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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 -
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 -
Comparative Biochemistry and... Jan 2022The present review provides a comparative insight into structure, function and control of leptin system in fishes, herptiles, birds and mammals. In general, leptin acts... (Review)
Review
The present review provides a comparative insight into structure, function and control of leptin system in fishes, herptiles, birds and mammals. In general, leptin acts as an anorexigenic hormone since its administration results in decrease of food intake in vertebrates. Nonetheless, functional paradox arises in fishes from contradictory observations on level of leptin during fasting and re-feeding. In addition, leptin is shown to modulate metabolic functions in fishes, reptiles, birds and mammals. Leptin also regulates reproductive and immune functions though more studies are warranted in non-mammalian vertebrates. The expression of leptin and its receptor is influenced by numerous factors including sex steroids, stress and stress-induced catecholamines and glucocorticoids though their effect in non-mammalian vertebrates is hard to be generalized due to limited studies.
Topics: Animals; Fishes; Leptin; Mammals; Receptors, Leptin; Vertebrates
PubMed: 34343670
DOI: 10.1016/j.cbpb.2021.110652 -
The New England Journal of Medicine Jun 2023
Topics: Humans; Obesity; Receptors, Leptin
PubMed: 37314711
DOI: 10.1056/NEJMe2301915 -
Proceedings of the National Academy of... Jan 2024Leptin protein was thought to be unique to leptin receptor (LepR), but the phenotypes of mice with mutation in LepR [ (diabetes)] and leptin [ (obese)] are not...
Leptin protein was thought to be unique to leptin receptor (LepR), but the phenotypes of mice with mutation in LepR [ (diabetes)] and leptin [ (obese)] are not identical, and the cause remains unclear. Here, we show that , but not , mice had defect in tenotomy-induced heterotopic ossification (HO), implicating alternative ligand(s) for LepR might be involved. Ligand screening revealed that ANGPTL4 (angiopoietin-like protein 4), a stress and fasting-induced factor, was elicited from brown adipose tissue after tenotomy, bound to LepR on PRRX1 mesenchymal cells at the HO site, thus promotes chondrogenesis and HO development. Disruption of LepR in PRRX1 cells, or lineage ablation of LepR cells, or deletion of ANGPTL4 impeded chondrogenesis and HO in mice. Together, these findings identify ANGPTL4 as a ligand for LepR to regulate the formation of acquired HO.
Topics: Animals; Mice; Leptin; Ligands; Mice, Inbred C57BL; Ossification, Heterotopic; Osteogenesis; Receptors, Leptin
PubMed: 38147550
DOI: 10.1073/pnas.2310685120 -
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 -
Best Practice & Research. Clinical... Oct 2015The adipokine leptin realizes signal transduction via four different leptin receptor (OB-R) isoforms. The amount of functionally active OB-R, however, is affected by... (Review)
Review
The adipokine leptin realizes signal transduction via four different leptin receptor (OB-R) isoforms. The amount of functionally active OB-R, however, is affected by constitutive shedding of the extracellular domain. The product of the cleavage process, the so-called soluble leptin receptor (sOB-R), is the main binding protein for leptin in human blood and modulates its bioavailability. Concentrations of sOB-R are differentially regulated in metabolic disorders, such as type 1 diabetes mellitus or obesity, and can, therefore, enhance or reduce leptin sensitivity. Lipotoxicity and apoptosis increase OB-R cleavage via ADAM10-dependent mechanisms. In contrast, although increased sOB-R concentrations seem to directly inhibit leptin effects, reduced amounts of sOB-R may reflect decreased membrane expression of OB-R. These findings, in part, explain alterations of leptin sensitivity that are associated with changes in serum sOB-R concentrations seen in metabolic disorders.
Topics: ADAM10 Protein; Animals; Apoptosis; Diabetes Mellitus, Type 1; Humans; Leptin; Obesity; Receptors, Leptin
PubMed: 26522452
DOI: 10.1016/j.beem.2015.08.002 -
Journal of Biomolecular Structure &... Apr 2023The leptin-leptin receptor complex is at the very core of energy homeostasis and immune system regulation, among many other functions. In this work, we built homology...
The leptin-leptin receptor complex is at the very core of energy homeostasis and immune system regulation, among many other functions. In this work, we built homology models of leptin and the leptin binding domain (LBD) of the receptor from humans and mice. Docking analyses were used to obtain the coordinates of the native leptin-LBD complexes and a mixed heterodimer formed by human leptin and mouse LBD. Molecular dynamics (MD) simulations were performed using all models (monomers and heterodimers) as initial coordinates and the GROMACS program. The overall structural and dynamical behaviors are similar for the three complexes. Upon MD simulations, several new interactions appear. In particular, hydrophobic interactions, with more than 90% persistence, seem to be the most relevant for the stability of the dimers, as well as the pair formed by Asp85 and Arg468. This analysis provides structural and dynamical information, at the atomistic level, about the mechanism of leptin-LBD complex formation and leptin receptor activation. This knowledge might be used in the rational drug design of therapeutics to modulate leptin signaling.Communicated by Ramaswamy H. Sarma.
Topics: Humans; Animals; Mice; Leptin; Receptors, Leptin; Protein Binding; Molecular Dynamics Simulation; Drug Design; Molecular Docking Simulation
PubMed: 35075977
DOI: 10.1080/07391102.2022.2029568 -
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 -
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