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Acta Histochemica Sep 2016The hormone leptin is produced by mature adipocytes and plays an important role in regulating food intake and energy metabolism through its interaction with the leptin...
The hormone leptin is produced by mature adipocytes and plays an important role in regulating food intake and energy metabolism through its interaction with the leptin receptor. In addition to roles in obesity and obesity-related diseases, leptin has been reported to affect the components and secretion of bile in leptin-deficient mice. Furthermore, gallbladder diseases such as cholelithiasis are known to be associated with serum leptin concentrations in humans. We hypothesized that the canine gallbladder is a source of leptin and that the leptin receptor may be localized in the gallbladder, where it plays a role in regulating the function of this organ. The aim of this study was to demonstrate the presence and expression patterns of leptin and its receptors in normal canine gallbladders using reverse transcriptase-PCR (RT-PCR) and immunohistochemistry. Clinically normal gallbladder tissue samples were obtained from four healthy beagle dogs with similar body condition scores. RT-PCR and sequencing of the amplified PCR products revealed the presence of leptin mRNA and its receptors in the gallbladder. Immunohistochemical investigations demonstrated the expression of leptin and its receptors in the luminal single columnar and tubuloalveolar glandular epithelial cells. In conclusion, the results of this study demonstrated the presence of leptin and its receptors in the gallbladders of dogs. Leptin and its receptor were both localized throughout the cytoplasm of luminal and glandular epithelial cells. These results suggested that the gallbladder is not only a source of leptin, but also a target of leptin though autocrine/paracrine mechanisms. The results of this study could increase the understanding of both the normal physiological functions of the gallbladder and the pathophysiological mechanisms of gallbladder diseases characterized by leptin system dysfunction.
Topics: Animals; Dogs; Gallbladder; Immunohistochemistry; Leptin; Obesity; RNA, Messenger; Receptors, Leptin
PubMed: 27660197
DOI: 10.1016/j.acthis.2016.09.002 -
Biomolecules Oct 2023Globally, bladder cancer (BC) is one of the ten most common tumors. Obesity is a worldwide problem associated with an increased BC risk. Considering that levels of...
Globally, bladder cancer (BC) is one of the ten most common tumors. Obesity is a worldwide problem associated with an increased BC risk. Considering that levels of leptin and/or its receptor are often deregulated in obese individuals, we hypothesized that they could contribute to BC. To test this hypothesis, we utilized a case-control study in which 116 patients with a confirmed diagnosis of BC and 116 controls were recruited. The serum levels of leptin and leptin receptor were measured. Patients and controls were also genotyped for SNPs in the (rs7799039, rs791620, and rs2167270) and genes (rs1137100, rs1137101, and rs1805094). The univariate analysis indicated that BC patients had significantly higher levels of leptin and lower levels of leptin receptor ( < 0.05). Moreover, rs7799039 of and rs1137101 of were associated with BC ( < 0.05). In the multivariate analysis, leptin receptor levels were protective (OR: 0.98, 95% CI = 0.97-0.99, = 0.002) while the GG genotype of rs1137101 of increased BC risk (OR: 3.42, 95% CI = 1.27-9.20, = 0.02). These findings highlight that lifestyle changes could be useful in preventing BC and that disturbances in energy metabolism could play a role in the pathobiology of BC.
Topics: Humans; Leptin; Receptors, Leptin; Case-Control Studies; Obesity; Polymorphism, Single Nucleotide; Urinary Bladder Neoplasms; Genetic Predisposition to Disease
PubMed: 37892180
DOI: 10.3390/biom13101498 -
Oncotarget Nov 2015The prevalence of global obesity is increasing. Obesity is associated with general cancer-related morbidity and mortality and is a known risk factor for development of... (Review)
Review
The prevalence of global obesity is increasing. Obesity is associated with general cancer-related morbidity and mortality and is a known risk factor for development of specific cancers. A recent large systematic review of 24 studies based on meta-analysis of 11,149 patients with prostate cancer showed a significant correlation between obesity and the risk of advanced prostate cancer. Further, a sustained reduction in BMI correlates with a decreased risk of developing aggressive disease. On the other hand, the correlation between consuming different products and prostate cancer occurrence/risk is limited.Here, we review the role of adipose tissue from an endocrine perspective and outline the effect of adipokines on cancer metabolism, with particular focus on leptin. Leptin exerts its physiological and pathological effects through modification of intracellular signalling, most notably activating the Janus kinase (JAK) 2/signal transducer and activator of transcription (STAT) 3 pathway and recently shown sphingolipid pathway. Both high levels of leptin in circulation and leptin receptor mutation are associated with prostate cancer risk in human patients; however, the in vivo mechanistic evidence is less conclusive.Given the complexity of metabolic cancer pathways, it is possible that leptin may have varying effects on prostate cancer at different stages of its development, a point that may be addressed by further epidemiological studies.
Topics: Adipose Tissue; Animals; Carcinogenesis; Genetic Predisposition to Disease; Humans; Janus Kinases; Leptin; Male; Obesity; Polymorphism, Genetic; Prostatic Neoplasms; Receptors, Leptin; STAT3 Transcription Factor; Signal Transduction
PubMed: 26376613
DOI: 10.18632/oncotarget.5574 -
International Journal of Clinical and... 2011Leptin is a multifunctional adipose-derived cytokines that play a critical role in bodyweight homeostasis and energy balance. Recently, leptin and leptin receptor... (Review)
Review
Leptin is a multifunctional adipose-derived cytokines that play a critical role in bodyweight homeostasis and energy balance. Recently, leptin and leptin receptor dysreulation have been reported in variety of malignant cells including thyroid. Leptin modulates growth and proliferation of cancer cells via activation of various growth and survival signaling pathways including JAK/STAT, PI3-kinase/AKT and/or Map kinases. In this review, current understanding of leptin's role in the pathogenesis of thyroid cancer has been described.
Topics: Humans; Leptin; Receptors, Leptin; Signal Transduction; Thyroid Neoplasms
PubMed: 22076163
DOI: No ID Found -
Molecular Medicine (Cambridge, Mass.) Jul 2023Obesity-related asthma is a kind of nonallergic asthma with excessive neutrophil infiltration in the airways. However, the underlying mechanisms have been poorly...
BACKGROUND
Obesity-related asthma is a kind of nonallergic asthma with excessive neutrophil infiltration in the airways. However, the underlying mechanisms have been poorly elucidated. Among the adipokines related to obesity, leptin is related to the inflammatory response. However, little is understood about how leptin acts on the leptin receptor (obR) in neutrophilic airway inflammation in obesity-associated asthma. We explored the inflammatory effects of leptin/obR signaling in an obesity-related neutrophilic airway inflammation mouse model.
METHODS
We established a neutrophilic airway inflammation mouse model using lipopolysaccharide (LPS)/ovalbumin (OVA) sensitization and OVA challenge (LPS + OVA/OVA) in lean, obese, or db/db (obR deficiency) female mice. Histopathological, bronchoalveolar lavage fluid (BALF) inflammatory cell, and lung inflammatory cytokine analyses were used to analyze airway inflammation severity. Western blotting, flow cytometry, reverse transcription-polymerase chain reaction (RT-PCR), and enzyme-linked immunosorbent assay (ELISA) were used to evaluate the underlying mechanisms. In vitro bone marrow-derived macrophage (BMDM) and bone marrow-derived neutrophil experiments were performed.
RESULTS
We found that the serum leptin level was higher in obese than in lean female mice. Compared to LPS/OVA + OVA-treated lean female mice, LPS/OVA + OVA-treated obese female mice had higher peribronchial inflammation levels, neutrophil counts, Th1/Th17-related inflammatory cytokine levels, M1 macrophage polarization levels, and long isoform obR activation, which could be decreased by the obR blockade (Allo-Aca) or obR deficiency, suggesting a critical role of leptin/obR signaling in the pathogenesis of obesity-related neutrophilic airway inflammation in female mice. In in vitro experiments, leptin synergized with LPS/IFN-γ to promote the phosphorylation of the long isoform obR and JNK/STAT3/AKT signaling pathway members to increase M1 macrophage polarization, which was reversed by Allo-Aca. Moreover, leptin/obR-mediated M1 macrophage activity significantly elevated CXCL2 production and neutrophil recruitment by regulating the JNK/STAT3/AKT pathways. In clinical studies, obese patients with asthma had higher serum leptin levels and M1 macrophage polarization levels in induced sputum than non-obese patients with asthma. Serum leptin levels were positively correlated with M1 macrophage polarization levels in patients with asthma.
CONCLUSIONS
Our results demonstrate leptin/obR signaling plays an important role in the pathogenesis of obesity-related neutrophilic airway inflammation in females by promoting M1 macrophage polarization.
Topics: Animals; Female; Mice; Asthma; Bronchoalveolar Lavage Fluid; Cytokines; Disease Models, Animal; Inflammation; Leptin; Lipopolysaccharides; Lung; Macrophages; Mice, Inbred BALB C; Obesity; Ovalbumin; Proto-Oncogene Proteins c-akt; Receptors, Leptin; Signal Transduction
PubMed: 37488474
DOI: 10.1186/s10020-023-00702-w -
Molekuliarnaia Biologiia 2021The hormone leptin is produced in adipocytes of white adipose tissue and crosses the blood-brain barrier. Leptin receptors are present in the brain regions that are...
The hormone leptin is produced in adipocytes of white adipose tissue and crosses the blood-brain barrier. Leptin receptors are present in the brain regions that are involved in higher cognitive functions. In particular, leptin directly influences the glutamate receptor trafficking in CA3 → CA1 synapses to increase the phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3) level, which is controlled by phosphoinositide 3-kinase (PI3K). It is well recognized that glutamate receptor trafficking involves at least some components of the insulin signaling cascade. However, the effects of leptin and insulin hormones differ at the cell and behavioral levels and often oppose each other. The domain organization of synaptic proteins was analyzed for CA1 field neurons. A molecular mechanism of leptin effects in the hippocampus was assumed to involve a cross-talk of the molecular pathways of the leptin receptors and NMDA-type glutamate receptors. Non-receptor protein kinases of the Src subfamily and, in particular, kinase Fyn are part of glutamate receptor macrocomplexes and are involved in regulating the efficiency of synaptic transmission. Fyn was assumed to utilize its SH2 domain to interact with leptin receptors directly or through other proteins and contribute to leptin signaling through the PI3K signaling pathway. The hypothesis explains experimental findings and sheds further light on the fine tuning of hormone-dependent modulation of hippocampal synaptic processes.
Topics: Glutamic Acid; Hippocampus; Leptin; Phosphatidylinositol 3-Kinases; Receptors, Leptin; Receptors, N-Methyl-D-Aspartate; Synapses
PubMed: 34097685
DOI: 10.31857/S0026898421030150 -
Bioscience Reports Jun 2019Some pilot studies already tried to investigate potential associations of leptin () and LEP receptor () variants with coronary artery disease (CAD). However, the... (Meta-Analysis)
Meta-Analysis
Some pilot studies already tried to investigate potential associations of leptin () and LEP receptor () variants with coronary artery disease (CAD). However, the results of these studies were not consistent. Thus, we performed the present meta-analysis to explore associations between variants and CAD in a larger pooled population. Systematic literature research of PubMed, Web of Science, Embase and CNKI was performed to identify eligible case-control studies on associations between variants and CAD. The initial search was conducted in September 2018 and the latest update was performed in December 2018. Q test and statistic were employed to assess between-study heterogeneities. If probability value(-value) of Q test was less than 0.1 or was greater than 50%, random-effect models (REMs) would be used to pool the data. Otherwise, fixed-effect models (FEMs) would be applied for synthetic analyses. A total of ten studies published between 2006 and 2018 were eligible for analyses (1989 cases and 2601 controls). Pooled analyses suggested that rs7799039 variant was significantly associated with CAD under over-dominant model (=0.0007, odds ratio (OR) = 1.36, 95% confidence interval (CI): 1.14-1.63, = 41%, FEM) in overall population, and this significant finding was further confirmed in East Asians in subsequent subgroup analyses. However, no positive findings were observed for rs1137100 and rs1137101 variants in overall and subgroup analyses. Our meta-analysis suggested that rs7799039 variant might affect individual susceptibility to CAD.
Topics: Coronary Artery Disease; Genetic Predisposition to Disease; Humans; Leptin; Polymorphism, Genetic; Receptors, Leptin
PubMed: 31113873
DOI: 10.1042/BSR20190466 -
International Journal of Molecular... Jul 2020Gangliosides are essential components of cell membranes and are involved in a variety of physiological processes, including cell growth, differentiation, and... (Review)
Review
Gangliosides are essential components of cell membranes and are involved in a variety of physiological processes, including cell growth, differentiation, and receptor-mediated signal transduction. They regulate functions of proteins in membrane microdomains, notably receptor tyrosine kinases such as insulin receptor (InsR) and epidermal growth factor receptor (EGFR), through lateral association. Studies during the past two decades using knockout (KO) or pharmacologically inhibited cells, or KO mouse models for glucosylceramide synthase (GCS; ), GM3 synthase (GM3S; ), and GD3 synthase (GD3S; ) have revealed essential roles of gangliosides in hypothalamic control of energy balance. The a-series gangliosides GM1 and GD1a interact with leptin receptor (LepR) and promote LepR signaling through activation of the JAK2/STAT3 pathway. Studies of GM3S KO cells have shown that the extracellular signal-regulated kinase (ERK) pathway, downstream of the LepR signaling pathway, is also modulated by gangliosides. Recent studies have revealed crosstalk between the LepR signaling pathway and other receptor signaling pathways (e.g., InsR and EGFR pathways). Gangliosides thus have the ability to modulate the effects of leptin by regulating functions of such receptors, and by direct interaction with LepR to control signaling.
Topics: Animals; Energy Metabolism; ErbB Receptors; Gangliosides; Humans; Hypothalamus; MAP Kinase Signaling System; Mice; Mice, Knockout; Receptors, Leptin; Sialyltransferases
PubMed: 32731387
DOI: 10.3390/ijms21155349 -
International Journal of Molecular... May 2016In mammals, leptin is a peripheral satiety factor that inhibits feeding by regulating a variety of appetite-related hormones in the brain. However, most of the previous...
In mammals, leptin is a peripheral satiety factor that inhibits feeding by regulating a variety of appetite-related hormones in the brain. However, most of the previous studies examining leptin in fish feeding were performed with mammalian leptins, which share very low sequence homologies with fish leptins. To elucidate the function and mechanism of endogenous fish leptins in feeding regulation, recombinant goldfish leptin-AI and leptin-AII were expressed in methylotrophic yeast and purified by immobilized metal ion affinity chromatography (IMAC). By intraperitoneal (IP) injection, both leptin-AI and leptin-AII were shown to inhibit the feeding behavior and to reduce the food consumption of goldfish in 2 h. In addition, co-treatment of leptin-AI or leptin-AII could block the feeding behavior and reduce the food consumption induced by neuropeptide Y (NPY) injection. High levels of leptin receptor (lepR) mRNA were detected in the hypothalamus, telencephalon, optic tectum and cerebellum of the goldfish brain. The appetite inhibitory effects of leptins were mediated by downregulating the mRNA levels of orexigenic NPY, agouti-related peptide (AgRP) and orexin and upregulating the mRNA levels of anorexigenic cocaine-amphetamine-regulated transcript (CART), cholecystokinin (CCK), melanin-concentrating hormone (MCH) and proopiomelanocortin (POMC) in different areas of the goldfish brain. Our study, as a whole, provides new insights into the functions and mechanisms of leptins in appetite control in a fish model.
Topics: Animals; Brain; Eating; Feeding Behavior; Fish Proteins; Gene Expression Regulation; Goldfish; Leptin; Neuropeptide Y; Receptors, Leptin; Recombinant Proteins
PubMed: 27249000
DOI: 10.3390/ijms17060783 -
International Journal of Molecular... Jul 2021Leptin is a cytokine that regulates appetite and energy expenditure, where in fishes it is primarily produced in the liver and acts to mobilize carbohydrates. Most...
Leptin is a cytokine that regulates appetite and energy expenditure, where in fishes it is primarily produced in the liver and acts to mobilize carbohydrates. Most fishes have only one leptin receptor (LepR/LepRA1), however, paralogs have recently been documented in a few species. Here we reveal a second leptin receptor (LepRA2) in rainbow trout that is 77% similar to trout LepRA1. Phylogenetic analyses show a salmonid specific genome duplication event as the probable origin of the second LepR in trout. Tissues distributions showed tissue specific expression of these receptors, with highest in the ovaries, nearly 50-fold higher than . Interestingly, was most highly expressed in the liver while hepatic levels were low. Feed deprivation elicited a decline in plasma leptin, an increase in hepatic by one week and remained elevated at two weeks, while liver expression of remained low. By contrast, muscle mRNA increased at one and two weeks of fasting, while adipose was concordantly lower in fasted fish. transcript levels were not affected in muscle and fat. These data show and are differentially expressed across tissues and during feed deprivation, suggesting paralog- and tissue-specific functions for these leptin receptors.
Topics: Adipose Tissue; Amino Acid Sequence; Animals; Appetite; Energy Metabolism; Fasting; Fish Proteins; Leptin; Liver; Muscles; Oncorhynchus mykiss; Phylogeny; RNA, Messenger; Receptors, Leptin; Sequence Alignment
PubMed: 34299350
DOI: 10.3390/ijms22147732