-
Journal of Neuroendocrinology May 2019Nutrition and growth are important signals for pubertal development, although how they are perceived and integrated in brain circuits has not been well defined. Growth... (Review)
Review
Nutrition and growth are important signals for pubertal development, although how they are perceived and integrated in brain circuits has not been well defined. Growth hormones and metabolic cues both recruit phosphatidylinositol 3-kinase (PI3K) signalling in hypothalamic sites, although whether they converge into the same neuronal population(s) is also not known. In this review, we discuss recent findings from our laboratory showing the role of PI3K subunits in cells directly responsive to the adipocyte-derived hormone leptin in the coordination of growth, pubertal development and fertility. Mice with deletion of PI3K p110α and p110β catalytic subunits in leptin receptor cells (LR ) have a lean phenotype associated with increased energy expenditure, locomotor activity and thermogenesis. The LR mice also show deficient growth and delayed puberty. Deletion of a single subunit (ie, p110α) in LR cells (LR ) causes a similar phenotype of increased energy expenditure, deficient growth and delayed pubertal development, indicating that these functions are preferably controlled by p110α. The LR mice show enhanced leptin sensitivity in metabolic regulation but, remarkably, these mice are unresponsive to the effects of leptin on growth and puberty. PI3K is also recruited by insulin and a subpopulation of LR neurones is responsive to i.c.v. insulin administration. Deletion of insulin receptor in LR cells causes no changes in body weight or linear growth and induces only a mild delay in pubertal completion. Our findings demonstrate that PI3K in LR cells plays an essential role in growth and reproduction. We will also discuss the potential neural pathways underlying these effects.
Topics: Animals; Growth; Humans; Neurons; Neurosecretory Systems; Phosphatidylinositol 3-Kinases; Puberty; Receptors, Leptin; Reproduction; Signal Transduction
PubMed: 30618188
DOI: 10.1111/jne.12685 -
International Journal of Environmental... Apr 2017Few studies have assessed the association between leptin receptor (LEPR) gene polymorphism and the risk of cardiovascular disease (CVD). Of the few epidemiological... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
Few studies have assessed the association between leptin receptor (LEPR) gene polymorphism and the risk of cardiovascular disease (CVD). Of the few epidemiological studies on this topic, the results are still controversial.
METHODS
PubMed and Embase were screened for studies from their inception to 9 October 2016. The pooled odds ratio (OR) with the corresponding confidence intervals (CI) were used to measure the effect size for studies that reported the association under allelic, homozygous, and dominant models. Pre-specified characteristics were conducted in the subgroup analysis. Heterogeneity between subgroups was evaluated by meta-regression analysis.
RESULTS
Seven eligible studies involving 44,133 participants were included in our meta-analysis. Borderline significant association was observed between the LEPR gene polymorphism (rs1137101, rs1137100, rs6700896, and rs8179183) and the increased risk of CVD with considerable heterogeneity under the allelic model, and the overall pooled OR (95% CI) was 1.10 (0.99, 1.22). The LEPR gene variant rs6700896, 109G allele, and 109GG genotype were significantly associated with the increased risk of CVD. Furthermore, stratified group analysis revealed that the association was more pronounced for stroke. Race-differences might also cause the considerable heterogeneity and non-significant association.
CONCLUSIONS
This is the first systematic review and meta-analysis to investigate the association between LEPR gene variants and CVD risk. Some LEPR gene variants were significantly associated with the increased risk of CVD. However, the present study is limited in its small number of included studies, considerable heterogeneity, and observational study design. Further research is still warranted to confirm the magnitude of the association.
Topics: Cardiovascular Diseases; Humans; Polymorphism, Genetic; Receptors, Leptin; Risk
PubMed: 28368354
DOI: 10.3390/ijerph14040375 -
Frontiers in Immunology 2021Adipose tissue secretes various peptides, including leptin. This hormone acts through the leptin receptor (Ob-R), which is expressed ubiquitously on the surface of... (Review)
Review
Adipose tissue secretes various peptides, including leptin. This hormone acts through the leptin receptor (Ob-R), which is expressed ubiquitously on the surface of various cells, including breast cancer cells and immune cells. Increasing evidence points to an interaction between the tumor microenvironment, tumor cells, and the immune system. Leptin plays an important role in breast cancer tumorigenesis and may be implicated in activation of the immune system. While breast cancer cannot be considered an immunogenic cancer, the triple-negative subtype is an exception. Specific immune cells - tumor infiltrating lymphocytes - are involved in the immune response and act as predictive and prognostic factors in certain breast cancer subtypes. The aim of this article is to review the interaction between adipose tissue, through the expression of leptin and its receptor, and the adaptive immune system in breast cancer.
Topics: Adipose Tissue; Animals; Breast; Breast Neoplasms; Carcinogenesis; Disease Models, Animal; Female; Humans; Immunity, Cellular; Leptin; Lymphocytes, Tumor-Infiltrating; Mice, Transgenic; Receptors, Leptin; T-Lymphocytes, Cytotoxic; Tumor Microenvironment
PubMed: 34868066
DOI: 10.3389/fimmu.2021.784823 -
Frontiers in Bioscience (Landmark... Jun 2011The identification of spontaneous mutations in the leptin- and leptin receptor (ObR)-encoding ob and db gene, respectively, opened up a new field in obesity research.... (Review)
Review
The identification of spontaneous mutations in the leptin- and leptin receptor (ObR)-encoding ob and db gene, respectively, opened up a new field in obesity research. Leptin, an adipocyte-derived hormone, mirrors the body's fat stores and thereby informs the brain about the body's energy status. In the hypothalamus, leptin triggers specific neuronal subpopulations, like POMC and AgRP/NPY neurons, and activates several intracellular signaling events, including the JAK/STAT, MAPK, PI3K and mTOR pathway, which eventually translates into decreased food intake and increased energy expenditure. Leptin is also involved in the regulation of other physiological processes including reproduction, bone homeostasis and immune function. Here, we review the pathways that are activated upon ObR activation, how ObR expression is controlled and the molecular mechanisms leading to leptin resistance, i.e. the inability to adequately respond to elevated leptin levels and therefore a primary risk factor for obesity.
Topics: AMP-Activated Protein Kinases; Animals; Blood-Brain Barrier; Endoplasmic Reticulum; Humans; Janus Kinases; Leptin; MAP Kinase Signaling System; Models, Biological; Obesity; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Receptors, Leptin; STAT Transcription Factors; Signal Transduction; Stress, Physiological; TOR Serine-Threonine Kinases
PubMed: 21622208
DOI: 10.2741/3885 -
Frontiers in Immunology 2023Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease mainly mediated by IgG autoantibody. While follicular helper T (Tfh) cells are crucial for...
BACKGROUND
Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease mainly mediated by IgG autoantibody. While follicular helper T (Tfh) cells are crucial for supporting IgG autoantibody generation in human SLE, underlying mechanisms for Tfh cell mal-differentiation remain unclear.
METHODS
In total, 129 SLE patients and 37 healthy donors were recruited for this study. Circulating leptin was determined by ELISA from patients with SLE and healthy individuals. CD4 T cells isolated from SLE patients and healthy donors were activated with anti-CD3/CD28 beads under cytokine-unbiased conditions in the presence or absence of recombinant leptin protein, followed by detection for Tfh cell differentiation by quantifying intracellular transcription factor Bcl-6 and cytokine IL-21. AMPK activation was assessed by analyzing phosphor-AMPK using phosflow cytometry and immunoblots. Leptin receptor expression was determined using flow cytometry and its overexpression was achieved by transfection with an expression vector. Humanized SLE chimeras were induced by injecting patients' immune cells into immune-deficient NSG mice and used for translational studies.
RESULTS
Circulating leptin was elevated in patients with SLE, inversely associated with disease activity. In healthy individuals, leptin efficiently inhibited Tfh cell differentiation through inducing AMPK activation. Meanwhile, leptin receptor deficiency was a feature of CD4 T cells in SLE patients, impairing the inhibitory effect of leptin on the differentiation of Tfh cells. As a result, we observed the coexistence of high circulating leptin and increased Tfh cell frequencies in SLE patients. Accordingly, overexpression of leptin receptor in SLE CD4 T cells abrogated Tfh cell mal-differentiation and IgG anti-dsDNA generation in humanized lupus chimeras.
CONCLUSION
Leptin receptor deficiency blocks the inhibitory effect of leptin on SLE Tfh cell differentiation, serving as a promising therapeutic target for lupus management.
Topics: Humans; Animals; Mice; T-Lymphocytes, Helper-Inducer; Receptors, Leptin; Leptin; AMP-Activated Protein Kinases; Lupus Erythematosus, Systemic; Autoantibodies; Immunoglobulin G
PubMed: 37006245
DOI: 10.3389/fimmu.2023.1157731 -
Gynecological Endocrinology : the... Dec 2023Published evidence indicated that the leptin receptor (LEPR) gene polymorphisms are associated with polycystic ovary syndrome (PCOS) risk. However, studies on the... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
Published evidence indicated that the leptin receptor (LEPR) gene polymorphisms are associated with polycystic ovary syndrome (PCOS) risk. However, studies on the association between the polymorphisms of LEPR gene are inconsistent or even controversial.
MATERIAL AND METHODS
We conducted this meta-analysis to explore the more precise relationship between LEPR polymorphisms and PCOS risk. Relevant articles were searched with five online databases up to March 1 2023. Odds ratios (OR) with 95% confidence intervals (CI) were selected to examine the statistical strength of each genetic model. Moreover, RNA secondary structure and variant effects of these loci were examined with in silico analysis.
RESULTS
Overall, 11 publications were analyzed, and the pooled results did not present any significant association between rs1137101 A/G polymorphism and PCOS risk in general population and some subgroup analysis. But the significant association were observed in Asian population (AG vs. AA: OR = 0.51, 95%CI = 0.32-0.81, = .01, I=0%; AG + GG vs. AA: OR = 0.41, 95%CI = 0.26-0.65, < .01, I=25.9%). Moreover, similar positive associations were also observed in rs1805096 polymorphism with PCOS risk.
CONCLUSION
In summary, our meta-analysis suggested that the LEPR gene polymorphisms might be associated with PCOS susceptibility. Owing to the limited studies and small sample size in our meta-analysis, more well-designed studies from different races were needed to be conducted to verify the current results.
Topics: Female; Humans; Asian People; Genetic Predisposition to Disease; Polycystic Ovary Syndrome; Polymorphism, Single Nucleotide; Receptors, Leptin
PubMed: 37935245
DOI: 10.1080/09513590.2023.2279565 -
Cell Reports May 2023Crosstalk among organs/tissues is important for regulating systemic metabolism. Here, we demonstrate inter-organ crosstalk between hepatic insulin and hypothalamic...
Crosstalk among organs/tissues is important for regulating systemic metabolism. Here, we demonstrate inter-organ crosstalk between hepatic insulin and hypothalamic leptin actions, which maintains survival during food shortages. In inducible liver insulin receptor knockout mice, body weight is increased with hyperphagia and decreased energy expenditure, accompanied by increased circulating leptin receptor (LepR) and decreased hypothalamic leptin actions. Additional hepatic LepR deficiency reverses these metabolic phenotypes. Thus, decreased hepatic insulin action suppresses hypothalamic leptin action with increased liver-derived soluble LepR. Human hepatic and circulating LepR levels also correlate negatively with hepatic insulin action indices. In mice, food restriction decreases hepatic insulin action and energy expenditure with increased circulating LepR. Hepatic LepR deficiency increases mortality with enhanced energy expenditure during food restriction. The liver translates metabolic cues regarding energy-deficient status, which is reflected by decreased hepatic insulin action, into soluble LepR, thereby suppressing energy dissipation and assuring survival during food shortages.
Topics: Animals; Mice; Humans; Leptin; Insulin; Liver; Body Weight; Hypothalamus; Mice, Knockout; Receptors, Leptin; Energy Metabolism
PubMed: 37116488
DOI: 10.1016/j.celrep.2023.112415 -
Biomolecules Mar 2022Leptin is a pleiotropic hormone known for regulating appetite and metabolism. To characterize the role of leptin signaling in rainbow trout, we used CRISPR/Cas9 genome...
Leptin is a pleiotropic hormone known for regulating appetite and metabolism. To characterize the role of leptin signaling in rainbow trout, we used CRISPR/Cas9 genome editing to disrupt the leptin receptor (LepR) genes, and . We compared wildtype (WT) and mutant fish that were either fed to satiation or feed deprived for six weeks. The LepR mutants exhibited a hyperphagic phenotype, which led to heavier body weight, faster specific growth rate, increased viscero- and hepatosomatic indices, and greater condition factor. Muscle glycogen, plasma leptin, and leptin transcripts () were also elevated in fed LepR mutant fish. Expression levels of several hypothalamic genes involved in feed regulation were analyzed (, , , , , , ). No differences were detected between fed WT and mutants except for (proopiomelanocortin-b), where levels were 7.5-fold higher in LepR fed mutants, suggesting that expression is regulated by leptin signaling. Fatty acid (FA) content did not statistically differ in muscle of fed mutant fish compared to WT. However, fasted mutants exhibited significantly lower muscle FA concentrations, suggesting that LepR mutants exhibit increased FA mobilization during fasting. These data demonstrate a key role for leptin signaling in lipid and energy mobilization in a teleost fish.
Topics: Animals; Fasting; Fatty Acids; Hyperphagia; Leptin; Oncorhynchus mykiss; Pro-Opiomelanocortin; Receptors, Leptin
PubMed: 35454105
DOI: 10.3390/biom12040516 -
Journal of Veterinary Internal Medicine Jan 2017Leptin and its receptor play a role in several disease processes such as pancreatitis and heart disease. However, their association with gallbladder mucocele (GBM) in...
BACKGROUND
Leptin and its receptor play a role in several disease processes such as pancreatitis and heart disease. However, their association with gallbladder mucocele (GBM) in dogs has not been reported.
HYPOTHESIS/OBJECTIVES
To evaluate differences in the expression of leptin and leptin receptor between dogs with and without GBM.
ANIMALS
Twenty-five healthy dogs, including 9 laboratory beagle dogs, and 22 client-owned dogs with GBM.
METHODS
Serum leptin concentration was determined in blood samples of all dogs by ELISA. Canine gallbladder samples were collected from 9 dogs with GBM that underwent surgery for therapeutic purposes and from 9 healthy laboratory beagle dogs as a normal control group. Samples were analyzed for leptin and leptin receptor mRNA by real-time polymerase chain reaction.
RESULTS
Serum leptin concentration was significantly higher in dogs with GBM than in healthy dogs (medians of 7.03 and 2.18 ng/mL, respectively; P < .001). Patients with GBM that had undergone surgery had significantly higher serum leptin concentrations than those that had not (medians of 12.2 and 4.09 ng/mL, respectively; P = .001). However, no difference in serum leptin concentration was found between dogs with GBM with or without endocrinopathies. The mRNA expression levels of leptin and its receptor were significantly increased in the gallbladder tissues of dogs with GBM.
CONCLUSIONS AND CLINICAL IMPORTANCE
Dysregulation of leptin might be involved in the pathophysiology of GBM, and leptin concentrations might be associated with GBM severity.
Topics: Animals; Cholelithiasis; Dog Diseases; Dogs; Enzyme-Linked Immunosorbent Assay; Female; Gallbladder; Leptin; Male; Pedigree; Receptors, Leptin
PubMed: 28032399
DOI: 10.1111/jvim.14612 -
Trends in Endocrinology and Metabolism:... Jan 2010The leptin receptor was discovered as a leptin binding protein, which is highly expressed in the choroid plexus. Mapping of the gene's chromosomal locations in rodents... (Review)
Review
The leptin receptor was discovered as a leptin binding protein, which is highly expressed in the choroid plexus. Mapping of the gene's chromosomal locations in rodents revealed that mutations in Lepr were the basis of obesity/diabetes mutations in rodents and humans. Genetic manipulations that target Lepr expression in specific neurons or hypothalamic areas have generated insights into the modes by which body composition and reproductive function are modulated by the leptin receptor. These animal models have also been instrumental in identifying diabetes susceptibility genes. In this review we discuss the evidence that supports the concept of networked functions of leptin receptor as it pertains to feeding, substrate utilization and reproduction.
Topics: Adiposity; Animals; Diabetes Mellitus; Female; Fertility; Genetic Predisposition to Disease; Humans; Infertility, Female; Infertility, Male; Male; Obesity; Receptors, Leptin
PubMed: 19854659
DOI: 10.1016/j.tem.2009.07.004