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International Journal of Molecular... Jul 2020Gangliosides are essential components of cell membranes and are involved in a variety of physiological processes, including cell growth, differentiation, and... (Review)
Review
Gangliosides are essential components of cell membranes and are involved in a variety of physiological processes, including cell growth, differentiation, and receptor-mediated signal transduction. They regulate functions of proteins in membrane microdomains, notably receptor tyrosine kinases such as insulin receptor (InsR) and epidermal growth factor receptor (EGFR), through lateral association. Studies during the past two decades using knockout (KO) or pharmacologically inhibited cells, or KO mouse models for glucosylceramide synthase (GCS; ), GM3 synthase (GM3S; ), and GD3 synthase (GD3S; ) have revealed essential roles of gangliosides in hypothalamic control of energy balance. The a-series gangliosides GM1 and GD1a interact with leptin receptor (LepR) and promote LepR signaling through activation of the JAK2/STAT3 pathway. Studies of GM3S KO cells have shown that the extracellular signal-regulated kinase (ERK) pathway, downstream of the LepR signaling pathway, is also modulated by gangliosides. Recent studies have revealed crosstalk between the LepR signaling pathway and other receptor signaling pathways (e.g., InsR and EGFR pathways). Gangliosides thus have the ability to modulate the effects of leptin by regulating functions of such receptors, and by direct interaction with LepR to control signaling.
Topics: Animals; Energy Metabolism; ErbB Receptors; Gangliosides; Humans; Hypothalamus; MAP Kinase Signaling System; Mice; Mice, Knockout; Receptors, Leptin; Sialyltransferases
PubMed: 32731387
DOI: 10.3390/ijms21155349 -
International Journal of Molecular... May 2016In mammals, leptin is a peripheral satiety factor that inhibits feeding by regulating a variety of appetite-related hormones in the brain. However, most of the previous...
In mammals, leptin is a peripheral satiety factor that inhibits feeding by regulating a variety of appetite-related hormones in the brain. However, most of the previous studies examining leptin in fish feeding were performed with mammalian leptins, which share very low sequence homologies with fish leptins. To elucidate the function and mechanism of endogenous fish leptins in feeding regulation, recombinant goldfish leptin-AI and leptin-AII were expressed in methylotrophic yeast and purified by immobilized metal ion affinity chromatography (IMAC). By intraperitoneal (IP) injection, both leptin-AI and leptin-AII were shown to inhibit the feeding behavior and to reduce the food consumption of goldfish in 2 h. In addition, co-treatment of leptin-AI or leptin-AII could block the feeding behavior and reduce the food consumption induced by neuropeptide Y (NPY) injection. High levels of leptin receptor (lepR) mRNA were detected in the hypothalamus, telencephalon, optic tectum and cerebellum of the goldfish brain. The appetite inhibitory effects of leptins were mediated by downregulating the mRNA levels of orexigenic NPY, agouti-related peptide (AgRP) and orexin and upregulating the mRNA levels of anorexigenic cocaine-amphetamine-regulated transcript (CART), cholecystokinin (CCK), melanin-concentrating hormone (MCH) and proopiomelanocortin (POMC) in different areas of the goldfish brain. Our study, as a whole, provides new insights into the functions and mechanisms of leptins in appetite control in a fish model.
Topics: Animals; Brain; Eating; Feeding Behavior; Fish Proteins; Gene Expression Regulation; Goldfish; Leptin; Neuropeptide Y; Receptors, Leptin; Recombinant Proteins
PubMed: 27249000
DOI: 10.3390/ijms17060783 -
PloS One 2011Three non-synonymous single nucleotide polymorphisms (Q223R, K109R and K656N) of the leptin receptor gene (LEPR) have been tested for association with obesity-related... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Three non-synonymous single nucleotide polymorphisms (Q223R, K109R and K656N) of the leptin receptor gene (LEPR) have been tested for association with obesity-related outcomes in multiple studies, showing inconclusive results. We performed a systematic review and meta-analysis on the association of the three LEPR variants with BMI. In addition, we analysed 15 SNPs within the LEPR gene in the CoLaus study, assessing the interaction of the variants with sex.
METHODOLOGY/PRINCIPAL FINDINGS
We searched electronic databases, including population-based studies that investigated the association between LEPR variants Q223R, K109R and K656N and obesity- related phenotypes in healthy, unrelated subjects. We furthermore performed meta-analyses of the genotype and allele frequencies in case-control studies. Results were stratified by SNP and by potential effect modifiers. CoLaus data were analysed by logistic and linear regressions and tested for interaction with sex. The meta-analysis of published data did not show an overall association between any of the tested LEPR variants and overweight. However, the choice of a BMI cut-off value to distinguish cases from controls was crucial to explain heterogeneity in Q223R. Differences in allele frequencies across ethnic groups are compatible with natural selection of derived alleles in Q223R and K109R and of the ancient allele in K656N in Asians. In CoLaus, the rs10128072, rs3790438 and rs3790437 variants showed interaction with sex for their association with overweight, waist circumference and fat mass in linear regressions.
CONCLUSIONS
Our systematic review and analysis of primary data from the CoLaus study did not show an overall association between LEPR SNPs and overweight. Most studies were underpowered to detect small effect sizes. A potential effect modification by sex, population stratification, as well as the role of natural selection should be addressed in future genetic association studies.
Topics: Animals; Cohort Studies; Gene Frequency; Genotype; Humans; Overweight; Polymorphism, Single Nucleotide; Receptors, Leptin
PubMed: 22028824
DOI: 10.1371/journal.pone.0026157 -
International Journal of Molecular... Jul 2021Leptin is a cytokine that regulates appetite and energy expenditure, where in fishes it is primarily produced in the liver and acts to mobilize carbohydrates. Most...
Leptin is a cytokine that regulates appetite and energy expenditure, where in fishes it is primarily produced in the liver and acts to mobilize carbohydrates. Most fishes have only one leptin receptor (LepR/LepRA1), however, paralogs have recently been documented in a few species. Here we reveal a second leptin receptor (LepRA2) in rainbow trout that is 77% similar to trout LepRA1. Phylogenetic analyses show a salmonid specific genome duplication event as the probable origin of the second LepR in trout. Tissues distributions showed tissue specific expression of these receptors, with highest in the ovaries, nearly 50-fold higher than . Interestingly, was most highly expressed in the liver while hepatic levels were low. Feed deprivation elicited a decline in plasma leptin, an increase in hepatic by one week and remained elevated at two weeks, while liver expression of remained low. By contrast, muscle mRNA increased at one and two weeks of fasting, while adipose was concordantly lower in fasted fish. transcript levels were not affected in muscle and fat. These data show and are differentially expressed across tissues and during feed deprivation, suggesting paralog- and tissue-specific functions for these leptin receptors.
Topics: Adipose Tissue; Amino Acid Sequence; Animals; Appetite; Energy Metabolism; Fasting; Fish Proteins; Leptin; Liver; Muscles; Oncorhynchus mykiss; Phylogeny; RNA, Messenger; Receptors, Leptin; Sequence Alignment
PubMed: 34299350
DOI: 10.3390/ijms22147732 -
Nature Communications Mar 2023For survival, it is crucial for eating behaviours to be sequenced through two distinct seeking and consummatory phases. Heterogeneous lateral hypothalamus (LH) neurons...
For survival, it is crucial for eating behaviours to be sequenced through two distinct seeking and consummatory phases. Heterogeneous lateral hypothalamus (LH) neurons are known to regulate motivated behaviours, yet which subpopulation drives food seeking and consummatory behaviours have not been fully addressed. Here, in male mice, fibre photometry recordings demonstrated that LH leptin receptor (LepR) neurons are correlated explicitly in both voluntary seeking and consummatory behaviours. Further, micro-endoscope recording of the LH neurons demonstrated that one subpopulation is time-locked to seeking behaviours and the other subpopulation time-locked to consummatory behaviours. Seeking or consummatory phase specific paradigm revealed that activation of LH neurons promotes seeking or consummatory behaviours and inhibition of LH neurons reduces consummatory behaviours. The activity of LH neurons was increased via Neuropeptide Y (NPY) which acted as a tonic permissive gate signal. Our results identify neural populations that mediate seeking and consummatory behaviours and may lead to therapeutic targets for maladaptive food seeking and consummatory behaviours.
Topics: Mice; Male; Animals; Receptors, Leptin; Hunger; Hypothalamus; Neurons; Consummatory Behavior; Leptin
PubMed: 36932069
DOI: 10.1038/s41467-023-37044-4 -
Revista Espanola de Enfermedades... Apr 2007Gastric carcinoma is a rare but important malignancy. The link between leptin, a cytokine that is elevated in obese individuals, and cancer development has been... (Review)
Review
Gastric carcinoma is a rare but important malignancy. The link between leptin, a cytokine that is elevated in obese individuals, and cancer development has been proposed. It is noted that leptin and its receptor may play a positive role in the progression in gastric cancer. However, the exact mechanism resulting form the interaction between leptin and leptin receptor has never been clarified. Here, the author used a new gene ontology technology to predict the molecular function and biological process due to the interaction between leptin and leptin receptor. Comparing to leptin and leptin receptor, the leptin-leptin receptor poses the same function and biological process as leptin receptor. This can confirm that leptin receptor has a significant suppressive effect on the expression of leptin. Loss of hormone activity and disturbance of normal cell signaling pathway of leptin can be seen. Blocking of receptor might be rational therapeutic strategy.
Topics: Humans; Leptin; Receptors, Cell Surface; Receptors, Leptin; Stomach Neoplasms
PubMed: 17590101
DOI: 10.4321/s1130-01082007000400003 -
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 -
The Journal of Reproduction and... Jun 2022Factors associated with high milk production levels have been linked to alterations in the endometrial epidermal growth factor (EGF) profile, a cause of reduced...
Factors associated with high milk production levels have been linked to alterations in the endometrial epidermal growth factor (EGF) profile, a cause of reduced fertility in dairy cows. Therefore, we examined the leptin system that connects nutritional status and reproduction in dairy cattle related to reduced fertility in repeat breeder cows. Plasma leptin concentrations were measured in 18 heifers, 20 high-yielding control cows, and 26 repeat breeder cows, showing an altered EGF profile. Then, all repeat breeder cows were infused with seminal plasma (SP) into the vagina at the next estrus to normalize the EGF profile, while heifers and control cows were infused with vehicle alone. All animals were examined for EGF profiles. Eighteen repeat breeder cows, nine heifers, and nine control cows were also determined for leptin receptor (Ob-R) expression levels in the estrous cycle before and after the infusion. SP normalized the EGF profile in 53.8% of the repeat breeder cows. Leptin concentrations were similar in all groups, regardless of the treatment results for the EGF profile. In contrast, Ob-R levels in repeat breeder and control cows were similar and higher than those in heifers before SP treatment. Ob-R in repeat breeders showing a normal EGF profile after treatment decreased to an intermediate level between heifers and control cows and may provide a clue to take measures against repeat breeding in dairy cows.
Topics: Animals; Cattle; Endometrium; Epidermal Growth Factor; Female; Fertility; Leptin; Receptors, Leptin; Semen
PubMed: 35228409
DOI: 10.1262/jrd.2021-142 -
Asian Pacific Journal of Cancer... Jan 2014Leptin and its receptor are involved in breast carcinogenesis as mitogenic factors. Therefore, they could be considered as targets for breast cancer therapy. Expression...
Leptin and its receptor are involved in breast carcinogenesis as mitogenic factors. Therefore, they could be considered as targets for breast cancer therapy. Expression of the leptin receptor gene could be modulated by leptin secretion. Silibinin and curcumin are herbal compounds with anti-cancer activity against breast cancer. The aim of this study was to assess their potential to inhibit of expression of the leptin gene and its receptor and leptin secretion. Cytotoxic effects of the two agents on combination on T47D breast cancer cells was investigated by MTT assay test after 24h treatment. With different concentrations the levels of leptin, leptin receptor genes expression were measured by reverse-transcription real-time PCR. Amount of secreted leptin in the culture medium was determined by ELISA. Data were statistically analyzed by one-way ANOVA test. The silibinin and curcumin combination inhibited growth of T47D cells in a dose dependent manner. There were also significant difference between control and treated cells in leptin expression and the quantity of secreted leptin with a relative decrease in leptin receptor expression. In conclusion, these herbal compounds inhibit the expression and secretion of leptin and it could probably be used as drug candidates for breast cancer therapy through leptin targeting in the future.
Topics: Antineoplastic Agents; Antioxidants; Breast Neoplasms; Cell Proliferation; Curcumin; Drug Therapy, Combination; Enzyme-Linked Immunosorbent Assay; Female; Gene Expression Regulation, Neoplastic; Humans; Leptin; Real-Time Polymerase Chain Reaction; Receptors, Leptin; Signal Transduction; Silybin; Silymarin
PubMed: 24377502
DOI: 10.7314/apjcp.2013.14.11.6595 -
Metabolism: Clinical and Experimental Oct 2022Neuronal primary cilia are known to be a required organelle for energy balance and leptin action. However, whether primary cilia directly mediate adaptive responses...
OBJECTIVE
Neuronal primary cilia are known to be a required organelle for energy balance and leptin action. However, whether primary cilia directly mediate adaptive responses during starvation is yet unknown. Therefore, we investigated the counterregulatory roles of primary cilia, and their related leptin action in energy-depleted condition.
METHOD
We generated leptin receptor (LepR) neuron-specific primary cilia knockout (Ift88 KO) mice. Leptin-mediated electrophysiological properties of the neurons in fasting condition were assessed using patch-clamp technique. Adaptive responses and neuroendocrine reflexes were measured by monitoring counterregulatory hormones.
RESULTS
In fasting state, the leptin-induced neuronal excitability and leptin homeostasis were impaired in Ift88 KO. In addition, the Ift88 KO exhibited aberrant fasting responses including lesser body weight loss, decreased energy expenditure, and lower heat generation compared to wild-type littermates. Furthermore, the primary cilia in LepR neurons are necessary for counterregulatory responses and leptin-mediated neuroendocrine adaptation to starvation.
CONCLUSION
Our results demonstrated that the neuronal primary cilia are crucial neuronal components mediating the adaptive counterregulatory responses to starvation.
Topics: Animals; Cilia; Energy Metabolism; Fasting; Leptin; Mice; Neurons; Receptors, Leptin
PubMed: 35926636
DOI: 10.1016/j.metabol.2022.155273