Leptin beyond body weight regulation—Current concepts concerning its role in immune function and inflammation

doi:10.1016/j.cellimm.2007.09.004

Cellular Immunology

Volume 252, Issues 1–2, 2008, Pages 139-145

https://doi.org/10.1016/j.cellimm.2007.09.004 Get rights and content

Abstract

Leptin, a 16 kDa non-glycosylated polypeptide produced primarily by adipocytes and released into the systemic circulation, exerts a multitude of regulatory functions including energy utilization and storage, regulation of various endocrine axes, bone metabolism, and thermoregulation. In addition to leptin’s best known role as regulator of energy homeostasis, several studies indicate that leptin plays a pivotal role in immune and inflammatory response. Because of its dual nature as a hormone and cytokine, leptin can be nowadays considered the link between neuroendocrine and immune system. The increase in leptin production that occurs during infections and inflammatory processes strongly suggests that this adipokine is a part of the cytokines network which governs inflammatory/immune response and host defence mechanisms. Indeed, leptin plays a relevant role in inflammatory processes involving either innate or adaptive immune responses. Several studies have implicated leptin in the pathogenesis of autoimmune inflammatory conditions such as encephalomyelitis, type I diabetes, bowel inflammation and also articular degenerative diseases such as rheumatoid arthritis and osteoarthritis. Although the mechanisms by which leptin exerts its action as modulator of inflammatory/immune response are likely to be more complex than predicted and far to be completely depicted, there is a general consensus about its pivotal role as pro-inflammatory and immune-modulating agent. Here, we review the most recent advances on leptin biology with a particular attention to its adipokine facet, even though its role as metabolic hormone will be also addressed.

Section snippets

Leptin: a master adipokine

Leptin is a 16 kDa non-glycosylated peptide hormone, encoded by the obese (ob) gene, the murine homolog of human LEP gene, and chiefly synthesized and secreted by adipocytes [1]. From a structural viewpoint, leptin belongs to the type I cytokine super-family with a four alpha helical bundle motif. Leptin is an anorexic peptide which is primarily known for its role as a hypothalamic modulator of food intake, body weight and fat stores. Circulating leptin levels are straight correlated to adipose

Leptin receptors

Leptin exerts its biological actions through the activation of its cognate receptors which are encoded by the diabetes (db) gene and belong to the class I cytokine receptor super-family, which includes receptors for IL-6, LIF, CNTF, OSM, G-CSF and gp130. db gene alternative splicing gives rise to six receptor isoforms with cytoplasmic domains of different length, including one soluble form (Ob-Re), four short forms (Ob-Ra, Ob-Rc, Ob-Rd and Ob-Rf) and one long-functional isoform, known as Ob-Rb

Leptin biological activities

Leptin is now considered as the functional link between energy homeostasis and immune system. Early studies, focused on leptin’s anorexigenic action, showed that this hormone is able to maintain an adequate energy homeostasis by integrating different orexigenic and anorexigenic signals.

Leptin participates in the control of food intake by acting on an intricate neuronal circuit which involves hypothalamic and brainstem nuclei [14]. Both in humans and rodents leptin levels are closely correlated

Leptin and immune system

It has been shown that leptin receptor deficient db/db mice suffers from thymus atrophy [16], and that ob/ob leptin deficient mice are immune-deficient, suggesting a relevant role for leptin in immunity, not only by maintaining energy homeostasis but also by regulating the function of immune cells. Later studies showed a wide range of direct leptin’s actions on immune responses, reinforcing the concept that leptin could be involved in immune modulation [10], [17], [18].

Specifically, leptin has

Leptin in inflammatory/immune pathologies

In addition to the above reviewed immune regulatory actions, recent evidence shows that leptin acts as a pro-inflammatory cytokine. It has been shown that different inflammatory stimuli, including IL-1, IL-6 or lipopolysaccharide (LPS), regulate leptin mRNA expression as well as circulating leptin levels [30]. Furthermore, leptin is produced by inflammatory-regulatory cells, suggesting that leptin expression could trigger or participate in the inflammatory process through direct paracrine or

Leptin and articular degenerative diseases

Among several neuro-endocrine mediators, leptin likely plays a major role in the pathogenesis of relevant autoimmune/inflammatory joint diseases such as rheumatoid arthritis and osteoarthritis. Leptin deficient mice develop resistance to experimental antigen-induced arthritis in comparison with wild type mice [34]. In addition, fasting-associated leptin decrease leads to CD4⁺ lymphocyte hypo-reactivity and increased IL-4 secretion in patients with rheumatoid arthritis [45]. Our group has

Conclusions

It is now clear that leptin plays relevant multiple roles in the body and the magnitude of increasing interest on this matter is allowing us to dissect the intricate interplay among white adipose tissue, its associated adipokines, and metabolic alterations and immunity/inflammation. Even many of the aspects remain unclear and incomplete, several therapeutically perspectives are opening out. At present, there are strong evidences about leptin’s activity on immune system that have enlightened

Acknowledgments

Some of the research described in this article has been supported by the Spanish Ministry of Health, Fondo de Investigacion Sanitaria, Instituto de Salud Carlos III (FIS PI 05/0525, PI030115, PI050419), and Xunta de Galicia. RL is a recipient of a pre-doctoral fellowship funded by the Instituto de Salud Carlos III (Exp. 05/01019). RG is a recipient of a project-associated fellowship from the Instituto de Salud Carlos III (FIS 05/0525). O.G. and F.L. are recipients of a contract under the

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Citation Excerpt :
Placenta, gastric epithelium,T-cells, osteoblasts and intralobular ducts of major salivary glands are other sources of leptin secretion.8 Leptin is involved in endocrine axis regulation, thermoregulation, lipid, glucose and bone metabolism, cardiovascular functions.9 It is also sensitive to immune inflammatory response suggesting its possible role in periodontal inflammation.10
Periodontitis causes oxidative stress and reduce total antioxidant levels. The aim of this study was to determine the effect of non-surgical periodontal treatment on leptin levels and total antioxidant capacity in chronic periodontitis.
A total of 35 chronic periodontitis (ChP) patients and 35 systemically and periodontal healthy subjects were enrolled in this study. Further, the ChP group received nonsurgical periodontal therapy (NSPT). Leptin and total antioxidant capacity (TAOC) was measured in serum and saliva samples at baseline, 3 months and 6 months after non-surgical periodontal therapy. Clinical parameters measured were measured at baseline, 1, 3 and 6 months interval.
The mean serum leptin and TAOC levels in control group were significantly higher compared to chronic periodontitis group (p < 0.05). The control group had lower mean salivary leptin levels and higher mean salivary TAOC levels as compared to periodontitis group(p < 0.05). Clinical parameters were improved in ChP group post therapy (p < 0.05). However, the periodontal treatment showed insignificant changes in serum and salivary leptin and TAOC levels.
Chronic periodontitis is significantly associated with serum and salivary TAOC and leptin levels. Non surgical periodontal therapy didn't alter the local and systemic TAOC and leptin levels.
Immunosenescence and inflammaging in the aging process: age-related diseases or longevity?
2021, Ageing Research Reviews
During aging the immune system (IS) undergoes remarkable changes that collectively are known as immunosenescence. It is a multifactorial and dynamic phenomenon that affects both natural and acquired immunity and plays a critical role in most chronic diseases in older people. For a long time, immunosenescence has been considered detrimental because it may lead to a low-grade, sterile chronic inflammation we proposed to call "inflammaging" and a progressive reduction in the ability to trigger effective antibody and cellular responses against infections and vaccinations. Recently, many scientists revised this negative meaning because it can be considered an essential adaptation/remodeling resulting from the lifelong immunological biography of single individuals from an evolutionary perspective. Inflammaging can be considered an adaptive process because it can trigger an anti-inflammatory response to counteract the age-related pro-inflammatory environment. Centenarians represent a valuable model to study the beneficial changes occurring in the IS with age. These extraordinary individuals reached the extreme limits of human life by slowing down the aging process and, in most cases, delaying, avoiding or surviving the major age-associated diseases. They indeed show a complex and heterogeneous phenotype determined by an improved ability to adapt and remodel in response to harmful stimuli. This review aims to point out the intimate relationship between immunosenescence and inflammaging and how these processes impact unsuccessful aging rather than longevity. We also describe the gut microbiota age-related changes as one of the significant triggers of inflammaging and the sex/gender differences in the immune system of the elderly, contributing to the sex/gender disparity in terms of epidemiology, pathophysiology, symptoms and severity of age-related diseases. Finally, we discuss how these phenomena could influence the susceptibility to COVID-19 infection.
Invited review: Mechanisms of hypophagia during disease
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Suppression of appetite, or hypophagia, is among the most recognizable effects of disease in livestock, with the potential to impair growth, reproduction, and lactation. The continued evolution of the field of immunology has led to a greater understanding of the immune and endocrine signaling networks underlying this conserved response to disease. Inflammatory mediators, especially including the cytokines tumor necrosis factor-α and interleukin-1β, are likely pivotal to disease-induced hypophagia, based on findings in both rodents and cattle. However, the specific mechanisms linking a cytokine surge to decreased feeding behavior are more difficult to pin down and likely include direct effects on appetite centers in the brain, alteration of gastric motility, and modulation of other endocrine factors that influence appetite and satiety. These insights into the mechanisms for disease-induced hypophagia have great relevance for management of neonatal calves, mature cows transitioning to lactation, and cows experiencing mastitis; however, it is not necessarily the case that increasing feed intake by any means possible will improve health outcomes for diseased cattle. We explore conflicting effects of hypophagia on immune responses, which may be impaired by the lack of specific substrates, versus apparent benefits for controlling the growth of some pathogens. Anti-inflammatory strategies have shown promise for promoting recovery of feed intake following some conditions but not others. Finally, we explore the potential for early disease detection through automated monitoring of feeding behavior and consider which strategies may be implemented to respond to early hypophagia.
Association of LEPR polymorphisms with predisposition and inflammatory response in anti-tuberculosis drug-induced liver injury: A pilot prospective investigation in Western Chinese Han population
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Citation Excerpt :
So far, six alternatively spliced isoforms of LEPRa-f have been identified. Among them, only the long form, LEPRb, can transmit intracellular leptin signaling (Lago et al., 2008). The human LEPR gene contains a number of SNPs, and many of such polymorphisms in this gene have been shown to be significantly associated with obesity-related disorders (Yang and Niu, 2018; Nowzari et al., 2018) and various types of human malignant tumors (Abdu Allah et al., 2018; Méndez-Hernández et al., 2017).
Previous studies have proposed leptin/leptin receptor (LEPR) pathway has a potential role in the oxidative stress induction as well as in immune and inflammatory responses; however, the effects of leptin/LEPR signaling on anti-tuberculosis drug-induced liver injury (ATLI) remain unexplored. Here, we aimed to investigate the potential relationships between LEPR polymorphisms and ATLI risk and clinical characteristics.
In total, this prospective study included 745 tuberculosis subjects with isoniazid and rifampin co-administration from West China. Six candidate single nucleotide polymorphisms (SNPs) in LEPR gene were genotyped by using a custom-by-design 48-Plex SNPscan kit. All subjects were monitored for six months to assess the occurrence of ATLI. Genetic association analysis at both the single-SNP and haplotype levels was performed. Significant SNPs were further explored in relation to clinical features and inflammatory response of ATLI cases.
ATLI was identified in 118 of 745 subjects with a prevalence rate of 15.84%. Significant differences were observed in the allele and genotype distribution of LEPR rs2025804 in ATLI cases compared to non-ATLI controls (allele: OR = 1.64, 95% CI = 1.15–2.32, adjusted-p = .036; dominant model: OR = 1.73, 95% CI = 1.14–2.61, adjusted-p = 0.054; additive model: OR = 1.64, 95% CI = 1.15–2.34, adjusted-p = 0.036). Haplotype AA comprising of rs2025804 and rs2104564 was associated with a 1.58-fold increased predisposition to ATLI with p = 0.013. Furthermore, among ATLI patients, individuals carrying minor allele-containing genotypes in rs10889551, rs2025804 and rs2104564 loci had higher levels of C-reactive protein as compared to those homozygous major allele carriers, at p of 0.002, 0.057 and 0.012, respectively.
Ours is the first study which shows that LEPR polymorphisms may increase the risk for ATLI and may influence the inflammatory response in ATLI patients among Western Chinese Han tuberculosis patients.
Modulation of intestinal microbiota and immunometabolic parameters by caloric restriction and lactic acid bacteria
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The objective of this work was to evaluate the effect of a caloric restriction diet with and without the administration of Lactobacillus fermentum CRL1446, Lactobacillus casei CRL431 and Lactococcus lactis CRL1434, on immunemetabolic parameters and the composition of intestinal microbiota in mice.
The supplementation of the caloric restriction diet with L. fermentum CRL1446 showed a bifidogenic effect and was able to maintain the abundance of the genus Lactobacillus over time. On the other hand, this strain showed hypocholesterolemic and hypoglycemic properties as well as inducing a decrease in plasma leptin levels.
L. casei CRL431 administration increased the abundance of the Lactobacillus genera in the intestinal microbiota, which would improve the absorption of nutrients from the diet. This strain restores glucose values decreased by the diet in addition to inducing an increase in leptin and cytokines.
Lac. lactis CRL1434 showed greater immunomodulatory capacity, without significantly affecting the composition of the intestinal microbiota. It had hypoglycemic properties and induced a decrease in leptin concentrations.
L. fermentum CRL1446 and Lac. lactis CRL1434 could be potentially probiotic strains useful to correct the immuno-metabolic alterations associated with obesity, while L. casei CRL431 is a more suitable strain to be used in cases of malnutrition where it is sought to improve the absorption of nutrients and protection against infections, in addition to the stimulation of the immune system.
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Osteoarthritis is the most prevalent form of aging-related joint diseases, and its etiology is still not fully understood. Obesity has been recognized as one of the most significant and potentially preventable risk factors for osteoarthritis. Beyond mechanical loading, adipokines, including leptin, visfatin, adiponectin, resistin and others, are demonstrated to have metabolic implications in the pathogenesis and progression in obesity-induced osteoarthritis by modulating the pro/anti-inflammatory and anabolic/catabolic balance, apoptosis, matrix remodeling and subchondral bone ossification. Accordingly, adipokines emerge as potential candidates to link these two entities, and may serve as putative targets for disease-modifying drugs for osteoarthritis, especially for obese patients. Here we summarize studies over the past decades on the pivotal role of adipokine family in osteoarthritis, and aim to shed a light on the causative link between obesity and osteoarthritis. Notably, due to difficulties in separation of the metabolic effect from the mechanical effect of fat excess, researches on osteoarthritis in non-weight-bearing joints may provide a promising direction and more emphasis shall be put on them in future.

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^☆: Conflict of interest statement: There are no conflicts of interest.

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ReviewLeptin beyond body weight regulation—Current concepts concerning its role in immune function and inflammation☆

Abstract

Section snippets

Leptin: a master adipokine

Leptin receptors

Leptin biological activities

Leptin and immune system

Leptin in inflammatory/immune pathologies

Leptin and articular degenerative diseases

Conclusions

Acknowledgments

FEBS Lett.

Life Sci.

Mol. Cell. Endocrinol.

J. Biol. Chem.

Life Sci.

Biochem. Biophys. Res. Commun.

Med. Hypotheses

Positional cloning of the mouse obese gene and its human homologue

Nature

Role of leptin in the neuroendocrine response to fasting

Nature

The role of falling leptin levels in the neuroendocrine and metabolic adaptation to short-term starvation in healthy men

J. Clin. Invest.

Effects of prolonged hyperinsulinemia on serum leptin in normal human subjects

J. Clin. Invest.

Glucocorticoids as counterregulatory hormones of leptin: toward an understanding of leptin resistance

Diabetes

Multiple cytokines and acute inflammation raise mouse leptin levels: potential role in inflammatory anorexia

J. Exp. Med.

Plasma leptin levels in healthy children and adolescents: dependence on body mass index, body fat mass, gender, pubertal stage, and testosterone

Clin. Endocrinol. Metab.

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Rheumatology (Oxford)

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Nature

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High-dose leptin activates human leukocytes via receptor expression on monocytes

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Am. J. Physiol. Lung Cell. Mol. Physiol.

Leptin potentiates IFN-gamma-induced expression of nitric oxide synthase and cyclo-oxygenase-2 in murine macrophage J774A.1

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J. Leukoc. Biol.

Leptin regulates functional capacities of polymorphonuclear neutrophils

Free Radic. Res.

Involvement of leptin signaling in the survival and maturation of bone marrow-derived dendritic cells

Eur. J. Immunol.

Review
Leptin beyond body weight regulation—Current concepts concerning its role in immune function and inflammation☆