scholarly journals Astrocyte Leptin Receptor (ObR) and Leptin Transport in Adult-Onset Obese Mice

Endocrinology ◽  
2008 ◽  
Vol 149 (6) ◽  
pp. 2798-2806 ◽  
Author(s):  
Weihong Pan ◽  
Hung Hsuchou ◽  
Yi He ◽  
Amul Sakharkar ◽  
Courtney Cain ◽  
...  
Keyword(s):  
Leptin Receptor ◽  
Spontaneous Mutation ◽  
Brain Perfusion ◽  
Leptin Resistance ◽  
Immunofluorescent Staining ◽  
Adult Onset ◽  
Cerebral Microvessels ◽  
System Sensitivity ◽  
Perfusion Studies ◽  
Unknown Significance

The agouti viable yellow (Avy) spontaneous mutation generates an unusual mouse phenotype of agouti-colored coat and adult-onset obesity with metabolic syndrome. Persistent production of agouti signaling protein in Avy mice antagonizes melanocortin receptors in the hypothalamus. To determine how this disruption of neuroendocrine circuits affects leptin transport across the blood-brain barrier (BBB), we measured leptin influx in Avy and B6 control mice after the development of obesity, hyperleptinemia, and increased adiposity. After iv bolus injection, 125I-leptin crossed the BBB significantly faster in young (2 month old) B6 mice than in young Avy mice or in older (8 month old) mice of either strain. This difference was not observed by in situ brain perfusion studies, indicating the cause being circulating factors, such as elevated leptin levels or soluble receptors. Thus, Avy mice showed peripheral leptin resistance. ObRa, the main transporting receptor for leptin at the BBB, showed no change in mRNA expression in the cerebral microvessels between the age-matched (2 month old) Avy and B6 mice. Higher ObRb mRNA was seen in the Avy microvasculature with unknown significance. Immunofluorescent staining unexpectedly revealed that many of the ObR(+) cells were astrocytes and that the Avy mice showed significantly more ObR(+) astrocytes in the hypothalamus than the B6 mice. Although leptin permeation from the circulation was slower in the Avy mice, the increased ObR expression in astrocytes and increased ObRb mRNA in microvessels suggest the possibility of heightened central nervous system sensitivity to circulating leptin.

scholarly journals Developmental Changes of Leptin Receptors in Cerebral Microvessels: Unexpected Relation to Leptin Transport

Endocrinology ◽  
2007 ◽  
Vol 149 (3) ◽  
pp. 877-885 ◽  
Author(s):  
Weihong Pan ◽  
Hung Hsuchou ◽  
Hong Tu ◽  
Abba J. Kastin
Keyword(s):  
Leptin Receptor ◽  
Brain Perfusion ◽  
Developmental Changes ◽  
Pcr Analysis ◽  
Receptor Subtypes ◽  
Cerebral Microvessels ◽  
Leptin Receptors ◽  
Age Related ◽  
Significant Difference ◽  
Age Related Changes

The adipokine leptin participates not only in the regulation of feeding and obesity in adults but also in neonatal development. It crosses the blood-brain barrier (BBB) by receptor-mediated transport. Leptin concentrations in blood differ between neonates and adults. We determined the developmental changes of leptin receptor subtypes in the cerebral microvessels composing the BBB and examined their expected correlation with leptin transport across the BBB. Total RNA was extracted from enriched cerebral microvessels of mice 1, 7, 14, and 60 d of age for real-time RT-PCR analysis of leptin receptor subtypes. In cerebral microvessels from neonates, ObRa, ObRb, ObRc, and ObRe mRNA were all higher than in adults, but ObRd was not detectable. Hypothalamus showed similar age-related changes except for ObRb, which was higher in adults. The homologous receptor gp130 did not show significant age-related changes in either region. Despite the increase of leptin receptors, leptin permeation across the BBB after iv injection was less in the neonates. In situ brain perfusion with blood-free buffer showed no significant difference in the brain uptake of leptin between neonates and adults, indicating an antagonistic role of leptin-binding proteins in the circulation, especially the soluble receptor ObRe. The results are consistent with our previous finding that ObRe antagonizes leptin endocytosis in cultured endothelia and transport from blood to brain in mice. Overall, the developmental changes observed for leptin receptors unexpectedly failed to correlate with the entry of leptin into brain, and this may indicate different functions of the receptors in neonates and adults.

scholarly journals Endospanin 1 Determines the Balance of Leptin-Regulated Hypothalamic Functions

2018 ◽  
Vol 108 (2) ◽  
pp. 132-141
Author(s):  
Clara Roujeau ◽  
Ralf Jockers ◽  
Julie Dam
Keyword(s):  
Signaling Pathways ◽  
Intracellular Trafficking ◽  
Leptin Receptor ◽  
Leptin Resistance ◽  
Human Obesity ◽  
Leptin Signaling ◽  
Diet Induced Obesity ◽  
Important Regulator ◽  
Neuronal Plasma Membrane ◽  
Underlying Mechanisms

Endospanin 1 (Endo1), a protein encoded in humans by the same gene than the leptin receptor (ObR), and increased by diet-induced obesity, is an important regulator of ObR trafficking and cell surface exposure, determining leptin signaling strength. Defective intracellular trafficking of the leptin receptor to the neuronal plasma membrane has been proposed as a mechanism underlying the development of leptin resistance observed in human obesity. More recently, Endo1 has emerged as a mediator of “selective leptin resistance.” The underlying mechanisms of the latter are not completely understood, but the possibility of differential activation of leptin signaling pathways was suggested among others. In this respect, the expression level of Endo1 is crucial for the appropriate balance between different leptin signaling pathways and leptin functions in the hypothalamus and is likely participating in selective leptin resistance for the control of energy and glucose homeostasis.

scholarly journals Phlorotannins from Ecklonia cava Attenuates Palmitate-Induced Endoplasmic Reticulum Stress and Leptin Resistance in Hypothalamic Neurons

Marine Drugs ◽  
2019 ◽  
Vol 17 (10) ◽  
pp. 570 ◽  
Author(s):  
Seyeon Oh ◽  
Myeongjoo Son ◽  
Junwon Choi ◽  
Chang Hu Choi ◽  
Kook Yang Park ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Leptin Receptor ◽  
Saturated Fatty Acids ◽  
Receptor Expression ◽  
Leptin Resistance ◽  
Ecklonia Cava ◽  
Hypothalamic Neurons ◽  
Potent Effect ◽  
Stress Markers

Leptin resistance in the hypothalamus has an essential role in obesity. Saturated fatty acids such as palmitate bind to Toll-like receptor 4 (TLR4) and lead to endoplasmic reticulum (ER) stress and leptin resistance. In this study, we evaluated whether extracts of Ecklonia cava would attenuate the ER stress induced by palmitate and reduce leptin resistance in hypothalamic neurons and microglia. We added palmitate to these cells to mimic the environment induced by high-fat diet in the hypothalamus and evaluated which of the E. cava phlorotannins—dieckol (DK), 2,7-phloroglucinol-6,6-bieckol (PHB), pyrogallol-phloroglucinol-6,6-bieckol (PPB), or phlorofucofuroeckol-A (PFFA)—had the most potent effect on attenuating leptin resistance. TLR4 and NF-κB expression induced by palmitate was attenuated most effectively by PPB in both hypothalamic neurons and microglia. ER stress markers were increased by palmitate and were attenuated by PPB in both hypothalamic neurons and microglia. Leptin resistance, which was evaluated as an increase in SOCS3 and a decrease in STAT3 with leptin receptor expression, was increased by palmitate and was decreased by PPB in hypothalamic neurons. The culture medium from palmitate-treated microglia increased leptin resistance in hypothalamic neurons and this resistance was attenuated by PPB. In conclusion, PPB attenuated leptin resistance by decreasing ER stress in both hypothalamic neurons and microglia.

scholarly journals Possible involvement of 4-hydroxy-2-nonenal in the pathogenesis of leptin resistance in obesity

2019 ◽  
Vol 316 (5) ◽  
pp. C641-C648 ◽  
Author(s):  
Toru Hosoi ◽  
Ayaka Kuwamura ◽  
Mina Thon ◽  
Kyoji Tsuchio ◽  
Amer Ali Abd El-Hafeez ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Leptin Receptor ◽  
Neuroblastoma Cell ◽  
Initiation Factor ◽  
Leptin Resistance ◽  
Human Neuroblastoma Cell ◽  
Human Neuroblastoma ◽  
Stat3 Phosphorylation ◽  
Induced Signal

Insensitivity to the antiobesity hormone, leptin, has been suggested to be involved in the pathogenesis of obesity. However, the pathological mechanisms underlying the development of leptin resistance are not well-understood. This study aimed to examine the pathological mechanisms of leptin resistance in obesity. In the present study, we found that 4-hydroxy-2-nonenal (4-HNE), an aldehyde, may be involved in the development of leptin resistance. The SH-SY5Y-Ob-Rb human neuroblastoma cell line, transfected to express the Ob-Rb leptin receptor stably, was treated with 4-HNE, and leptin-induced signal transduction was analyzed. We found that 4-HNE dose- and time-dependently inhibited leptin-induced signal transducer and activator of transcription 3 (STAT3) phosphorylation, a major antiobesity signal of leptin. On the other hand, 4-HNE did not affect tyrosine phosphorylation of broad cellular proteins, suggesting that the inhibitory effect may be selective to leptin signaling. Mechanistically, 4-HNE induced the eukaryotic initiation factor 2α-CCAAT/enhancer-binding protein homologous protein arm of endoplasmic reticulum stress signaling, which may be involved in the pathogenesis of leptin resistance. Overall, these results suggest that 4-HNE may partly affect endoplasmic reticulum stress-induced unfolded protein response signaling and may be involved in the pathogenesis of leptin resistance.

scholarly journals Changes in Expression of the Genes for the Leptin Signaling in Hypothalamic-Pituitary Selected Areas and Endocrine Responses to Long-Term Manipulation in Body Weight and Resistin in Ewes

2020 ◽  
Vol 21 (12) ◽  
pp. 4238
Author(s):  
Dorota Anna Zieba ◽  
Weronika Biernat ◽  
Malgorzata Szczesna ◽  
Katarzyna Kirsz ◽  
Justyna Barć ◽  
...  
Keyword(s):  
Body Weight ◽  
Leptin Receptor ◽  
Fat Body ◽  
Density Lipoprotein ◽  
Reproductive Hormones ◽  
Leptin Resistance ◽  
Nonesterified Fatty Acid ◽  
Cytokine Signaling ◽  
Leptin Signaling

Both long-term undernutrition and overnutrition disturb metabolic balance, which is mediated partially by the action of two adipokines, leptin and resistin (RSTN). In this study, we manipulated the diet of ewes to produce either a thin (lean) or fat (fat) body condition and investigated how RSTN affects endocrine and metabolic status under different leptin concentrations. Twenty ewes were distributed into four groups (n = 5): the lean and fat groups were administered with saline (Lean and Fat), while the Lean-R (Lean-Resistin treated) and Fat-R (Fat-Resistin treated) groups received recombinant bovine resistin. Plasma was assayed for LH, FSH, PRL, RSTN, leptin, GH, glucose, insulin, total cholesterol, nonesterified fatty acid (NEFA), high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol and triglycerides. Expression levels of a suppressor of cytokine signaling (SOCS-3) and the long form of the leptin receptor (LRb) were determined in selected brain regions, such as the anterior pituitary, hypothalamic arcuate nucleus, preoptic area and ventro- and dorsomedial nuclei. The results indicate long-term alterations in body weight affect RSTN-mediated effects on metabolic and reproductive hormones concentrations and the expression of leptin signaling components: LRb and SOCS-3. This may be an adaptive mechanism to long-term changes in adiposity during the state of long-day leptin resistance.

P4416Influence of rosuvastatin on the secretion of leptin and its receptor by adipocytes isolated from different adipose depots in patients with ischemic heart disease

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
Y A Dyleva ◽  
O Gruzdeva ◽  
E Uchasova ◽  
D Borodkina ◽  
E Belik ◽  
...  
Keyword(s):  
Cell Culture ◽  
Heart Disease ◽  
Ischemic Heart Disease ◽  
Leptin Receptor ◽  
Artery Bypass ◽  
Coronary Bypass ◽  
Economic Problem ◽  
Ischemic Heart ◽  
Leptin Resistance

Abstract Obesity is still a major health, social and economic problem throughout the world. Recently, it is important to study the role of adipokines of adipose tissue of various localization in the development of cardiovascular diseases, as well as methods for their pharmacological correction. Purpose The study was to evaluate the effect of rosuvastatin on the secretion of leptin and its receptor by adipocytes of different localization, as well as on the expression of their genes in patients with ischemic heart disease. Methods 29 patients with coronary heart disease which will be held coronary bypass surgery. Adipocytes were isolated from the samples of SAT, EAT and PVAT obtained during coronary artery bypass grafting, which were cultured for 24 hours with rosuvastatin 1 μmol/l and 5 μmol/l. A day later, the concentration of leptin and the leptin receptor in cell culture was determined. All study was carried out in compliance with the Helsinki Declaration, and its protocol was approved by the Ethical Committee of Research Institute. Statistical analysis was performed using Statistica 10.0. All patients gave written informed consent to participate in the study. Results 1 μmol/l of rosuvastatin increased the level of leptin 1.6 and 2.9 times higher in adipocytes SAT compared with EAT and PVAT, respectively, and 1.8 times higher in EAT than in PVAT, which is consistent with the results of expression leptin gene. The concentration of rosuvastatin 5 μmol/l had an effect only on adipocytes SAT, increasing the level of leptin 1.6 and 2.2 times in comparison with adipocytes EAT and PVAT. Rosuvastatin had no significant effect on leptin receptor soluble levels. The free leptin index was higher in adipocytes SAT in the presence of 1 μmol/l of rosuvastatin 1.6 and 2.8 times in comparison with adipocytes of EAT and PVAT. Conclusion The concentration of rosuvastatin 1 μmol/l had a more pronounced effect on adipocytes compared to a concentration of 5 μmol/l and increased the level of leptin and its expression in cell culture. At the same time, a high content of leptin under conditions of low expression of a soluble receptor to leptin in the presence of rosuvastatin 1 μmol/l can lead to leptin resistance, more pronounced in SAT adipocytes.

scholarly journals Astrocytic leptin-receptor knockout mice show partial rescue of leptin resistance in diet-induced obesity

2013 ◽  
Vol 114 (6) ◽  
pp. 734-741 ◽  
Author(s):  
Bhavaani Jayaram ◽  
Weihong Pan ◽  
Yuping Wang ◽  
Hung Hsuchou ◽  
Aurelien Mace ◽  
...  
Keyword(s):  
Heat Dissipation ◽  
Leptin Receptor ◽  
Uncoupling Protein ◽  
Subcutaneous Fat ◽  
Leptin Resistance ◽  
Blood Concentrations ◽  
Leptin Signaling ◽  
Diet Induced Obesity ◽  
Soluble Leptin Receptor ◽  
Similar Body

To determine how astrocytic leptin signaling regulates the physiological response of mice to diet-induced obesity (DIO), we performed metabolic analyses and hypothalamic leptin signaling assays on astrocytic leptin-receptor knockout (ALKO) mice in which astrocytes lack functional leptin receptor (ObR) signaling. ALKO mice and wild-type (WT) littermate controls were studied at different stages of DIO with measurement of body wt, percent fat, metabolic activity, and biochemical parameters. When fed regular chow, the ALKO mice had similar body wt, percent fat, food intake, heat dissipation, respiratory exchange ratio, and activity as their WT littermates. There was no change in blood concentrations of triglyceride, soluble leptin receptor (sObR), mRNA for leptin and uncoupling protein 1 (UCP1) in adipose tissue, and insulin sensitivity. Unexpectedly, in response to a high-fat diet the ALKO mice had attenuated hyperleptinemia and sObR, a lower level of leptin mRNA in subcutaneous fat, and a paradoxical increase in UCP1 mRNA. Thus, ALKO mice did not show the worsening of obesity that occurs with normal WT mice and the neuronal ObR mutation that results in morbid obesity. The findings are consistent with a competing, counterregulatory model between neuronal and astrocytic leptin signaling.

Brain Perfusion Studies by Xenon-Enhanced CT Using Washin/Washout Study Protocols

1991 ◽  
Vol 15 (5) ◽  
pp. 816-822 ◽  
Author(s):  
Willi A. Kalender ◽  
Arkadiusz Polacin ◽  
Heidi Eidloth ◽  
Shiro Kashiwagi ◽  
Tetsuo Yamashita ◽  
...  
Keyword(s):  
Brain Perfusion ◽  
Study Protocols ◽  
Perfusion Studies ◽  
Enhanced Ct

scholarly journals Leptin resistance: a prediposing factor for diet-induced obesity

2009 ◽  
Vol 296 (3) ◽  
pp. R493-R500 ◽  
Author(s):  
Philip J. Scarpace ◽  
Yi Zhang
Keyword(s):  
Weight Gain ◽  
Leptin Receptor ◽  
Causative Factor ◽  
Leptin Resistance ◽  
Chow Diet ◽  
High Fat ◽  
Diet Induced Obesity ◽  
Dietary Fructose ◽  
Complex Chronic Disease ◽  
Obesity Syndrome

Obesity is a resilient and complex chronic disease. One potential causative factor in the obesity syndrome is leptin resistance. Leptin behaves as a potent anorexic and energy-enhancing hormone in most young or lean animals, but its effects are diminished or lacking in the obese state associated with a normal genetic background. Emerging evidence suggests that leptin resistance predisposes the animal to exacerbated diet-induced obesity (DIO). Elevation of central leptin in young, lean rats induces a leptin resistance that precludes obesity on a chow diet but accelerates high-fat (HF)-induced obesity. Similarly, chronic dietary fructose consumption evokes a leptin resistance that causes obesity only upon HF exposure. Inherent central leptin insensitivity also contributes to dietary weight gain in certain obesity-prone rats. Conversely, aged, leptin-resistant animals are obese with continuous chow feeding and demonstrate aggravated obesity when challenged with an HF diet. Additionally, a submaximal central blockade with a leptin antagonist leads to obesity on both chow and HF diets, as is the case in rodents with leptin receptor deficiency of genetic origin. Despite the differences in the incidence of obesity on a chow diet, all of these forms of leptin resistance predispose rodents to aggravated HF-mediated obesity. Moreover, once leptin resistance takes hold, it aggravates DIO, and the leptin resistance and obesity compound one another, promoting a vicious cycle of escalating weight gain.

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