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Biologie Aujourd'hui 2018Receptors are the master regulators conveying the information provided by the hormone from the extracellular environment to the intracellular milieu. As a result, the... (Review)
Review
Receptors are the master regulators conveying the information provided by the hormone from the extracellular environment to the intracellular milieu. As a result, the level of receptors at the cell surface can determine the signaling strength. Regulation of receptor trafficking to the cell surface or receptor retention processes in intracellular compartments are key mechanisms for leptin receptor (ObR) activity. An alteration of these mechanisms leads to the development of obesity. However, the canonical mechanism of plasma membrane receptors activation is challenged by the discovery that intracellular receptors also have their own signaling activity inside specific intracellular compartments. These intracellular receptors can trigger signaling that regulates a particular function, different from, or in continuity with, surface receptor signaling. We will address both these aspects by focusing particularly on the case of the leptin receptor (ObR), i.e., i) the regulation of its level of exposure to the cell surface and its impact on the development of obesity, and ii) the discovery of its location and signaling in some intracellular compartments.
Topics: Animals; Cell Membrane; Humans; Leptin; Obesity; Organelles; Protein Transport; Receptors, Leptin; Signal Transduction; Subcellular Fractions
PubMed: 30362454
DOI: 10.1051/jbio/2018020 -
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 -
Sleep Jun 2021Obesity leads to obstructive sleep apnea (OSA), which is recurrent upper airway obstruction during sleep, and obesity hypoventilation syndrome (OHS), hypoventilation...
STUDY OBJECTIVES
Obesity leads to obstructive sleep apnea (OSA), which is recurrent upper airway obstruction during sleep, and obesity hypoventilation syndrome (OHS), hypoventilation during sleep resulting in daytime hypercapnia. Impaired leptin signaling in the brain was implicated in both conditions, but mechanisms are unknown. We have previously shown that leptin stimulates breathing and treats OSA and OHS in leptin-deficient ob/ob mice and leptin-resistant diet-induced obese mice and that leptin's respiratory effects may occur in the dorsomedial hypothalamus (DMH). We hypothesized that leptin receptor LepRb-deficient db/db mice have obesity hypoventilation and that restoration of leptin signaling in the DMH will increase ventilation during sleep in these animals.
METHODS
We measured arterial blood gas in unanesthetized awake db/db mice. We subsequently infected these animals with Ad-LepRb or control Ad-mCherry virus into the DMH and measured ventilation during sleep as well as CO2 production after intracerebroventricular (ICV) infusions of phosphate-buffered saline or leptin.
RESULTS
Awake db/db mice had elevated CO2 levels in the arterial blood. Ad-LepRb infection resulted in LepRb expression in the DMH neurons in a similar fashion to wildtype mice. In LepRb-DMH db/db mice, ICV leptin shortened REM sleep and increased inspiratory flow, tidal volume, and minute ventilation during NREM sleep without any effect on the quality of NREM sleep or CO2 production. Leptin had no effect on upper airway obstruction in these animals.
CONCLUSION
Leptin stimulates breathing and treats obesity hypoventilation acting on LepRb-positive neurons in the DMH.
Topics: Animals; Hypothalamus; Leptin; Mice; Mice, Obese; Receptors, Leptin; Sleep
PubMed: 33624805
DOI: 10.1093/sleep/zsab046 -
Cell Metabolism Jul 2021Knowledge of how leptin receptor (LepR) neurons of the mediobasal hypothalamus (MBH) access circulating leptin is still rudimentary. Employing intravital microscopy, we...
Knowledge of how leptin receptor (LepR) neurons of the mediobasal hypothalamus (MBH) access circulating leptin is still rudimentary. Employing intravital microscopy, we found that almost half of the blood-vessel-enwrapping pericytes in the MBH express LepR. Selective disruption of pericytic LepR led to increased food intake, increased fat mass, and loss of leptin-dependent signaling in nearby LepR neurons. When delivered intravenously, fluorescently tagged leptin accumulated at hypothalamic LepR pericytes, which was attenuated upon pericyte-specific LepR loss. Because a paracellular tracer was also preferentially retained at LepR pericytes, we pharmacologically targeted regulators of inter-endothelial junction tightness and found that they affect LepR neuronal signaling and food intake. Optical imaging in MBH slices revealed a long-lasting, tonic calcium increase in LepR pericytes in response to leptin, suggesting pericytic contraction and vessel constriction. Together, our data indicate that LepR pericytes facilitate localized, paracellular blood-brain barrier leaks, enabling MBH LepR neurons to access circulating leptin.
Topics: Animals; Appetite Regulation; Feeding Behavior; Female; Hypothalamus; Leptin; Male; Mice; Mice, Transgenic; Neurons; Pericytes; Receptors, Leptin; Signal Transduction
PubMed: 34129812
DOI: 10.1016/j.cmet.2021.05.017 -
American Journal of Physiology.... May 2020Previous studies indicate that inhibition of food intake by leptin is mediated by an integrated response to activation of hypothalamic and hindbrain receptors. This...
Previous studies indicate that inhibition of food intake by leptin is mediated by an integrated response to activation of hypothalamic and hindbrain receptors. This study tested whether loss of hindbrain leptin receptor signaling changed sensitivity to forebrain leptin. Injections of leptin-conjugated saporin (Lep-Sap) into the medial nucleus of the solitary tract (NTS) were used to destroy hindbrain leptin receptor-expressing neurons of male Sprague-Dawley rats. Controls were injected with saporin conjugated with a nonsense peptide (Blk-Sap). Lep-Sap had no effect on daily food intake or body weight, but expression of phosphorylated signal transducer and activator of transcription 3 (pSTAT3) in the NTS following a peripheral injection of leptin was abolished 26 days after Lep-Sap injections. To test forebrain leptin sensitivity, Lep-Sap and Blk-Sap rats received third-ventricle injections of 0, 0.05, 0.1, 0.25, or 0.5 μg leptin. Food intake was inhibited by 0.25 and 0.5 μg leptin in Blk-Sap rats, but there was no significant effect of leptin on food intake of Lep-Sap rats. There was no difference in hypothalamic pSTAT3 in unstimulated conditions, but pSTAT3 was lower in the dorsomedial region of the ventromedial nucleus of the hypothalamus (VMH) of Lep-Sap rats compared with Blk-Sap rats following a third-ventricle injection of 0.25 μg leptin. These results are consistent with previous data showing that loss of VMH leptin receptor-expressing cells prevents weight loss caused by fourth-ventricle leptin infusion and show that the integrated response between the hindbrain and forebrain is heavily dependent on leptin activity in the VMH.
Topics: Animals; Body Weight; Eating; Leptin; Male; Neurons; Prosencephalon; Rats; Rats, Sprague-Dawley; Receptors, Leptin; Rhombencephalon; Ventromedial Hypothalamic Nucleus
PubMed: 32228323
DOI: 10.1152/ajpendo.00020.2020 -
Journal of Investigative Medicine : the... Oct 2009The discovery of leptin in 1994 has led to remarkable advances in obesity research. We now know that leptin is a cytokinelike hormone that is produced in adipose tissue... (Review)
Review
The discovery of leptin in 1994 has led to remarkable advances in obesity research. We now know that leptin is a cytokinelike hormone that is produced in adipose tissue and plays a pivotal role in regulation of energy balance and in a variety of additional processes via actions in the central nervous system. This symposium review covers current understandings of neuronal leptin receptor signaling and mechanisms of obesity-related leptin resistance in the central nervous system and provides recent insights into the regulation of peripheral glucose balance by central leptin action in rodents.
Topics: Animals; Brain; Drug Resistance; Leptin; Obesity; Pro-Opiomelanocortin; Receptors, Leptin; Signal Transduction
PubMed: 20029269
DOI: 10.2310/JIM.0b013e3181bb0d49 -
Current Pharmaceutical Design 2014The OB-receptor or leptin receptor (LR) is crucial for energy homeostasis and regulation of food uptake. Leptin is a 16 kDa hormone that is mainly secreted by fat cells... (Review)
Review
Leptin and the OB-receptor as anti-obesity target: recent in silico advances in the comprehension of the protein-protein interaction and rational drug design of anti- obesity lead compounds.
The OB-receptor or leptin receptor (LR) is crucial for energy homeostasis and regulation of food uptake. Leptin is a 16 kDa hormone that is mainly secreted by fat cells into the bloodstream. Under normal circumstances, circulating leptin levels are proportionate to the fat body mass. Sensing of elevated leptin levels by the hypothalamic neuro-circuitry activates a negative feedback loop resulting in reduced food intake and increased energy expenditure. Decreased leptin concentrations lead to opposite effects. Therefore, rational design of leptin agonists/antagonists could be an appealing challenge in the battle against obesity. The Leptin/LR interactions have been studied in several works by means of different molecular modelling approaches, spreading from homology modelling to manual docking. No small molecules have ever been proposed as agonists of the Ob receptor but researchers' efforts focused only on leptin-related synthetic peptides as receptor antagonists and on peptidomimetics. In this review we try to track a timeline of obtained in silico information to clarify the mechanism of interaction between leptin and its receptor, together to summarize the more recent efforts to propose new drugs usable in anti-obesity therapy. Final considerations could be useful starting points for the rational drug design of new lead compounds.
Topics: Anti-Obesity Agents; Body Weight; Drug Design; Humans; Infant, Newborn; Leptin; Models, Molecular; Obesity; Protein Binding; Receptors, Leptin; Risk Factors; Signal Transduction
PubMed: 24180400
DOI: 10.2174/13816128113196660743 -
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 -
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 -
BMC Cancer Mar 2023Effective screening and treatment have reduced the number of women dying from breast cancer (BC). However, the long-term sequelae of BC treatment and psychosocial...
BACKGROUND
Effective screening and treatment have reduced the number of women dying from breast cancer (BC). However, the long-term sequelae of BC treatment and psychosocial factors seriously affect the life quality of BC patients and survivors. Therefore, the discovery and application of targeted biomarkers to improve the functional outcome and life quality of BC patients is necessary.
AIMS
To explore the impact of leptin (LEP)/ leptin receptor (LEPR) expression on occurrence and survival of BC.
METHODS
Totally 132 primary BC and 66 non-BC patients who underwent surgery in department of breast surgery in Shanxi Cancer Hospital from January to October in 2009 were enrolled in this retrospective study. LEP and LEPR were examined in BC tissues, benign breast tissues, para-carcinoma tissues using immunohistochemical staining. Kaplan-Meier curve was generated to test survival time.
RESULTS
The high level expression of LEP and LEPR in BC tissues were significantly higher than that in benign breast tissues and in para-carcinoma tissues (all P < 0.05). The LEP expression in patients with lymph node metastases was significantly higher than that in patients without lymph nodes metastases (P = 0.002). LEPR expression was correlated with higher Ki-67 rate (P = 0.002). LEP and LEPR both had no impact on survival (all P > 0.05).
CONCLUSIONS
High LEP/LEPR expression were risk factors for occurrence of BC, but without impact on survival.
Topics: Humans; Female; Leptin; Retrospective Studies; Breast Neoplasms; Receptors, Leptin; Carcinoma; Biomarkers; Polymorphism, Single Nucleotide
PubMed: 36941557
DOI: 10.1186/s12885-023-10617-8