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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 -
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 -
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 -
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 -
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 -
International Journal of Molecular... May 2019Leptin, an adipocyte-derived hormone and its receptor (ObR) expressed in the hypothalamus are well known as an essential regulator of appetite and energy expenditure.... (Review)
Review
Leptin, an adipocyte-derived hormone and its receptor (ObR) expressed in the hypothalamus are well known as an essential regulator of appetite and energy expenditure. Obesity induces abundant leptin production, however, reduced sensitivity to leptin leads to the development of metabolic disorders, so called leptin resistance. The stomach has been identified as an organ that simultaneously expresses leptin and ObR. Accumulating evidence has shown gastric leptin to perform diverse functions, such as those in nutrient absorption and carcinogenesis in the gastrointestinal system, independent of its well-known role in appetite regulation and obesity. Overexpression of leptin and phosphorylated ObR is implicated in gastric cancer in humans and in murine model, and diet-induced obesity causes precancerous lesions in the stomach in mice. While the underlying pathomechanisms remain unclear, leptin signaling can affect gastric mucosal milieu. In this review, we focus on the significant role of the gastric leptin signaling in neoplasia and tumorigenesis in stomach in the context of hereditary and diet-induced obesity.
Topics: Animals; Carcinogenesis; Humans; Leptin; Obesity; Receptors, Leptin; Stomach Neoplasms
PubMed: 31141984
DOI: 10.3390/ijms20112622 -
Biomolecules Jul 2021Leptin, a multifunctional hormone primarily, but not exclusively, secreted in adipose tissue, is implicated in a wide range of biological functions that control... (Review)
Review
Leptin, a multifunctional hormone primarily, but not exclusively, secreted in adipose tissue, is implicated in a wide range of biological functions that control different processes, such as the regulation of body weight and energy expenditure, reproductive function, immune response, and bone metabolism. In addition, leptin can exert angiogenic and mitogenic actions in peripheral organs. Leptin biological activities are greatly related to its interaction with the leptin receptor. Both leptin excess and leptin deficiency, as well as leptin resistance, are correlated with different human pathologies, such as autoimmune diseases and cancers, making leptin and leptin receptor important drug targets. The development of leptin signaling modulators represents a promising strategy for the treatment of cancers and other leptin-related diseases. In the present manuscript, we provide an update review about leptin-activity modulators, comprising leptin mutants, peptide-based leptin modulators, as well as leptin and leptin receptor specific monoclonal antibodies and nanobodies.
Topics: Animals; Binding Sites; Humans; Leptin; Peptides; Receptors, Leptin; Single-Domain Antibodies
PubMed: 34356668
DOI: 10.3390/biom11071045 -
Current Opinion in Nephrology and... Mar 2023Endothelial dysfunction is a major risk factor for many cardiovascular diseases, notably hypertension. Obesity increases the risk of endothelial dysfunction in... (Review)
Review
PURPOSE OF REVIEW
Endothelial dysfunction is a major risk factor for many cardiovascular diseases, notably hypertension. Obesity increases the risk of endothelial dysfunction in association with increasing production of the adipokine leptin. Preclinical studies have begun to unravel the mechanisms whereby leptin leads to the development of endothelial dysfunction, which are sex-specific. This review will summarize recent findings of mechanisms of leptin-induced endothelial impairment in both male and females and in pregnancy.
RECENT FINDINGS
Leptin receptors are found in high concentrations in the central nervous system (CNS), via which leptin promotes appetite suppression and upregulates sympathetic nervous system activation. However, leptin receptors are expressed in many other tissues, including the vascular endothelial cells and smooth muscle cells. Recent studies in mice with vascular endothelial or smooth muscle-specific knockdown demonstrate that endothelial leptin receptor activation plays a protective role against endothelial dysfunction in male animals, but not necessarily in females. Clinical studies indicate that women may be more sensitive to obesity-associated vascular endothelial dysfunction. Emerging preclinical data indicates that leptin and progesterone increase aldosterone production and endothelial mineralocorticoid receptor activation, respectively. Furthermore, decades of clinical studies indicate that leptin levels increase in the hypertensive pregnancy disorder preeclampsia, which is characterized by systemic endothelial dysfunction. Leptin infusion in mice induces the clinical characteristics of preeclampsia, including endothelial dysfunction.
SUMMARY
Novel preclinical data indicate that the mechanisms whereby leptin promotes endothelial dysfunction are sex-specific. Leptin-induced endothelial dysfunction may also play a role in hypertensive pregnancy as well.
Topics: Male; Female; Humans; Mice; Animals; Leptin; Endothelial Cells; Pre-Eclampsia; Receptors, Leptin; Obesity; Hypertension
PubMed: 36598435
DOI: 10.1097/MNH.0000000000000867