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Mucosal Immunology Sep 2012Enhanced susceptibility to infection has long been recognized in children with congenital deficiency of leptin or its receptor. Studies in mice have demonstrated that... (Review)
Review
Enhanced susceptibility to infection has long been recognized in children with congenital deficiency of leptin or its receptor. Studies in mice have demonstrated that leptin deficiency affects both the innate and acquired immune systems. Here, we review recent studies that demonstrate the impact on immunity of a common non-synonomous polymorphism of the leptin receptor. In a Bangladesh cohort of children, the presence of two copies of the ancestral Q223 allele was significantly associated with resistance to amebiasis. Children and mice with at least one copy of the leptin receptor 223R mutation were more susceptible to amebic colitis. Leptin signaling in the intestinal epithelium and downstream STAT3 (signal transducer and activator of transcription 3) and SHP2 (Src homology phosphatase 2) signaling were required for protection in the murine model of amebic colitis. Murine models have also implicated leptin in protection from other infections, including Mycobacterium tuberculosis, Klebsiella pneumoniae, and Streptococcus pneumoniae. Thus, the role of leptin signaling in infectious disease and specifically leptin-mediated protection of the intestinal epithelium will be the focus of this review.
Topics: Animals; Child; Disease Models, Animal; Dysentery, Amebic; Genetic Predisposition to Disease; Humans; Immunity, Mucosal; Intestinal Mucosa; Leptin; Mice; Polymorphism, Genetic; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Receptors, Leptin; STAT3 Transcription Factor; Signal Transduction
PubMed: 22692456
DOI: 10.1038/mi.2012.40 -
Cancer Biology & Medicine Jun 2023Leptin (LEP) is an obesity-associated adipokine associated with tumor cell growth. We examined the relevance of genetic variants of and leptin receptor () to colorectal...
OBJECTIVE
Leptin (LEP) is an obesity-associated adipokine associated with tumor cell growth. We examined the relevance of genetic variants of and leptin receptor () to colorectal cancer (CRC) survival by using data from the Newfoundland Familial Colorectal Cancer Study.
METHODS
A total of 532 patients newly diagnosed with CRC between 1997 and 2003 were followed up until April 2010. Data on their demographics and lifestyles were collected questionnaires. Genotyping of blood samples was performed with the Illumina Human Omni-Quad Bead chip. Multivariable Cox models were used to assess the relationships of 35 tag single-nucleotide polymorphisms (SNPs) in and with overall survival (OS), disease-free survival (DFS), and CRC-specific survival.
RESULTS
At the gene level, was associated with DFS ( = 0.017), and was associated with both DFS ( = 0.021) and CRC-specific survival ( = 0.013) in patients with CRC. In single-SNP analysis, rs11763517, rs9436301, and rs7602 were associated with DFS after adjustment for multiple testing. The haplotypes G-C-T (rs7534511-rs9436301-rs1887285) and A-A-G (rs7602-rs970467-rs9436748) were associated with prolonged OS among patients with CRC overall (G-C-T: HR, 0.63; 95% CI, 0.43-0.93; A-A-G: HR, 0.59; 95% CI, 0.38-0.91) and those diagnosed with colon cancer (G-C-T: HR, 0.54; 95% CI, 0.34-0.86; A-A-G: HR, 0.49; 95% CI, 0.29-0.83). Similar results were observed for DFS. Moreover, significant interactions were found among rs7602 (A G), rs1171278 (T . C), red meat intake, and BMI status: the associations between these variants and prolonged DFS were limited to patients with below-median red meat consumption and body mass index (BMI) < 25 kg/m.
CONCLUSIONS
Polymorphic variations in the and genes were associated with survival of patients after CRC diagnosis. The /-CRC survival association was modified by participants' red meat intake and BMI.
Topics: Humans; Leptin; Receptors, Leptin; Genetic Predisposition to Disease; Polymorphism, Single Nucleotide; Colorectal Neoplasms
PubMed: 37282602
DOI: 10.20892/j.issn.2095-3941.2022.0635 -
Nihon Rinsho Men'eki Gakkai Kaishi =... 2017Leptin is secreted from adipocytes and acts mainly on the hypothalamus causing weight loss due to suppression of appetite and increased energy expenditure. On the other... (Review)
Review
Leptin is secreted from adipocytes and acts mainly on the hypothalamus causing weight loss due to suppression of appetite and increased energy expenditure. On the other hand, the leptin receptor is also expressed in hematopoietic cells and its action on the immune system has become known, and the significance of leptin in autoimmune diseases has gradually become clear. It has been shown that leptin acts as an exacerbating factor in many autoimmune diseases and it is suggested that inhibition of leptin signal may be a novel therapeutic method for autoimmune diseases. In this article, we will outline the significance of leptin in the immune system based on the current reports.
Topics: Adipocytes; Appetite; Arthritis, Rheumatoid; Autoimmune Diseases; Disease Progression; Energy Metabolism; Hematopoietic Stem Cells; Humans; Hypothalamus; Leptin; Lupus Erythematosus, Systemic; Molecular Targeted Therapy; Receptors, Leptin; Signal Transduction; Weight Loss
PubMed: 28747601
DOI: 10.2177/jsci.40.155 -
Stem Cell Reviews and Reports Apr 2021Hematopoietic stem cells (HSCs) give rise to all blood and immune cells in the body. These rare cells reside in the hypoxic niche of the bone marrow (BM) where they are... (Review)
Review
Hematopoietic stem cells (HSCs) give rise to all blood and immune cells in the body. These rare cells reside in the hypoxic niche of the bone marrow (BM) where they are subjected to a complex network of regulatory factors including cellular and molecular components. To sustain hematopoiesis over the lifetime of an individual, HSCs maintain distinctive metabolic programs, and in recent years nutritional factors have been increasingly recognized as critical regulators of HSC numbers and functions. Leptin (LEP), a neuroendocrine messenger, and its receptor (LEPR) are well-known for their immunomodulatory and energy balancing effects; yet, how LEP/LEPR signaling plays a role in hematopoiesis is under-appreciated. In this review, we summarize and highlight recent work that demonstrated involvement of LEP/LEPR in hematopoiesis under steady state or stress-associated situations as well as in pathological conditions such as cardiovascular diseases and malignancies. Although the field is only in its infancy, these studies suggest evidence of potential clinical applications and proof-of-principle for more in-depth future research. Under steady state, only a minor subset of long-term hematopoietic stem cells (HSCs) express LEPR. Upon irradiation, LEPRHSCs exhibited robust repopulating capacity in long-term engraftment studies that outcompeted LEPRHSCs. LEPR stromal cells secrete critical niche factors including stem cell factor (SCF) and pleiotrophin (PTN) to support HSCs and progenitor cells. LEPR signaling mediated protective effects of fasting in ALL but not AML leukemias.
Topics: Hematopoiesis; Hematopoietic Stem Cells; Humans; Leptin; Receptors, Leptin
PubMed: 33598894
DOI: 10.1007/s12015-021-10132-y -
The Journal of Maternal-fetal &... Dec 2023Leptin signaling plays an important role in regulating metabolism and reproduction. In the present study, we investigated the relationship between polymorphisms of...
OBJECTIVE
Leptin signaling plays an important role in regulating metabolism and reproduction. In the present study, we investigated the relationship between polymorphisms of leptin receptor () gene A223G and A668G and preeclampsia (PE) and evaluated influences of genotypes on clinical, metabolic, and oxidative stress indices in Chinese women.
METHODS
This is a case-control study including 322 patients with PE and 1295 healthy pregnant women. The two polymorphisms were genotyped by polymerase chain reaction-restriction fragments length polymorphism method. Clinical and biochemical parameters were analyzed.
RESULTS
The frequencies of the AA + AG genotypes (28.6% vs. 36.1%) and A allele (14.9% vs. 19.8%) of A223G polymorphism, and those of the AA + AG genotypes (17.7% vs. 24.6%) and A allele (9.0% vs. 12.9%) of A668G polymorphism were significantly lower in the PE group than those in the control group. The 223A and 668A alleles were protective factors against PE in the regression model, which included age and delivery body mass index as covariates (OR = 0.684, 95% CI: 0.506-0.926, = .014; OR = 0.650, 95% CI: 0.456-0.927, = .017, respectively). When the GG/GG combined genotype served as the reference category, the 668A/223A combined allele had further enhanced the protective effect on PE (OR = 0.558, 95% CI: 0.374-0.833, = .004). Patients possessing the 223A allele had higher total antioxidant capacity and lower oxidative stress index ( < .05), while those with the 668A allele had higher high-density lipoprotein cholesterol levels ( = .045) compared with those carrying the corresponding GG genotype.
CONCLUSIONS
The 223A and 668A alleles of polymorphisms are genetic protective factors for PE in Chinese women. The two alleles may exert a beneficial effect on oxidative stress and lipid metabolism in patients.
Topics: Female; Humans; Pregnancy; Case-Control Studies; East Asian People; Gene Frequency; Genetic Predisposition to Disease; Genotype; Polymorphism, Single Nucleotide; Pre-Eclampsia; Receptors, Leptin
PubMed: 37150847
DOI: 10.1080/14767058.2023.2207708 -
Vascular Pharmacology Oct 2022Leptin plays a crucial role in blood pressure (BP) regulation, notably in the context of obesity through central sympatho-mediated pressor effects. Leptin also relaxes...
Leptin plays a crucial role in blood pressure (BP) regulation, notably in the context of obesity through central sympatho-mediated pressor effects. Leptin also relaxes arteries via endothelial (EC) leptin receptor (LepR)-mediated increases in nitric oxide (NO) bioavailability. Herein, we investigated whether leptin-mediated increases in NO bioavailability represent a buffering mechanism against leptin-induced sympatho-activation. We tested the direct contribution of LepR to BP regulation in physiological conditions and in response to chronic leptin infusion using mice deficient in LepR. LepR deficiency did not alter baseline metabolic profile nor leptin-induced reduction in adiposity and increases in energy expenditure. LepR mice demonstrated no increase in baseline BP and heart rate (HR) (MAP: LepR:94.7 ± 1.6, LepR:95.1 ± 1.8 mmHg; HR:LepR:492.4 ± 11.7, LepR:509.5 ± 13.4 bpm) nor in response to leptin (MAP, LepR:101.1 ± 1.7, LepR:101.7 ± 1.8 mmHg; HR, LepR:535.6 ± 11.1, LepR:539.3 ± 14.2 bpm). Moreover, baseline neurogenic control of BP and HR was preserved in LepR mice as well as leptin-mediated increases in sympathetic control of BP and HR and decreases in vagal tone. Remarkably, LepR deficiency did not alter endothelium-dependent relaxation in resistance vessels, nor NO contribution to vasodilatation. Lastly, leptin induced similar increases in adrenergic contractility in mesenteric arteries from both LepR and LepR mice. Collectively, these results demonstrate that the NO buffering effects of leptin are absent in resistance arteries and do not contribute to BP regulation. We provide further evidence that leptin-mediated hypertension involves increased vascular sympatho-activation and extend these findings by demonstrating for the first time that increased cardiac sympatho-activation and reduced vagal tone also contribute to leptin-mediated hypertension.
Topics: Adrenergic Agents; Animals; Endothelium; Hypertension; Leptin; Male; Mice; Nitric Oxide; Obesity; Receptors, Leptin
PubMed: 35914636
DOI: 10.1016/j.vph.2022.107093 -
BMC Cancer Mar 2023Effective screening and treatment have reduced the number of women dying from breast cancer (BC). However, the long-term sequelae of BC treatment and psychosocial...
BACKGROUND
Effective screening and treatment have reduced the number of women dying from breast cancer (BC). However, the long-term sequelae of BC treatment and psychosocial factors seriously affect the life quality of BC patients and survivors. Therefore, the discovery and application of targeted biomarkers to improve the functional outcome and life quality of BC patients is necessary.
AIMS
To explore the impact of leptin (LEP)/ leptin receptor (LEPR) expression on occurrence and survival of BC.
METHODS
Totally 132 primary BC and 66 non-BC patients who underwent surgery in department of breast surgery in Shanxi Cancer Hospital from January to October in 2009 were enrolled in this retrospective study. LEP and LEPR were examined in BC tissues, benign breast tissues, para-carcinoma tissues using immunohistochemical staining. Kaplan-Meier curve was generated to test survival time.
RESULTS
The high level expression of LEP and LEPR in BC tissues were significantly higher than that in benign breast tissues and in para-carcinoma tissues (all P < 0.05). The LEP expression in patients with lymph node metastases was significantly higher than that in patients without lymph nodes metastases (P = 0.002). LEPR expression was correlated with higher Ki-67 rate (P = 0.002). LEP and LEPR both had no impact on survival (all P > 0.05).
CONCLUSIONS
High LEP/LEPR expression were risk factors for occurrence of BC, but without impact on survival.
Topics: Humans; Female; Leptin; Retrospective Studies; Breast Neoplasms; Receptors, Leptin; Carcinoma; Biomarkers; Polymorphism, Single Nucleotide
PubMed: 36941557
DOI: 10.1186/s12885-023-10617-8 -
Leptin and Cancer: Updated Functional Roles in Carcinogenesis, Therapeutic Niches, and Developments.International Journal of Molecular... Mar 2021Leptin is an obesity-associated adipokine that is known to regulate energy metabolism and reproduction and to control appetite via the leptin receptor. Recent work has... (Review)
Review
Leptin is an obesity-associated adipokine that is known to regulate energy metabolism and reproduction and to control appetite via the leptin receptor. Recent work has identified specific cell types other than adipocytes that harbor leptin and leptin receptor expression, particularly in cancers and tumor microenvironments, and characterized the role of this signaling axis in cancer progression. Furthermore, the prognostic significance of leptin in various types of cancer and the ability to noninvasively detect leptin levels in serum samples have attracted attention for potential clinical applications. Emerging findings have demonstrated the direct and indirect biological effects of leptin in regulating cancer proliferation, metastasis, angiogenesis and chemoresistance, warranting the exploration of the underlying molecular mechanisms to develop a novel therapeutic strategy. In this review article, we summarize and integrate transcriptome and clinical data from cancer patients together with the recent findings related to the leptin signaling axis in the aforementioned malignant phenotypes. In addition, a comprehensive analysis of leptin and leptin receptor distribution in a pancancer panel and in individual cell types of specific organs at the single-cell level is presented, identifying those sites that are prone to leptin-mediated tumorigenesis. Our results shed light on the role of leptin in cancer and provide guidance and potential directions for further research for scientists in this field.
Topics: Adipocytes; Animals; Carcinogenesis; Humans; Leptin; Neoplasms; Obesity; Receptors, Leptin; Signal Transduction; Tumor Microenvironment
PubMed: 33799880
DOI: 10.3390/ijms22062870 -
PloS One 2022The present study, in addition to molecular characterization of leptin (lepa) and its receptor (lepr) of spotted snakehead Channa punctata, is focussed on...
The present study, in addition to molecular characterization of leptin (lepa) and its receptor (lepr) of spotted snakehead Channa punctata, is focussed on physicochemical, structural, evolutionary and selection pressure analyses which are poorly elucidated in teleosts in spite of that existence of these genes is well reported in several fish species. The putative full-length Lep and Lepr of C. punctata showed conserved structural and functional domains, especially the residues responsible for structural integrity and signal transduction. Conversely, residues predicted essential for Lep-Lepr interaction displayed divergence between teleosts and tetrapods. Impact of substitutions/deletions predicted using protein variation effect analyser tool highlighted species specificity in ligand-receptor interaction. Physicochemical properties of ligand and receptor predicted for the first time in vertebrates revealed high aliphatic and instability indices for both Lepa and Lepr, indicating thermostability of proteins but their instability under ex vivo conditions. Positive grand average of hydropathy score of Lepa suggests its hydrophobic nature conjecturing existence of leptin binding proteins in C. punctata. In addition to disulphide bonding, a novel posttranslational modification (S-126 phosphorylation) was predicted in Lepa of C. punctata. In Lepr, disulphide bond formation and N-linked glycosylation near WSXWS motif in ECD, and phosphorylation at tyrosine residues in ICD were predicted. Leptin and its receptor sequence of C. punctata cladded with its homolog from C. striata and C. argus of order Anabantiformes. Leptin system of Anabantiformes was phylogenetically closer to that of Pleuronectiformes, Scombriformes and Perciformes. Selection pressure analysis showed higher incidence of negative selection in teleostean leptin genes indicating limited adaptation in their structure and function. However, evidence of pervasive and episodic diversifying selection laid a foundation of co-evolution of Lepa and Lepr in teleosts.
Topics: Animals; Disulfides; Flatfishes; Leptin; Ligands; Receptors, Leptin
PubMed: 35797380
DOI: 10.1371/journal.pone.0270881 -
Journal of Animal Science Jan 2023Piglets with low birth weight present low vitality after farrowing, often leading to impaired weight gain during lactation. A recessive missense variant (C > T) for...
Piglets with low birth weight present low vitality after farrowing, often leading to impaired weight gain during lactation. A recessive missense variant (C > T) for increased appetite and fatness in the porcine leptin receptor gene (rs709596309) causes a negative maternal effect on the weight of piglets at weaning. However, it is not known whether this variant already exerts an effect on the birth weight and vitality of newborn piglets and on their growing capacity during lactation. An experiment was conducted using 668 purebred Duroc piglets (131 CC, 311 CT, and 226 TT) from 74 multiparous sows (9 CC, 43 CT, and 22 TT) and 14 boars (1 CC, 10 CT, and 3 TT). All piglets were individually weighed at birth and tested for vitality, which was assessed on a scale from 1 (low vitality) to 3 (high vitality) based on behavioral observations, including the status of the piglet immediately before the test. Only non-adopted piglets were considered for piglet performance at weaning. Inferences on the effect of the genotype on birth and weaning traits were done on a Bayesian setting based on 2-trait bivariate models including the effects of the piglet and the litter, as well as the genotype of the sow and the piglet, the sex of the piglet, and the parity number. Vitality and the status of the piglet before the test were analyzed using a liability threshold (probit) model. As compared to other genotypes, TT newborn piglets were 28 g heavier, were more vital (the probability of being scored as highly vital was 6.5% higher) and were more often found suckling before the test (the probability of being suckling at test was 6.5% higher). As a result, they grew more during lactation (153 g) and were heavier at weaning (169 g) than littermates of the two other genotypes, thus partly compensating for the limited maternal capacity of TT sows. Our findings provide evidence that appetite-influencing genes, such as the leptin receptor gene, have developmental implications from very early life stages.
Topics: Pregnancy; Animals; Swine; Female; Male; Receptors, Leptin; Birth Weight; Bayes Theorem; Litter Size; Weaning; Lactation
PubMed: 37659087
DOI: 10.1093/jas/skad296