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Metabolism: Clinical and Experimental Jan 2015The cloning of leptin in 1994 was an important milestone in obesity research. In those days obesity was stigmatized as a condition caused by lack of character and... (Review)
Review
The cloning of leptin in 1994 was an important milestone in obesity research. In those days obesity was stigmatized as a condition caused by lack of character and self-control. Mutations in either leptin or its receptor were the first single gene mutations found to cause morbid obesity, and it is now appreciated that obesity is caused by a dysregulation of central neuronal circuits. From the first discovery of the leptin deficient obese mouse (ob/ob), to the cloning of leptin (ob aka lep) and leptin receptor (db aka lepr) genes, much has been learned about leptin and its action in the central nervous system. The initial high hopes that leptin would cure obesity were quickly dampened by the discovery that most obese humans have increased leptin levels and develop leptin resistance. Nevertheless, leptin target sites in the brain represent an excellent blueprint for distinct neuronal circuits that control energy homeostasis. A better understanding of the regulation and interconnection of these circuits will further guide and improve the development of safe and effective interventions to treat obesity. This review will highlight our current knowledge about the hormone leptin, its signaling pathways and its central actions to mediate distinct physiological functions.
Topics: Animals; Central Nervous System; Humans; Leptin; Mutation; Receptors, Leptin; Signal Transduction
PubMed: 25305050
DOI: 10.1016/j.metabol.2014.09.010 -
Nature Communications Mar 2023Leptin is an adipocyte-derived protein hormone that promotes satiety and energy homeostasis by activating the leptin receptor (LepR)-STAT3 signaling axis in a subset of...
Leptin is an adipocyte-derived protein hormone that promotes satiety and energy homeostasis by activating the leptin receptor (LepR)-STAT3 signaling axis in a subset of hypothalamic neurons. Leptin signaling is dysregulated in obesity, however, where appetite remains elevated despite high levels of circulating leptin. To gain insight into the mechanism of leptin receptor activation, here we determine the structure of a stabilized leptin-bound LepR signaling complex using single particle cryo-EM. The structure reveals an asymmetric architecture in which a single leptin induces LepR dimerization via two distinct receptor-binding sites. Analysis of the leptin-LepR binding interfaces reveals the molecular basis for human obesity-associated mutations. Structure-based design of leptin variants that destabilize the asymmetric LepR dimer yield both partial and biased agonists that partially suppress STAT3 activation in the presence of wild-type leptin and decouple activation of STAT3 from LepR negative regulators. Together, these results reveal the structural basis for LepR activation and provide insights into the differential plasticity of signaling pathways downstream of LepR.
Topics: Humans; Leptin; Receptors, Leptin; Obesity; Hypothalamus; Neurons
PubMed: 37002197
DOI: 10.1038/s41467-023-37169-6 -
Nature Cell Biology Dec 2023The bone marrow contains peripheral nerves that promote haematopoietic regeneration after irradiation or chemotherapy (myeloablation), but little is known about how this...
The bone marrow contains peripheral nerves that promote haematopoietic regeneration after irradiation or chemotherapy (myeloablation), but little is known about how this is regulated. Here we found that nerve growth factor (NGF) produced by leptin receptor-expressing (LepR) stromal cells is required to maintain nerve fibres in adult bone marrow. In nerveless bone marrow, steady-state haematopoiesis was normal but haematopoietic and vascular regeneration were impaired after myeloablation. LepR cells, and the adipocytes they gave rise to, increased NGF production after myeloablation, promoting nerve sprouting in the bone marrow and haematopoietic and vascular regeneration. Nerves promoted regeneration by activating β2 and β3 adrenergic receptor signalling in LepR cells, and potentially in adipocytes, increasing their production of multiple haematopoietic and vascular regeneration growth factors. Peripheral nerves and LepR cells thus promote bone marrow regeneration through a reciprocal relationship in which LepR cells sustain nerves by synthesizing NGF and nerves increase regeneration by promoting the production of growth factors by LepR cells.
Topics: Bone Marrow; Receptors, Leptin; Bone Marrow Cells; Nerve Growth Factor; Hematopoietic Stem Cells; Nerve Regeneration
PubMed: 38012403
DOI: 10.1038/s41556-023-01284-9 -
Science Advances Jul 2022Alveolar macrophages (AMs) are critical mediators of pulmonary inflammation. Given the unique lung tissue environment, whether there exist AM-specific mechanisms that...
Alveolar macrophages (AMs) are critical mediators of pulmonary inflammation. Given the unique lung tissue environment, whether there exist AM-specific mechanisms that control inflammation is not known. Here, we found that among various tissue-resident macrophage populations, AMs specifically expressed , encoding receptor for a key metabolic hormone leptin. AM-intrinsic Lepr signaling attenuated pulmonary inflammation in vivo, manifested as subdued acute lung injury yet compromised host defense against infection. Lepr signaling protected AMs from necroptosis and thus constrained neutrophil recruitment and tissue damage secondary to release of proinflammatory cytokine interleukin-1α. Mechanistically, Lepr signaling sustained activation of adenosine monophosphate-activated protein kinase in a Ca influx-dependent manner and rewired cellular metabolism, thus preventing excessive lipid droplet formation and overloaded metabolic stress in a lipid-rich alveolar microenvironment. In conclusion, our results defined AM-expressed Lepr as a metabolic checkpoint of pulmonary inflammation and exemplified a macrophage tissue adaptation strategy for maintenance of immune homeostasis.
Topics: Humans; Inflammation; Leptin; Lung; Macrophages, Alveolar; Pneumonia; Receptors, Leptin
PubMed: 35857512
DOI: 10.1126/sciadv.abo3064 -
Developmental Cell Mar 2023Mammalian hematopoietic stem cells (HSCs) colonize the bone marrow during late fetal development, and this becomes the major site of hematopoiesis after birth. However,...
Mammalian hematopoietic stem cells (HSCs) colonize the bone marrow during late fetal development, and this becomes the major site of hematopoiesis after birth. However, little is known about the early postnatal bone marrow niche. We performed single-cell RNA sequencing of mouse bone marrow stromal cells at 4 days, 14 days, and 8 weeks after birth. Leptin-receptor-expressing (LepR) stromal cells and endothelial cells increased in frequency during this period and changed their properties. At all postnatal stages, LepR cells and endothelial cells expressed the highest stem cell factor (Scf) levels in the bone marrow. LepR cells expressed the highest Cxcl12 levels. In early postnatal bone marrow, SCF from LepR/Prx1 stromal cells promoted myeloid and erythroid progenitor maintenance, while SCF from endothelial cells promoted HSC maintenance. Membrane-bound SCF in endothelial cells contributed to HSC maintenance. LepR cells and endothelial cells are thus important niche components in early postnatal bone marrow.
Topics: Animals; Mice; Bone Marrow; Bone Marrow Cells; Endothelial Cells; Hematopoiesis; Hematopoietic Stem Cells; Mammals; Receptors, Leptin; Stem Cell Factor; Stem Cell Niche
PubMed: 36868235
DOI: 10.1016/j.devcel.2023.02.003 -
European Journal of Medical Research Nov 2010Leptin or obesity receptor (Ob-R) is a member of class I cytokine receptor family. Ob-R, expressed in six isoforms, is the product of alternative RNA splicing of db... (Review)
Review
Leptin or obesity receptor (Ob-R) is a member of class I cytokine receptor family. Ob-R, expressed in six isoforms, is the product of alternative RNA splicing of db gene. According to its structural differences, the receptor's isoforms are divided into three classes: long, short, and secretory isoforms. A long, fully active isoform of Ob-Rb is expressed mainly in the hypothalamus, where it takes part in energy homeostasis and in the regulation of secretory organs' activity. Ob-Rb is also present on all types of immune cells, involved in innate and adaptive immunity. Short leptin isoforms (Ob-Ra, Ob-Rc, Ob-Rd, and Ob-Re) that contain box 1 motif are able to bind JAK kinases (Janus kinases) as well as to activate some other signal transduction cascades. A soluble isoform (Ob-Re) can regulate serum leptin concentration and serve as a carrier protein delivering the hormone to its membrane receptors and is able to transduce the signal into the cell. JAK/STAT pathway plays the major role in leptin signal transduction through membrane receptors. Among all Ob-R isoforms, only full-length isoform (Ob-Rb) is able to fully transduce activation signal into the cell.
Topics: Animals; Humans; Polymorphism, Genetic; Receptors, Leptin; Signal Transduction
PubMed: 21147620
DOI: 10.1186/2047-783x-15-s2-50 -
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 -
International Journal of Molecular... Apr 2021Leptin and its receptor are essential for regulating food intake, energy expenditure, glucose homeostasis and fertility. Mutations within leptin or the leptin receptor... (Review)
Review
Leptin and its receptor are essential for regulating food intake, energy expenditure, glucose homeostasis and fertility. Mutations within leptin or the leptin receptor cause early-onset obesity and hyperphagia, as described in human and animal models. The effect of both heterozygous and homozygous variants is much more investigated than compound heterozygous ones. Recently, we discovered a spontaneous compound heterozygous mutation within the leptin receptor, resulting in a considerably more obese phenotype than described for the homozygous leptin receptor deficient mice. Accordingly, we focus on compound heterozygous mutations of the leptin receptor and their effects on health, as well as possible therapy options in human and animal models in this review.
Topics: Animals; Anti-Obesity Agents; Bariatric Surgery; Disease Models, Animal; Heterozygote; Humans; Hyperphagia; Mice; Mutation; Obesity; Receptors, Leptin; alpha-MSH
PubMed: 33922961
DOI: 10.3390/ijms22094475 -
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 -
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