper: PI3'K, phosphatidylinositol 3'-kinase; EAE, experimental autoimmune encephalomyelitis; rmetHuLeptin, recombinant human leptin.
Received for publication January 5, 2005. Accepted for publication January 27, 2005.
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TopAbstractIntroductionLeptin and leptin signaling...The role of leptin...Leptin and states of...Leptin, inflammation, and...Future directionsDisclosuresReferences |
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E. Papathanassoglou, K. El-Haschimi, X. C. Li, G. Matarese, T. Strom, and C. Mantzoros Leptin receptor expression and signaling in lymphocytes: kinetics during lymphocyte activation, role in lymphocyte survival, and response to high fat diet in mice. J. Immunol., June 15, 2006; 176(12): 7745 - 7752. [Abstract] [Full Text] [PDF]
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 C.-H. Lee, Y.-G. Chen, J. Chen, P. C. Reifsnyder, D. V. Serreze, M. Clare-Salzler, M. Rodriguez, C. Wasserfall, M. A. Atkinson, and E. H. Leiter Novel Leptin Receptor Mutation in NOD/LtJ Mice Suppresses Type 1 Diabetes Progression: II. Immunologic Analysis Diabetes, January 1, 2006; 55(1): 171 - 178. [Abstract] [Full Text] [PDF]
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E. H. Leiter and C.-H. Lee Mouse Models and the Genetics of Diabetes: Is There Evidence for Genetic Overlap Between Type 1 and Type 2 Diabetes? Diabetes, December 1, 2005; 54(suppl_2): S151 - S158. [Abstract] [Full Text] [PDF]
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