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1
Panić, Anastasija, Sanja Soskić, and Esma Isenović. "Leptin and its mechanism of action." Medicinska istrazivanja 49, no. 3 (2015): 36–41. http://dx.doi.org/10.5937/medist1502036p.
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Leptin is a hormone produced by the adipose tissue, which has effects on the central nervous system. Leptin is bound to its Ob receptor on hypo-thalamic neurons to inhibit feeding behavior and to increase sympathetically-mediated thermogenesis. In addition to anorexia and thermogenesis, leptin also has direct peripheral and central nervous system-mediated effects on the endocrine, vascular, hematopoietc, immune and musculoskeletal systems. Leptin accomplishes its effects using distributed network of leptin receptors and differential molecular signaling pathways. Leptinemia is increased in obesity because of increased adipocyte mass, but obese subjects exhibit resistance to the anorexic and metabolic effects of leptin. However, multiple studies have shown that leptin can increase sympathetic nerve activity to non-thermogenic tissues in rodents causing obesity-related hypertension. One potential explanation of this paradox is selective leptin resistance. Compared with large and persuasive number of studies on the sympathetic and blood pressure effects of leptin in experimental animals, relatively little attention was given to these effects of leptin in humans. This review article presents recent findings related to leptin and its mechanism of action, and also the role of leptin in patophysiological conditions.
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Gertler, A., Y. Sandowski, and N. Raver. "Recombinant leptin mutants and leptin binding proteins aimed to block leptin action in vivo." Proceedings of the British Society of Animal Science 2002 (2002): 48. http://dx.doi.org/10.1017/s1752756200007043.
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Obese protein (OB) also known as leptin serves as a protein signal secreted from adipose tissue and acts on a central nervous system that regulate ingestive behavior and energy balance (Campfield, 2000). The sequence of various leptins from 10 mammalian species was compiled and the 3D structure of human leptin mutant W100E was elucidated (Zhang et al., 1997). We have prepared recombinant leptins of sheep, chicken, cow and pig. Mammalian and chicken leptins are respectively 146 and 145 amino acid containing proteins found in circulation. Leptin in blood is found in both free and bound form; the main binding protein is the extracellular domain (ECD) of leptin receptor (Liu et al., 1997). One of the established functions of leptin, is its attenuating effect on the expression of NPY and other neuropeptides in hypothalamus that subsequently leads to decreased food intake (Campfield, 2000). Therefore it seems logical that blocking leptin receptors that are responsible for transferring it through the blood-brain barrier or for its action in hypothalamus will lead to increase in food intake. Leptin receptor belongs to cytokine receptor superfamily. Its ECD consists of ∷ 800 amino acids but it was suggested that only the cytokine homology subdomain II (CHD) consisting of ∷ 200 amino acids is responsible for binding (Fong et al., 1997). The objective of the present work is to prepare recombinant proteins aimed to block leptin action. We suggest two approaches (a) preparation of leptin antagonists capable of binding but not homodimerizing leptin receptors and (b) subcloning and preparing CHD II of leptin receptor responsible for binding of the hormone.
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Borodkina, Daria A., Olga V. Gruzdeva, Olga E. Akbasheva, Ekaterina V. Belik, Elena I. Palicheva, and Olga L. Barbarash. "Leptin resistance: unsolved diagnostic issues." Problems of Endocrinology 64, no. 1 (April 9, 2018): 62–66. http://dx.doi.org/10.14341/probl201864162-66.
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Leptin and its receptors are key regulators of body weight and energy homeostasis. A decrease in tissue sensitivity to leptin leads to the development of obesity, insulin resistance, dyslipidemia, etc. Currently, the phenomenon of leptin resistance is explained by a number of mechanisms, including impairment of gene structure, leptin transport through the blood-brain barrier, and leptin receptor signaling. However, it is not known, a decrease in the number of receptors of which area leads to the development of leptin resistance. No relationship has been found between the basal leptin level in obesity and expression of leptin receptors in the skeletal muscles. It is also important to investigate the contribution of fatty tissue of different localization to leptin secretion regulation and activity of its receptors. The term «leptin resistence» reflects a complex pathophysiological phenomenon with broad perspectives for study. In this review, we analyze methods of diagnosing leptin resistance.
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Borodkina, Daria A., Olga V. Gruzdeva, Olga E. Akbasheva, Ekaterina V. Belik, Elena I. Palicheva, and Olga L. Barbarash. "Leptin resistance: unsolved diagnostic issues." Problems of Endocrinology 64, no. 1 (April 9, 2018): 62–66. http://dx.doi.org/10.14341/probl8740.
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Leptin and its receptors are key regulators of body weight and energy homeostasis. A decrease in tissue sensitivity to leptin leads to the development of obesity, insulin resistance, dyslipidemia, etc. Currently, the phenomenon of leptin resistance is explained by a number of mechanisms, including impairment of gene structure, leptin transport through the blood-brain barrier, and leptin receptor signaling. However, it is not known, a decrease in the number of receptors of which area leads to the development of leptin resistance. No relationship has been found between the basal leptin level in obesity and expression of leptin receptors in the skeletal muscles. It is also important to investigate the contribution of fatty tissue of different localization to leptin secretion regulation and activity of its receptors. The term «leptin resistence» reflects a complex pathophysiological phenomenon with broad perspectives for study. In this review, we analyze methods of diagnosing leptin resistance.
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Skibicka, Karolina P., and Harvey J. Grill. "Hindbrain Leptin Stimulation Induces Anorexia and Hyperthermia Mediated by Hindbrain Melanocortin Receptors." Endocrinology 150, no. 4 (September 10, 2008): 1705–11. http://dx.doi.org/10.1210/en.2008-1316.
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Of the central nervous system receptors that could mediate the energy balance effects of leptin, those of the hypothalamic arcuate nucleus receive the greatest attention. Melanocortin receptors (MC-Rs) contribute to the feeding and energetic effects of hypothalamically delivered leptin. Energy balance effects of leptin are also mediated by extrahypothalamic neurons including the hindbrain nucleus tractus solitarius. Hindbrain leptin receptors play a role in leptin’s anorectic effects, but their contribution to its energetic effects and their functional interaction with melanocortin systems within the hindbrain remains unexplored. Here rats implanted with telemetric devices for recording energetic/cardiovascular responses were examined to determine whether: 1) hindbrain (fourth ventricular) leptin receptor stimulation triggers energetic and cardiovascular effects, 2) these effects are altered by a 6-wk high-fat diet maintenance, and 3) hindbrain MC-Rs mediate the thermogenic, cardiovascular, and anorexic effects of hindbrain leptin delivery. Results show that hindbrain leptin receptor stimulation produced long-lasting (>6 h) increases in core temperature and heart rate and also decreased food intake and body weight. These responses were not altered by high-fat maintenance, in contrast to what has been reported for forebrain leptin delivery. Fourth ventricular pretreatment with MC-R antagonist SHU 9119 completely abolished the hyperthermia, anorexia, and body weight loss seen with hindbrain-directed leptin but had no effects of its own. These data highlight a role for hindbrain leptin receptors in the initiation of energetic and anorexic responses and show that MCRs are part of the downstream mediation of hindbrain leptin-induced energy balance effects, paralleling effects observed for hypothalamic leptin receptors.
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Pan, Weihong, Hung Hsuchou, Hong Tu, and Abba J. Kastin. "Developmental Changes of Leptin Receptors in Cerebral Microvessels: Unexpected Relation to Leptin Transport." Endocrinology 149, no. 3 (November 26, 2007): 877–85. http://dx.doi.org/10.1210/en.2007-0893.
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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.
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Harris, Ruth B. S. "Leptin-induced increase in body fat content of rats." American Journal of Physiology-Endocrinology and Metabolism 304, no. 3 (February 1, 2013): E267—E281. http://dx.doi.org/10.1152/ajpendo.00251.2012.
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We previously reported that peripheral leptin infusions in chronically decrebrate rats, in which the forebrain is neurally isolated from the hindbrain, increased body fat and decreased energy expenditure. Any central leptin response in decerebrate rats would depend upon the hindbrain. Here, we tested whether selective activation of hindbrain leptin receptors increased body fat. Fourth ventricle infusion of 0.6 μg leptin/day for 12 days increased body fat by 13% with no increase in food intake. Third ventricle leptin infusions decreased food intake, body fat, and lean tissue with a maximal response at 0.3 μg leptin/day. To test whether hindbrain receptors opposed activity of hypothalamic receptors, rats received peripheral infusions of 40 μg leptin/day and increasing 4th ventricle doses of the leptin receptor antagonist mutein protein. Mutein (3.0 μg/day) reduced body fat in PBS-infused rats to the same level as leptin-infused rats and reduced lean tissue in all rats. Leptin, but not mutein, inhibited food intake. By contrast, 3.0 μg/day mutein in the 3rd ventricle increased food intake and body fat in both PBS- and leptin-infused rats. In basal conditions, hindbrain leptin receptors may antagonize activity of forebrain receptors to protect lean and fat tissue, but there is no evidence for an anabolic role for hindbrain receptors when leptin is elevated. In a dietary study, rats increased energy intake when offered lard and 30% sucrose solution in addition to chow. Peripheral leptin infusion exaggerated the gain in body fat without altering energy intake confirming the potential for leptin to increase adiposity.
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BENOMAR, Yacir, Anne-France ROY, Alain AUBOURG, Jean DJIANE, and Mohammed TAOUIS. "Cross down-regulation of leptin and insulin receptor expression and signalling in a human neuronal cell line." Biochemical Journal 388, no. 3 (June 7, 2005): 929–39. http://dx.doi.org/10.1042/bj20041621.
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Leptin and insulin are major signals to the hypothalamus to regulate energy homoeostasis and body adiposity. IR (insulin receptors) and leptin receptors (long isoform, ObRb) share a number of signalling cascades, such as JAK2/STAT-3 (Janus kinase 2/signal transduction and activator of transcription 3) and PI3K (phosphoinositide 3-kinase); the cross-talk between IR and ObRb have been described previously in non-neuronal cells. Differentiated human neuroblastoma (SH-SY5Y) cells express endogenous ObR and IR, and respond to leptin and insulin with stimulation of STAT-3 and MAPK (mitogen-activated protein kinase) phosphorylation, and PI3K activity. Insulin or leptin pre-treatment of SH-SY5Y cells increased basal STAT-3 phosphorylation, but abolished the acute effect of these hormones, and, interestingly, leptin pre-treatment abolished insulin effect and vice versa. Similar results were obtained for MAPK phosphorylation, but leptin or insulin pre-treatment did not completely abolish the acute effect of insulin or leptin. We have also showed that insulin and leptin are able to activate PI3K through IRS-1 (insulin receptor substrate 1) and IRS-2 respectively. Furthermore, leptin or insulin pre-treatment increased basal PI3K activity and IRS-1 or IRS-2 association with p85 and abolished acute insulin or leptin effect, in addition to the down-regulation of IRS-1 and IRS-2. Finally, insulin pre-treatment reduced leptin binding by approx. 60%, and leptin pre-treatment reduced the expression of insulin receptor by 40% in SH-SY5Y cells, which most likely accounts for the cross down-regulation of leptin and insulin receptors. These results provide evidence to suggest cross down-regulation of leptin and insulin receptors at both receptor and downstream signalling levels. This finding may contribute to the understanding of the complex relationship between leptin resistance and insulin resistance at the neuronal level.
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Boroń, Dariusz, Robert Nowakowski, Beniamin Oskar Grabarek, Nikola Zmarzły, and Marcin Opławski. "Expression Pattern of Leptin and Its Receptors in Endometrioid Endometrial Cancer." Journal of Clinical Medicine 10, no. 13 (June 24, 2021): 2787. http://dx.doi.org/10.3390/jcm10132787.
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The identification of novel molecular markers and the development of cancer treatment strategies are very important as cancer incidence is still very high. Obesity can contribute to cancer progression, including endometrial cancer. Adipocytes secrete leptin, which, when at a high level, is associated with an increased risk of cancer. The aim of this study was to determine the expression profile of leptin-related genes in the endometrial tissue samples and whole blood of patients. The study material included tissue samples and whole blood collected from 30 patients with endometrial cancer and 30 without cancer. Microarrays were used to assess the expression profile of leptin-related genes. Then, the expression of leptin (LEP), leptin receptor (LEPR), leptin receptor overlapping transcript (LEPROT), and leptin receptor overlapping transcript-like 1 (LEPROTL1) was determined by the Real-Time Quantitative Reverse Transcription Reaction (RT-qPCR). The serum leptin concentration was evaluated using Enzyme-linked immunosorbent assay (ELISA). Leptin and its receptors were overexpressed both at the mRNA and protein levels. Furthermore, there were strong positive correlations between leptin levels and patient Body Mass Index (BMI). Elevated levels of leptin and its receptors may potentially contribute to the progression of endometrial cancer. These observations may be useful in designing endometrial cancer treatment strategies.
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Wada, Nobuhiro, Satoshi Hirako, Fumiko Takenoya, Haruaki Kageyama, Mai Okabe, and Seiji Shioda. "Leptin and its receptors." Journal of Chemical Neuroanatomy 61-62 (November 2014): 191–99. http://dx.doi.org/10.1016/j.jchemneu.2014.09.002.
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Fernandez-Galaz, C., T. Fernandez-Agullo, F. Campoy, C. Arribas, N. Gallardo, A. Andres, M. Ros, and JM Carrascosa. "Decreased leptin uptake in hypothalamic nuclei with ageing in Wistar rats." Journal of Endocrinology 171, no. 1 (October 1, 2001): 23–32. http://dx.doi.org/10.1677/joe.0.1710023.
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Leptin interacts with specific receptors in hypothalamic nuclei and modulates energy balance. Growing evidence has shown the association of obesity and hyperleptinaemia with non-insulin-dependent diabetes mellitus and insulin resistance. The aged Wistar rat shows peripheral insulin resistance in the absence of obesity and alterations of glucose homeostasis. However, it is not known whether, in these animals, the leptin action is altered. Here we studied the effect of ageing on plasma leptin concentration and the ability of hypothalamic nuclei to capture i.c.v.-injected digoxigenin-labelled leptin. Our data indicate that 24-month-old animals are hyperleptinaemic. However, daily food intake was greater in old animals, suggesting that they are leptin resistant. Leptin uptake in the hypothalamus was reduced in old rats. This uptake was a receptor-mediated process as demonstrated by displacement. Leptin accumulation in hypothalamic nuclei was partially colocalized with neuropeptide Y fibres. Immunohistochemical and western blot analyses showed a lower amount of the long form of leptin receptors in the hypothalamus of aged rats. Analysis by RT-PCR also demonstrated a decreased expression of leptin receptor mRNA in old animals. We conclude that the lower leptin uptake may be explained, at least in part, by a decreased amount of receptors in hypothalamic neurones of the aged rats.
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Sahin, Gulcan Semra, Jose Luis Rodriguez-Llamas, Crystal Dillon, Igor Medina, Suzanne M. Appleyard, Jean-Luc Gaiarsa, and Gary A. Wayman. "Leptin increases GABAergic synaptogenesis through the Rho guanine exchange factor β-PIX in developing hippocampal neurons." Science Signaling 14, no. 683 (May 18, 2021): eabe4111. http://dx.doi.org/10.1126/scisignal.abe4111.
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Developing hippocampal neurons undergo rapid synaptogenesis in response to neurotrophic signals to form and refine circuit connections. The adipokine leptin is a satiety factor with neurotrophic actions, which potentiates both glutamatergic and GABAergic synaptogenesis in the hippocampus during neonatal development. Brief exposure to leptin enhances GABAA receptor–dependent synaptic currents in hippocampal neurons. Here, using molecular and electrophysiological techniques, we found that leptin increased the surface localization of GABAA receptors and the number of functional GABAergic synapses in hippocampal cultures from male and female rat pups. Leptin increased the interaction between GABAA receptors and the Rho guanine exchange factor β-PIX (a scaffolding protein at GABAergic postsynaptic sites) in a manner dependent on the kinase CaMKK. We also found that the leptin receptor and β-PIX formed a complex, the amount of which transiently increased upon leptin receptor activation. Furthermore, Tyr985 in the leptin receptor and the SH3 domain of β-PIX are crucial for this interaction, which was required for the developmental increase in GABAergic synaptogenesis. Our results suggest a mechanism by which leptin promotes GABAergic synaptogenesis in hippocampal neurons and reveal further complexity in leptin receptor signaling and its interactome.
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Taildeman, Jasmien, Claudina A. Pérez-Novo, Isabelle Rottiers, Liesbeth Ferdinande, Anouk Waeytens, Veerle De Colvenaer, Claus Bachert, et al. "Human mast cells express leptin and leptin receptors." Histochemistry and Cell Biology 131, no. 6 (February 25, 2009): 703–11. http://dx.doi.org/10.1007/s00418-009-0575-3.
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Lin, Yen-Chang, Jianying Huang, Stan Hileman, Karen H. Martin, Robert Hull, Mary Davis, and Han-Gang Yu. "Leptin decreases heart rate associated with increased ventricular repolarization via its receptor." American Journal of Physiology-Heart and Circulatory Physiology 309, no. 10 (November 15, 2015): H1731—H1739. http://dx.doi.org/10.1152/ajpheart.00623.2015.
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Leptin has been proposed to modulate cardiac electrical properties via β-adrenergic receptor activation. The presence of leptin receptors and adipocytes in myocardium raised a question as to whether leptin can directly modulate cardiac electrical properties such as heart rate and QT interval via its receptor. In this work, the role of local direct actions of leptin on heart rate and ventricular repolarization was investigated. We identified the protein expression of leptin receptors at cell surface of sinus node, atrial, and ventricular myocytes isolated from rat heart. Leptin at low doses (0.1–30 μg/kg) decreased resting heart rate; at high doses (150–300 μg/kg), leptin induced a biphasic effect (decrease and then increase) on heart rate. In the presence of high-dose propranolol (30 mg/kg), high-dose leptin only reduced heart rate and sometimes caused sinus pauses and ventricular tachycardia. The leptin-induced inhibition of resting heart rate was fully reversed by leptin antagonist. Leptin also increased heart rate-corrected QT interval (QTc), and leptin antagonist did not. In isolated ventricular myocytes, leptin (0.03–0.3 μg/ml) reversibly increased the action potential duration. These results supported our hypothesis that in addition to indirect pathway via sympathetic tone, leptin can directly decrease heart rate and increase QT interval via its receptor independent of β-adrenergic receptor stimulation. During inhibition of β-adrenergic receptor activity, high concentration of leptin in myocardium can cause deep bradycardia, prolonged QT interval, and ventricular arrhythmias.
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Moult, Peter R., and Jenni Harvey. "Regulation of glutamate receptor trafficking by leptin." Biochemical Society Transactions 37, no. 6 (November 19, 2009): 1364–68. http://dx.doi.org/10.1042/bst0371364.
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It is well established that leptin is a circulating hormone that enters the brain and regulates food intake and body weight via its hypothalamic actions. However, it is also known that leptin receptors are widely expressed in the CNS (central nervous system), and evidence is accumulating that leptin modulates many neuronal functions. In particular, recent studies have indicated that leptin plays an important role in the regulation of hippocampal synaptic plasticity. Indeed leptin-insensitive rodents display impairments in hippocampal synaptic plasticity and defects in spatial memory tasks. We have also shown that leptin facilitates the induction of hippocampal LTP (long-term potentiation) via enhancing NMDA (N-methyl-D-aspartate) receptor function and that leptin has the ability to evoke a novel form of NMDA receptor-dependent LTD (long-term depression). In addition, leptin promotes rapid alterations in hippocampal dendritic morphology and synaptic density, which are likely to contribute to the effects of this hormone on excitatory synaptic strength. Recent studies have demonstrated that trafficking of AMPA (α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) receptors is pivotal for activity-dependent hippocampal synaptic plasticity. However, little is known about how AMPA receptor trafficking processes are regulated by hormonal systems. In the present paper, we discuss evidence that leptin rapidly alters the trafficking of AMPA receptors to and away from hippocampal CA1 synapses. The impact of these leptin-driven changes on hippocampal excitatory synaptic function are discussed.
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Al-Shibli, Saad M., Norra Harun, Abdelkader E. Ashour, Mohd Hanif B. Mohd Kasmuri, and Shaikh Mizan. "Expression of leptin and leptin receptors in colorectal cancer—an immunohistochemical study." PeerJ 7 (October 2, 2019): e7624. http://dx.doi.org/10.7717/peerj.7624.
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Obesity is demonstrated to be a risk factor in the development of cancers of various organs, such as colon, prostate, pancreas and so on. Leptine (LEP) is the most renowned of the adipokines. As a hormone, it mediates its effect through leptin receptor (LEPR), which is widely expressed in various tissues including colon mucosa. In this study, we have investigated the degree of expression of LEP and LEPR in colorectal cancer (CRC). We collected 44 surgically resected colon cancer tissues along with normal adjacent colon tissue (NACT) from a sample of CRC patients from the Malaysian population and looked for leptin and leptin receptors using immunohistochemistry (IHC). All the samples showed low presence of both LEP and LEPR in NACT, while both LEP and LEPR were present at high intensity in the cancerous tissues with 100% and 97.7% prevalence, respectively. Both were sparsed in the cytoplasm and were concentrated beneath the cell membrane. However, we did not find any significant correlation between their expression and pathological parameters like grade, tumor size, and lymph node involvement. Our study further emphasizes the possible causal role of LEP and LEPR with CRC, and also the prospect of using LEPR as a possible therapeutic target.
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Hossner, Kim L. "Cellular, molecular and physiological aspects of leptin: Potential application in animal production." Canadian Journal of Animal Science 78, no. 4 (December 1, 1998): 463–72. http://dx.doi.org/10.4141/a98-061.
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This review encompasses the biochemistry and physiology of the newly discovered adipose hormone, leptin. Leptin appears to fulfill the role of the long sought after "lipostat", which functions to regulate energy intake in relation to body stores in the form of fat. Leptin is a 16 000 Dalton polypeptide which interacts with specific receptors in the hypothalamus to regulate food intake and body fat stores. Leptin receptors exist in several forms, which can be divided into those with small cytoplasmic domains and one with a single long cytoplasmic tail. The latter is thought to mediate most of leptin's effects, acting through the JAK-STAT signal transduction pathway. Several reports have shown direct effects of leptin on tissues with the short form of the leptin receptor. Specific effects of leptin on appetite, energy metabolism and reproduction are reviewed. Leptin may prove to be most useful to animal producers as a stimulant of the reproductive system or as a molecular marker to genetically select livestock for improved reproductive capacities or carcass characteristics, while leptin antagonists may improve metabolic rate and body composition. Key words: Leptin, obese protein, leptin receptor, review, livestock production
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Madiehe, Abram M., Tiffany D. Mitchell, and Ruth B. S. Harris. "Hyperleptinemia and reduced TNF-α secretion cause resistance of db/db mice to endotoxin." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 284, no. 3 (March 1, 2003): R763—R770. http://dx.doi.org/10.1152/ajpregu.00610.2002.
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Leptin deficiency in ob/ob mice increases susceptibility to endotoxic shock, whereas leptin pretreatment protects them against LPS-induced lethality. Lack of the long-form leptin receptor (Ob-Rb) in db/db mice causes resistance. We tested the effects of LPS in C57BL/6J db3J/db3J (BL/3J) mice, which express only the circulating leptin receptors, compared with C57BL/6J db/db (BL/6J) mice, which express all short-form and circulating isoforms of the leptin receptor. Intraperitoneal injections of LPS significantly decreased rectal temperature and increased leptin, corticosterone, and free TNF-α in fed and fasted BL/3J and BL/6J mice. TNF-α was increased three- and fourfold in BL/3J and BL/6J, respectively. LPS (100 μg) caused 50% mortality of fasted BL/6J mice but caused no mortality in fasted BL/3J mice. Pretreatment of fasted BL/3J mice with 30 μg leptin prevented the drop in rectal temperature, blunted the increase in corticosterone, but had no effect on TNF-α induced by 100 μg LPS. Taken together, these data provide evidence that fasted BL/3J mice are more resistant than BL/6J mice to LPS toxicity, presumably due to the absence of leptin receptors in BL/3J mice. This resistance may be due to high levels of free leptin cross-reacting with other cytokine receptors.
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Harvey, J., L. J. Shanley, D. O'Malley, and A. J. Irving. "Leptin: a potential cognitive enhancer?" Biochemical Society Transactions 33, no. 5 (October 26, 2005): 1029–32. http://dx.doi.org/10.1042/bst0331029.
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It is well documented that the hormone leptin signals information regarding the status of fat stores to hypothalamic nuclei, which in turn control feeding behaviour and body weight. However, leptin and its receptor are widely expressed in many extra-hypothalamic brain regions, including hippocampus, brain stem and cerebellum. Moreover, evidence is accumulating that leptin has other neuronal functions that are unrelated to its effects on energy homeostasis. Indeed a role for leptin in neuronal development has been suggested as leptin-deficient rodents display abnormal brain development and leptin actively participates in the development of the hypothalamus. In the hippocampus, leptin is a potential cognitive enhancer as genetically obese rodents with dysfunctional leptin receptors display impairments in hippocampal synaptic plasticity. Moreover, direct administration of leptin into the hippocampus can facilitate hippocampal LTP (long-term potentiation) in vivo and improve memory processing in mice. At the cellular level, we have also shown that leptin has the capacity to convert short-term potentiation into LTP. Here, we review the data that leptin influences hippocampal synaptic plasticity via enhancing NMDA (N-methyl-D-aspartate) receptor function. We also provide evidence that rapid trafficking of NMDA receptors to the plasma membrane may underlie the effects of leptin on excitatory synaptic strength.
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Cammisotto, Philippe G., Diane Gingras, Christian Renaud, Emile Levy, and Moïse Bendayan. "Secretion of soluble leptin receptors by exocrine and endocrine cells of the gastric mucosa." American Journal of Physiology-Gastrointestinal and Liver Physiology 290, no. 2 (February 2006): G242—G249. http://dx.doi.org/10.1152/ajpgi.00334.2005.
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Leptin is a hormone secreted by the gastric mucosa into the lumen of the stomach. It is present in its intact form in the intestine where it regulates nutrient absorption and intestinal mucosa integrity. We have identified the binding protein that protects leptin from the harsh conditions of the gastric juice. Immunoprecipitations and Western blot analyses demonstrated that leptin is present in the gastric mucosa and the gastric juice, bound to a protein corresponding to the extracellular domain of the leptin receptor. In the absence of this soluble receptor, leptin is rapidly degraded. Immunocytochemistry on rat gastric mucosa identified the cells and intracellular compartments involved in secretion of this complex. Leptin receptor extracellular domain and leptin are present along the rough endoplasmic reticulum-Golgi-granules secretory pathways and form a complex in the secretory granules of Chief and specific endocrine cells. The long-form membrane leptin receptor OB-Rb, the protease activator furin, and proprotein convertase 7 were found in Chief cell granules but not in those of endocrine cells. The shedding of the receptor occurs in the immature granules. It is concluded that in the immature secretory granules of Chief cells, furin activates proprotein convertase 7 that, in turn, cleaves the extracellular portion of membrane-bound leptin receptors. Leptin bound to its soluble receptor forms a complex that is resistant to the gastric juice. Endocrine cells, on the other hand, generate a soluble leptin receptor by mechanisms different from those of the exocrine cells.
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Karlsson, Cecilia, Kajsa Lindell, Eva Svensson, Christina Bergh, Peter Lind, Håkan Billig, Lena M. S. Carlsson, and Björn Carlsson. "Expression of Functional Leptin Receptors in the Human Ovary1." Journal of Clinical Endocrinology & Metabolism 82, no. 12 (December 1, 1997): 4144–48. http://dx.doi.org/10.1210/jcem.82.12.4446.
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The size of body fat stores is known to influence fertility, indicating a link between adipose tissue and the reproductive system. Studies in mice have identified the adipocyte-derived hormone, leptin (Ob protein), as a possible mediator of this effect. The aim of this study was to investigate the possibility that leptin may have direct effects on the human ovary. To probe this hypothesis we first analyzed the expression of leptin receptors in the human ovary. Transcripts encoding both the long and short isoforms of the leptin receptor were present in human granulosa cells and thecal cells; however, the short isoforms were expressed at much higher levels. Immunoreactive leptin was present in follicular fluid at levels similar to those found in serum. ob gene expression, however, was undetectable in the ovary, as determined by reverse transcription-PCR, whereas it was easily detected in adipose tissue. To determine whether leptin could induce a biological response in ovarian cells, we examined the effect of leptin on estradiol production in cultured granulosa cells. Leptin (100 ng/mL) inhibited LH (0.1 ng/mL)-stimulated estradiol production. In contrast, leptin had no effect on estradiol production in the absence of LH. In conclusion, this study has demonstrated that the leptin receptor is expressed in the human ovary, that leptin is present in follicular fluid, and that leptin can induce a biological response in ovarian cells. These results suggest that leptin may have a direct effect on the human ovary.
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Ricci, A. G., M. P. Di Yorio, and A. G. Faletti. "Inhibitory effect of leptin on the rat ovary during the ovulatory process." Reproduction 132, no. 5 (November 2006): 771–80. http://dx.doi.org/10.1530/rep.1.01164.
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The aims of this study were to investigate the negative action of leptin on some intraovarian ovulatory mediators during the ovulatory process and to assess whether leptin is able to alter the expression of its ovarian receptors. Immature rats primed with gonadotrophins were used to induce ovulation. Serum leptin concentration was diminished 4 h after human chorionic gonadotrophin (hCG) administration, whereas the ovarian expression of leptin receptors, measured by western blot, was increased by the gonadotrophin treatment. Serum progesterone level, ovulation rate and ovarian prostaglandin E (PGE) content were reduced in rats primed with equine chorionic gonadotrophin (eCG)/hCG and treated with acute doses of leptin (five doses of 5 μg each). These inhibitory effects were confirmed by in vitro studies, where the presence of leptin reduced the concentrations of progesterone, PGE and nitrites in the media of both ovarian explants and preovulatory follicle cultures. We also investigated whether these negative effects were mediated by changes in the expression of the ovarian leptin receptors. Since leptin treatment did not alter the expression of ovarian leptin receptor, the inhibitory effect of leptin on the ovulatory process may not be mediated by changes in the expression of its receptors at ovarian level, at least at the concentrations assayed. In summary, the ovulatory process was significantly inhibited in response to an acute treatment with leptin, and this effect may be due, at least in part, to the direct or indirect impairment of some ovarian factors, such as prostaglandins and nitric oxide.
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Uddin, Shahab, and Ramzi M. Mohammad. "Role of leptin and leptin receptors in hematological malignancies." Leukemia & Lymphoma 57, no. 1 (July 7, 2015): 10–16. http://dx.doi.org/10.3109/10428194.2015.1063145.
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Friedman, Jeffrey M. "Leptin, Leptin Receptors, and the Control of Body Weight." Nutrition Reviews 56 (April 27, 2009): S38—S46. http://dx.doi.org/10.1111/j.1753-4887.1998.tb01685.x.
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Li, Raymond H. W., Sandy C. S. Poon, Mei Y. Yu, and Y. F. Wong. "Expression of Placental Leptin and Leptin Receptors in Preeclampsia." International Journal of Gynecological Pathology 23, no. 4 (October 2004): 378–85. http://dx.doi.org/10.1097/01.pgp.0000139647.40620.c8.
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Pulido-Mendez, Magdalena, Juan De Sanctis, and Alexis Rodriguez-Acosta. "Leptin and leptin receptors during malaria infection in mice." Folia Parasitologica 49, no. 4 (December 1, 2002): 249–51. http://dx.doi.org/10.14411/fp.2002.046.
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Seeley, Randy J., Keith A. Yagaloff, Stewart L. Fisher, Paul Burn, Todd E. Thiele, Gertjan van Dijk, Denis G. Baskin, and Michael W. Schwartz. "Melanocortin receptors in leptin effects." Nature 390, no. 6658 (November 1997): 349. http://dx.doi.org/10.1038/37016.
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Hall, Michael E., Grant Smith, John E. Hall, and David E. Stec. "Cardiomyocyte-specific deletion of leptin receptors causes lethal heart failure in Cre-recombinase-mediated cardiotoxicity." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 303, no. 12 (December 15, 2012): R1241—R1250. http://dx.doi.org/10.1152/ajpregu.00292.2012.
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Although disruption of leptin signaling is associated with obesity as well as cardiac lipid accumulation and dysfunction, it has been difficult to separate the direct effects of leptin on the heart from those associated with the effects of leptin on body weight and fat mass. Using Cre-loxP recombinase technology, we developed tamoxifen-inducible, cardiomyocyte-specific leptin receptor-deficient mice to assess the role of leptin in regulating cardiac function. Cre recombinase activation in the heart resulted in transient reduction in left ventricular systolic function which recovered to normal levels by day 10. However, when cardiomyocyte leptin receptors were deleted in the setting of Cre recombinase-induced left ventricular dysfunction, irreversible lethal heart failure was observed in less than 10 days in all mice. Heart failure after leptin receptor deletion was associated with marked decreases of cardiac mitochondrial ATP, phosphorylated mammalian target of rapamycin (mTOR), and AMP-activated kinase (pAMPK). Our results demonstrate that specific deletion of cardiomyocyte leptin receptors, in the presence of increased Cre recombinase expression, causes lethal heart failure associated with decreased cardiac energy production. These observations indicate that leptin plays an important role in regulating cardiac function in the setting of cardiac stress caused by Cre-recombinase expression, likely through actions on cardiomyocyte energy metabolism.
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Cottrell, E. C., R. L. Cripps, J. S. Duncan, P. Barrett, J. G. Mercer, A. Herwig, and S. E. Ozanne. "Developmental changes in hypothalamic leptin receptor: relationship with the postnatal leptin surge and energy balance neuropeptides in the postnatal rat." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 296, no. 3 (March 2009): R631—R639. http://dx.doi.org/10.1152/ajpregu.90690.2008.
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In the adult brain, leptin regulates energy homeostasis primarily via hypothalamic circuitry that affects food intake and energy expenditure. Evidence from rodent models has demonstrated that during early postnatal life, leptin is relatively ineffective in modulating these pathways, despite the high circulating levels and the presence of leptin receptors within the central nervous system. Furthermore, in recent years, a neurotrophic role for leptin in the establishment of energy balance circuits has emerged. The precise way in which leptin exerts these effects, and the site of leptin action, is unclear. To provide a detailed description of the development of energy balance systems in the postnatal rat in relation to leptin concentrations during this time, endogenous leptin levels were measured, along with gene expression of leptin receptors and energy balance neuropeptides in the medial basal hypothalamus, using in situ hybridization. Expression of leptin receptors and both orexigenic and anorexigenic neuropeptides increased in the arcuate nucleus during the early postnatal period. At postnatal day 4 (P4), we detected dense leptin receptor expression in ependymal cells of the third ventricle (3V), which showed a dramatic reduction over the first postnatal weeks, coinciding with marked morphological changes in this region. An acute leptin challenge robustly induced suppressor of cytokine signaling-3 expression in the 3V of P4 but not P14 animals, revealing a clear change in the location of leptin action over this period. These findings suggest that the neurotrophic actions of leptin may involve signaling at the 3V during a restricted period of postnatal development.
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Guerra, Borja, Alfredo Santana, Teresa Fuentes, Safira Delgado-Guerra, Alfredo Cabrera-Socorro, Cecilia Dorado, and Jose A. L. Calbet. "Leptin receptors in human skeletal muscle." Journal of Applied Physiology 102, no. 5 (May 2007): 1786–92. http://dx.doi.org/10.1152/japplphysiol.01313.2006.
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Human skeletal muscle expresses leptin receptor mRNA; however, it remains unknown whether leptin receptors (OB-R) are also expressed at the protein level. Fourteen healthy men (age = 33.1 ± 2.0 yr, height = 175.9 ± 1.7 cm, body mass = 81.2 ± 3.8 kg, body fat = 22.5 ± 1.9%; means ± SE) participated in this investigation. The expression of OB-R protein was determined in skeletal muscle, subcutaneous adipose tissue, and hypothalamus using a polyclonal rabbit anti-human leptin receptor. Three bands with a molecular mass close to 170, 128, and 98 kDa were identified by Western blot with the anti-OB-R antibody. All three bands were identified in skeletal muscle: the 98-kDa and 170-kDa bands were detected in hypothalamus, and the 98-kDa and 128-kDa bands were detected in thigh subcutaneous adipose tissue. The 128-kDa isoform was not detected in four subjects, whereas in the rest its occurrence was fully explained by the presence of intermuscular adipose tissue, as demonstrated using an anti-perilipin A antibody. No relationship was observed between the basal concentration of leptin in serum and the 170-kDa band density. In conclusion, a long isoform of the leptin receptor with a molecular mass close to 170 kDa is expressed at the protein level in human skeletal muscle. The amount of 170-kDa protein appears to be independent of the basal concentration of leptin in serum.
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Hileman, Stanley M., Jens Tornøe, Jeffrey S. Flier, and Christian Bjørbæk. "Transcellular Transport of Leptin by the Short Leptin Receptor Isoform ObRa in Madin-Darby Canine Kidney Cells*." Endocrinology 141, no. 6 (June 1, 2000): 1955–61. http://dx.doi.org/10.1210/endo.141.6.7450.
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Abstract Leptin is an adipocyte-derived hormone that acts in specific regions of the brain to regulate body weight and neuroendocrine function. The mechanism by which leptin enters the brain is unknown. We previously reported that rat brain microvessels, which constitute the blood-brain barrier, contain large amounts of messenger RNA encoding a short form of the leptin receptor (ObRa), suggesting that this site may be important for receptor-mediated transport of leptin into the brain. The purpose of this study was to determine whether ObRa is capable of transcellular transport of intact leptin. A transwell system in which Madin-Darby Canine Kidney (MDCK) cells stably expressing ObRa are grown in a monolayer was used to determine receptor distribution on apical or basolateral cell surfaces and the capacity for directional transport of 125I-leptin. Binding of 125I-leptin was greater on the apical vs. the basolateral cell surface and transport of 125I-leptin occurred only in the apical to basolateral direction. 11% of transported radioactivity appearing in the basolateral chamber represented intact leptin as assessed by TCA precipitation analysis and by SDS-PAGE. Parental MDCK cells did not express leptin receptors and did not bind or transport 125I-leptin. Epidermal growth factor (EGF) binding and transport via endogenous EGF receptors in MDCK cells also was assessed. In contrast to leptin, specific binding of 125I-EGF occurred primarily on the basolateral cell surface and transport of 125I-EGF occurred predominantly in the basolateral to apical direction. These data show that ObRa is preferentially targeted to the apical cell membrane in MDCK cells and that leptin transport occurs, albeit at a low rate, in a unidirectional manner in the apical to basolateral direction. These findings may be relevant to the putative role of ObRa in receptor-mediated transport of leptin from the circulation into the brain.
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Cao, G. Y., R. V. Considine, and R. B. Lynn. "Leptin receptors in the adrenal medulla of the rat." American Journal of Physiology-Endocrinology and Metabolism 273, no. 2 (August 1, 1997): E448—E452. http://dx.doi.org/10.1152/ajpendo.1997.273.2.e448.
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Leptin is the protein product of the recently cloned obesity gene. Leptin receptor mRNA is found in a number of central and peripheral locations. The hypothalamus is a presumed site of action. However, little is known about the specific locations of the receptor in peripheral organs. Epinephrine has potent anorectic effects and can cause weight loss by a variety of mechanisms. Excretion of epinephrine is reduced in the ob/ob mouse, which lacks leptin, suggesting an effect by leptin on the adrenal medulla. In the current study, the presence of the leptin receptor was identified on epinephrine-secreting cells in the adrenal medulla. Immunohistochemical studies found dense leptin receptor-like immunoreactivity in the adrenal medulla with no labeling in the adrenal cortex. Double immunofluorescent labeling confirmed that the leptin receptor was present on cells that were phenylethanolamine N-methyltransferase-like immunoreactive and therefore were epinephrine-secreting cells. Leptin receptor mRNA in the adrenal medulla was detected by reverse transcriptase-polymerase chain reaction, with the majority of the mRNA coding for the short isoform (Ob-Ra) of the receptor. Finally, autoradiography was performed using 125I-labeled leptin; specific binding was found in the adrenal medulla, with no specific binding in the adrenal cortex. These results suggest that leptin may have a direct effect on epinephrine-secreting cells in the adrenal medulla. Epinephrine may play a role in mediating the effects of leptin to reduce body weight.
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AL-Barzinji, Ruqaya M., and Ahmed A. AL-Naqshbandi. "Estimation of Leptin and Leptin Receptor Concentrations in Seminal Plasma of Primary Infertile Men." Journal of the Faculty of Medicine Baghdad 59, no. 2 (July 2, 2017): 160–64. http://dx.doi.org/10.32007/jfacmedbagdad.592129.
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Background: There are many sources for Leptin secretion, and it is activated by binding with its receptor known as leptin receptor, that play a role in male infertility.Objective: To assess the levels of leptin and leptin receptors in seminal plasma among primary infertile men and its impact on semen parameters.Patients and Methods: A case control study of 75 primary infertile males and 40 healthy individuals who were enrolled in this study during March 2013 to May 2013. Estimation of age, body mass index (BMI), semen analysis, seminal plasma leptin, leptin receptor and testosterone hormone concentration were done for all study subjects.Results: Highly significant difference found in mean of semen parameters of infertile male compared with healthy controls. Mean concentration of seminal plasma leptin and leptin receptor of infertile men were significantly were elevated, while serum testosterone concentration significantly decreased compared with healthy control.Conclusion: There is emerging evidence that the leptin concentration negatively impacts fertility through its correlation with age, BMI, testosterone hormone and semen parameters.
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Guo, Zhihong, Haiyang Jiang, Xiangru Xu, Wenzhen Duan, and Mark P. Mattson. "Leptin-mediated Cell Survival Signaling in Hippocampal Neurons Mediated by JAK STAT3 and Mitochondrial Stabilization." Journal of Biological Chemistry 283, no. 3 (November 9, 2007): 1754–63. http://dx.doi.org/10.1074/jbc.m703753200.
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Leptin plays a pivotal role in the regulation of energy homeostasis and metabolism, primarily by acting on neurons in the hypothalamus that control food intake. However, leptin receptors are more widely expressed in the brain suggesting additional, as yet unknown, functions of leptin. Here we show that both embryonic and adult hippocampal neurons express leptin receptors coupled to activation of STAT3 and phosphatidylinositol 3-kinase-Akt signaling pathways. Leptin protects hippocampal neurons against cell death induced by neurotrophic factor withdrawal and excitotoxic and oxidative insults. The neuroprotective effect of leptin is antagonized by the JAK2-STAT3 inhibitor AG-490, STAT3 decoy DNA, and phosphatidylinositol 3-kinase/Akt inhibitors but not by an inhibitor of MAPK. Leptin induces the production of manganese superoxide dismutase and the anti-apoptotic protein Bcl-xL, and stabilizes mitochondrial membrane potential and lessens mitochondrial oxidative stress. Leptin receptor-deficient mice (db/db mice) are more vulnerable to seizure-induced hippocampal damage, and intraventricular administration of leptin protects neurons against seizures. By enhancing mitochondrial resistance to apoptosis and excitotoxicity, our findings suggest that leptin signaling serves a neurotrophic function in the developing and adult hippocampus.
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Schulz, Solveig, Carsten Hackel, and Wolfgang Weise. "Hormonal regulation of neonatal weight: placental leptin and leptin receptors." BJOG: An International Journal of Obstetrics and Gynaecology 107, no. 12 (December 2000): 1486–91. http://dx.doi.org/10.1111/j.1471-0528.2000.tb11672.x.
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Li, Raymond H. W., May M. Y. Yu, Annie N. Y. Cheung, and Y. F. Wong. "Expression of leptin and leptin receptors in gestational trophoblastic diseases." Gynecologic Oncology 95, no. 2 (November 2004): 299–306. http://dx.doi.org/10.1016/j.ygyno.2004.06.040.
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Wasim, Muhammad, Fazli Rabbi Awan, Syeda Sadia Najam, Abdul Rehman Khan, and Haq Nawaz Khan. "Role of Leptin Deficiency, Inefficiency, and Leptin Receptors in Obesity." Biochemical Genetics 54, no. 5 (June 16, 2016): 565–72. http://dx.doi.org/10.1007/s10528-016-9751-z.
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Seamon, Marissa, WonMo Ahn, Ai-Jun Li, Sue Ritter, and Ruth B. S. Harris. "Leptin receptor-expressing neurons in ventromedial nucleus of the hypothalamus contribute to weight loss caused by fourth ventricle leptin infusions." American Journal of Physiology-Endocrinology and Metabolism 317, no. 4 (October 1, 2019): E586—E596. http://dx.doi.org/10.1152/ajpendo.00205.2019.
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Leptin administration into the hindbrain, and specifically the nucleus of the solitary tract, increases phosphorylated signal transducer and activator of transcription 3 (pSTAT3), a marker of leptin receptor activation, in hypothalamic nuclei known to express leptin receptors. The ventromedial nucleus of the hypothalamus (VMH) shows the greatest response, with a threefold increase in pSTAT3. This experiment tested the importance of VMH leptin receptor-expressing neurons in mediating weight loss caused by fourth ventricle (4V) leptin infusion. Male Sprague-Dawley rats received bilateral VMH 75-nL injections of 260 ng/μL of leptin-conjugated saporin (Lep-Sap) or blank-saporin (Blk-Sap). After 23 days they were fitted with 4V infusion cannulas and 1 wk later adapted to housing in a calorimeter before they were infused with 0.9 μg leptin/day for 14 days. There was no effect of VMH Lep-Sap on weight gain or glucose clearance before leptin infusion. Leptin inhibited food intake and respiratory exchange ratio in Blk-Sap but not Lep-Sap rats. Leptin had no effect on energy expenditure or brown adipose tissue temperature of either group. Inguinal and epididymal fat were significantly reduced in leptin-treated Blk-Sap rats, but the response was greatly attenuated in Lep-Sap rats. VMH pSTAT3 was increased in leptin-treated Blk-Sap but not Lep-Sap rats. These results support the concept that leptin-induced weight loss results from an integrated response across different brain areas. They also support previous reports that VMH leptin receptors do not play a significant role in maintaining energy balance in basal conditions but limit weight gain during positive energy balance.
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Glasow, A., W. Kiess, U. Anderegg, A. Berthold, A. Bottner, and J. Kratzsch. "Expression of Leptin (Ob) and Leptin Receptor (Ob-R) in Human Fibroblasts: Regulation of Leptin Secretion by Insulin." Journal of Clinical Endocrinology & Metabolism 86, no. 9 (September 1, 2001): 4472–79. http://dx.doi.org/10.1210/jcem.86.9.7792.
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Leptin, a hormone of the cytokine family, is mainly synthesized by white adipocytes. As fibroblasts and adipocytes share a common stem cell origin, we hypothesized that connective tissue may be another candidate for leptin synthesis. We demonstrated leptin receptors, inclusive of all isoforms, on cultured fibroblasts (n = 13) by RT-PCR and immunohistochemistry. In contrast to its receptor, basal leptin mRNA expression and protein secretion were found in 8 of 13 cultures, reaching 1.4 ng/350,000 cells·24 h. Incubation with physiological insulin concentrations (1 nmol/liter) increased leptin secretion in fibroblast culture supernatants to 152% of basal levels. A maximal stimulation of the basal level up to 192% was found with 10 nmol/liter insulin after 24 h. Actinomycin D and cycloheximide abolished this effect, providing evidence that active RNA and protein synthesis are involved in insulin’s action. Completing these in vitro results, we could show protein expression for leptin and leptin receptors in fibroblasts by immunostaining of human skin biopsies in situ. In conclusion, we provide evidence of leptin synthesis and secretion by human fibroblasts that are regulated by insulin. Leptin produced by fibroblasts may thus exert important local autocrine and paracrine actions and contribute to the total plasma pool. Hence it might in part account for variations in body mass index-dependent reference ranges of leptin as well as disruptions in the relationship between fat content and leptin.
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Almabhouh, Fayez A., Faizatul Isyraqiah Ahmad Muhammad, Hisham Ibrahim, and Harbindarjeet Singh. "Leptin: a pleitropic factor in physiology." Journal of Clinical and Health Sciences 4, no. 2 (December 31, 2019): 31. http://dx.doi.org/10.24191/jchs.v4i2.7551.
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Leptin, a 16 kDa protein and a product of the ob/ob gene, has a tertiary structure similar to that of a cytokine. It is primarily secreted by white adipose tissue and its levels in the blood correlate positively with percentage body fat. Leptin was first identified in 1994 as a major factor that regulated food intake and energy balance. Leptin in the circulation exists either as a free monomeric hormone or bound to its soluble receptor. Its serum levels usually range from 0.5 to 37.7 ng/ml in males and 2.0 to 45.2 ng/ml in females. The half-life of leptin is between 20 - 30 minutes and it is eliminated mainly by the kidneys. However, research over the last 25 years has revealed numerous other physiological roles for leptin, including roles in inflammation, immune function, neuro-endocrine function, bone metabolism, blood pressure regulation and sexual maturation. Most of these roles have been identified from studies on leptin deficient rodents. Apart from energy balance and sexual maturation, where its role is direct and obvious, its actions on the rest of the other systems are permissive. Actions of leptin are both centrally and peripherally mediated involving receptors that are widely distributed in the body. Six leptin receptor isoforms, belonging to the class 1 cytokine receptor family, have been identified. These receptors are products of the OBR gene. The cellular actions of leptin are mediated through any one of five different signalling pathways that include the JAK-STAT, PI3K, MAPK, AMPK, and the mTOR signalling pathways.
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Machinal-Quélin, F., M. N. Dieudonné, M. C. Leneveu, R. Pecquery, and Y. Giudicelli. "Proadipogenic effect of leptin on rat preadipocytes in vitro: activation of MAPK and STAT3 signaling pathways." American Journal of Physiology-Cell Physiology 282, no. 4 (April 1, 2002): C853—C863. http://dx.doi.org/10.1152/ajpcell.00331.2001.
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Because leptin has recently been shown to induce proliferation and/or differentiation of different cell types through different pathways, the aim of the present study was to investigate, in vitro, the influence of leptin on adipogenesis in rat preadipocytes. A prerequisite to this study was to identify leptin receptors (Ob-Ra and Ob-Rb) in preadipocytes from femoral subcutaneous fat. We observed that expressions of Ob-Ra and Ob-Rb increase during adipogenesis. Furthermore, leptin induces an increase of p42/p44 mitogen-activated protein kinase phosphorylated isoforms in both confluent and differentiated preadipocytes and of STAT3 phosphorylation only in confluent preadipocytes. Moreover, exposure to leptin promoted activator protein-1 complex DNA binding activity in confluent preadipocytes. Finally, exposure of primary cultured preadipocytes from the subcutaneous area to leptin (10 nM) resulted in an increased proliferation ([3H]thymidine incorporation and cell counting) and differentiation (glycerol-3-phosphate dehydrogenase activity and mRNA levels of lipoprotein lipase, peroxisome proliferator-activated receptor-γ2, and c-fos). Altogether, these results indicate that, in vitro at least, leptin through its functional receptors exerts a proadipogenic action in subcutaneous preadipocytes.
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Li, Ying, Xiaoyin Wu, Shiyi Zhou, and Chung Owyang. "Low-affinity CCK-A receptors are coexpressed with leptin receptors in rat nodose ganglia: implications for leptin as a regulator of short-term satiety." American Journal of Physiology-Gastrointestinal and Liver Physiology 300, no. 2 (February 2011): G217—G227. http://dx.doi.org/10.1152/ajpgi.00356.2010.
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The paradigm for the control of feeding behavior has changed significantly. Research has shown that leptin, in the presence of CCK, may mediate the control of short-term food intake. This interaction between CCK and leptin occurs at the vagus nerve. In the present study, we aimed to characterize the interaction between CCK and leptin in the vagal primary afferent neurons. Single neuronal discharges of vagal primary afferent neurons innervating the gastrointestinal tract were recorded from rat nodose ganglia. Three groups of nodose ganglia neurons were identified: group 1 responded to CCK-8 but not leptin; group 2 responded to leptin but not CCK-8; group 3 responded to high-dose CCK-8 and leptin. In fact, the neurons in group 3 showed CCK-8 and leptin potentiation, and they responded to gastric distention. To identify the CCK-A receptor (CCKAR) affinity states that colocalize with the leptin receptor OB-Rb, we used CCK-JMV-180, a high-affinity CCKAR agonist and low-affinity CCKAR antagonist. As expected, immunohistochemical studies showed that CCK-8 administration significantly potentiated the increase in the number of c-Fos-positive neurons stimulated by leptin in vagal nodose ganglia. Administration of CCK-JMV-180 eliminated the synergistic interaction between CCK-8 and leptin. We conclude that both low- and high-affinity CCKAR are expressed in nodose ganglia. Many nodose neurons bearing low-affinity CCKAR express OB-Rb. These neurons also respond to mechanical distention. An interaction between CCKAR and OB-Rb in these neurons likely facilitates leptin mediation of short-term satiety.
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Cammisotto, Philippe G., Moise Bendayan, Alain Sané, Michel Dominguez, Carole Garofalo, and Émile Levy. "Receptor-Mediated Transcytosis of Leptin through Human Intestinal Cells In Vitro." International Journal of Cell Biology 2010 (2010): 1–13. http://dx.doi.org/10.1155/2010/928169.
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Gastric Leptin is absorbed by duodenal enterocytes and released on the basolateral side towards the bloodstream. We investigated in vitro some of the mechanisms of this transport. Caco-2/15 cells internalize leptin from the apical medium and release it through transcytosis in the basal medium in a time- temperature-dependent and saturable fashion. Leptin receptors are revealed on the apical brush-border membrane of the Caco-2 cells. RNA-mediated silencing of the receptor led to decreases in the uptake and basolateral release. Leptin in the basal medium was found bound to the soluble form of its receptor. An inhibitor of clathrin-dependent endocytosis (chlorpromazine) decreased leptin uptake. Confocal immunocytochemistry and the use of brefeldin A and okadaic acid revealed the passage of leptin through the Golgi apparatus. We propose that leptin transcytosis by intestinal cells depends on its receptor, on clathrin-coated vesicles and transits through the Golgi apparatus.
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Niv-Spector, Leonora, Dana Gonen-Berger, Isabelle Gourdou, Eva Biener, Eugene E. Gussakovsky, Yackir Benomar, Krishnan V. Ramanujan, et al. "Identification of the hydrophobic strand in the A–B loop of leptin as major binding site III: implications for large-scale preparation of potent recombinant human and ovine leptin antagonists." Biochemical Journal 391, no. 2 (October 10, 2005): 221–30. http://dx.doi.org/10.1042/bj20050457.
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Interaction of leptin with its receptors resembles that of interleukin-6 and granulocyte colony-stimulating factor, which interact with their receptors through binding sites I–III. Site III plays a pivotal role in receptors' dimerization or tetramerization and subsequent activation. Leptin's site III also mediates the formation of an active multimeric complex through its interaction with the IGD (immunoglobulin-like domain) of LEPRs (leptin receptors). Using a sensitive hydrophobic cluster analysis of leptin's and LEPR's sequences, we identified hydrophobic stretches in leptin's A–B loop (amino acids 39–42) and in the N-terminal end of LEPR's IGD (amino acids 325–328) that are predicted to participate in site III and to interact with each other in a β-sheet-like configuration. To verify this hypothesis, we prepared and purified to homogeneity (as verified by SDS/PAGE, gel filtration and reverse-phase chromatography) several alanine muteins of amino acids 39–42 in human and ovine leptins. CD analyses revealed that those mutations hardly affect the secondary structure. All muteins acted as true antagonists, i.e. they bound LEPR with an affinity similar to the wild-type hormone, had no agonistic activity and specifically inhibited leptin action in several leptin-responsive in vitro bioassays. Alanine mutagenesis of LEPR's IGD (amino acids 325–328) drastically reduced its biological but not binding activity, indicating the importance of this region for interaction with leptin's site III. FRET (fluorescence resonance energy transfer) microscopy experiments have documented that the transient FRET signalling occurring upon exposure to leptin results not from binding of the ligand, but from ligand-induced oligomerization of LEPRs mediated by leptin's site III.
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Hurley, Matthew M., Eden M. Anderson, Christopher Chen, Brian Maunze, Evan M. Hess, Megan E. Block, Neerali Patel, et al. "Acute Blockade of PACAP-Dependent Activity in the Ventromedial Nucleus of the Hypothalamus Disrupts Leptin-Induced Behavioral and Molecular Changes in Rats." Neuroendocrinology 110, no. 3-4 (June 6, 2019): 271–81. http://dx.doi.org/10.1159/000501337.
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Leptin signaling pathways, stemming primarily from the hypothalamus, are necessary for maintaining normal energy homeostasis and body weight. In both rodents and humans, dysregulation of leptin signaling leads to morbid obesity and diabetes. Since leptin resistance is considered a primary factor underlying obesity, understanding the regulation of leptin signaling could lead to therapeutic tools and provide insights into the causality of obesity. While leptin actions in some hypothalamic regions such as the arcuate nuclei have been characterized, less is known about leptin activity in the hypothalamic ventromedial nuclei (VMN). Recently, pituitary adenylate cyclase-activating polypeptide (PACAP) has been shown to reduce feeding behavior and alter metabolism when administered into the VMN in a pattern similar to that of leptin. In the current study, we examined whether leptin and PACAP actions in the VMN share overlapping pathways in the regulation of energy balance. Interestingly, PACAP administration into the VMN increased STAT3 phosphorylation and SOCS3 mRNA expression, both of which are hallmarks of leptin receptor activation. In addition, BDNF mRNA expression in the VMN was increased by both leptin and PACAP administration. Moreover, antagonizing PACAP receptors fully reversed the behavioral and cellular effects of leptin injections into the VMN. Electrophysiological studies further illustrated that leptin-induced effects on VMN neurons were blocked by antagonizing PACAP receptors. We conclude that leptin dependency on PACAP signaling in the VMN suggests a potential common signaling cascade, allowing a tonically and systemically secreted neuropeptide to be more precisely regulated by central neuropeptides.
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Houseknecht, K. L. "Leptin and its receptors: Modulation of the neuroendocrine axis." Proceedings of the British Society of Animal Science 2002 (2002): 229. http://dx.doi.org/10.1017/s1752756200008851.
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Leptin is a 16 kDa protein synthesized and secreted primarily by adipocytes. Leptin was discovered in 1994 as the gene product deficient in the obese ob/ob mouse. In addition to profound obesity, these animals are characterized by multiple, complex neuroendocrine disorders that manifest in severe insulin resistance and infertility. We now know that leptin is involved in the regulation of appetite, body weight, energy balance, reproduction and the neuroendocrine axis in animals and man. Additionally, leptin has been shown to regulate immune function and anorexia associated with disease.
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Knudson, Jarrod D., Ü. Deniz Dincer, Cuihua Zhang, Albert N. Swafford, Ryoji Koshida, Andrea Picchi, Marta Focardi, Gregory M. Dick, and Johnathan D. Tune. "Leptin receptors are expressed in coronary arteries, and hyperleptinemia causes significant coronary endothelial dysfunction." American Journal of Physiology-Heart and Circulatory Physiology 289, no. 1 (July 2005): H48—H56. http://dx.doi.org/10.1152/ajpheart.01159.2004.
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Obesity is associated with marked increases in plasma leptin concentration, and hyperleptinemia is an independent risk factor for coronary artery disease. As a result, the purpose of this investigation was to test the following hypotheses: 1) leptin receptors are expressed in coronary endothelial cells; and 2) hyperleptinemia induces coronary endothelial dysfunction. RT-PCR analysis revealed that the leptin receptor gene is expressed in canine coronary arteries and human coronary endothelium. Furthermore, immunocytochemistry demonstrated that the long-form leptin receptor protein (ObRb) is present in human coronary endothelium. The functional effects of leptin were determined using pressurized coronary arterioles (<130 μm) isolated from Wistar rats, Zucker rats, and mongrel dogs. Leptin induced pharmacological vasodilation that was abolished by denudation and the nitric oxide synthase inhibitor Nω-nitro-l-arginine methyl ester and was absent in obese Zucker rats. Intracoronary leptin dose-response experiments were conducted in anesthetized dogs. Normal and obese concentrations of leptin (0.1–3.0 μg/min ic) did not significantly change coronary blood flow or myocardial oxygen consumption; however, obese concentrations of leptin significantly attenuated the dilation to graded intracoronary doses of acetylcholine (0.3–30.0 μg/min). Additional experiments were performed in canine coronary rings, and relaxation to acetylcholine (6.25 nmol/l-6.25 μmol/l) was significantly attenuated by obese concentrations of leptin (625 pmol/l) but not by physiological concentrations of leptin (250 pmol/l). The major findings of this investigation were as follows: 1) the ObRb is present in coronary arteries and coupled to pharmacological, nitric oxide-dependent vasodilation; and 2) hyperleptinemia produces significant coronary endothelial dysfunction.
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Matheny, M., K. Y. E. Strehler, M. King, N. Tümer, and P. J. Scarpace. "Targeted leptin receptor blockade: role of ventral tegmental area and nucleus of the solitary tract leptin receptors in body weight homeostasis." Journal of Endocrinology 222, no. 1 (July 2014): 27–41. http://dx.doi.org/10.1530/joe-13-0455.
Full textAbstract:
The present investigation examined whether leptin stimulation of ventral tegmental area (VTA) or nucleus of the solitary tract (NTS) has a role in body weight homeostasis independent of the medial basal hypothalamus (MBH). To this end, recombinant adeno-associated viral techniques were employed to target leptin overexpression or overexpression of a dominant negative leptin mutant (leptin antagonist). Leptin antagonist overexpression in MBH or VTA increased food intake and body weight to similar extents over 14 days in rats. Simultaneous overexpression of leptin in VTA with antagonist in MBH resulted in food intake and body weight gain that were less than with control treatment but greater than with leptin alone in VTA. Notably, leptin overexpression in VTA increased P-STAT3 in MBH along with VTA, and leptin antagonist overexpression in the VTA partially attenuated P-STAT3 levels in MBH. Interestingly, leptin antagonist overexpression elevated body weight gain, but leptin overexpression in the NTS failed to modulate either food intake or body weight despite increased P-STAT3. These data suggest that leptin function in the VTA participates in the chronic regulation of food consumption and body weight in response to stimulation or blockade of VTA leptin receptors. Moreover, one component of VTA-leptin action appears to be independent of the MBH, and another component appears to be related to leptin receptor-mediated P-STAT3 activation in the MBH. Finally, leptin receptors in the NTS are necessary for normal energy homeostasis, but mostly they appear to have a permissive role. Direct leptin activation of NTS slightly increases UCP1 levels, but has little effect on food consumption or body weight.
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Morrison, Shaun F. "Activation of 5-HT1A receptors in raphe pallidus inhibits leptin-evoked increases in brown adipose tissue thermogenesis." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 286, no. 5 (May 2004): R832—R837. http://dx.doi.org/10.1152/ajpregu.00678.2003.
Full textAbstract:
To elucidate the central neural pathways contributing to the thermogenic component of the autonomic response to intravenous administration of leptin, experiments were conducted in urethane-chloralose-anesthetized, ventilated rats to address 1) the role of neurons in the rostral ventromedial medulla, including raphe pallidus (RPa), in the leptin-evoked stimulation of brown adipose tissue (BAT) sympathetic nerve activity (SNA); and 2) the potential thermolytic effect of 5-hydroxytryptamine1A (5-HT1A) receptors on RPa neurons that influence BAT thermogenesis. Leptin (1 mg/kg) administration increased BAT SNA by 1,219% of control, BAT temperature by 2.8°C, expired CO2 by 1.8%, heart rate by 90 beats/min, and mean arterial pressure by 12 mmHg. Microinjection of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) into RPa resulted in a prompt and sustained reversal of the leptin-evoked stimulation of BAT SNA, BAT thermogenesis, and heart rate, with these variables returning to their pre-leptin control levels. Subsequent microinjection of the selective 5-HT1A receptor antagonist WAY-100635 into RPa reversed the BAT thermolytic effects of 8-OH-DPAT, returning BAT SNA and BAT temperature to the elevated levels after leptin. In conclusion, activation of neurons in RPa, possibly BAT sympathetic premotor neurons, is essential for the increases in BAT SNA, BAT thermogenesis, and heart rate stimulated by intravenous administration of leptin. Neurons in RPa express 5-HT1A receptors whose activation leads to reversal of the BAT thermogenic and the cardiovascular responses to intravenous leptin, possibly through hyperpolarization of local sympathetic premotor neurons. These results contribute to our understanding of central neural substrates for the augmented energy expenditure stimulated by leptin.
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Minokoshi, Y., and B. B. Kahn. "Role of AMP-activated protein kinase in leptin-induced fatty acid oxidation in muscle." Biochemical Society Transactions 31, no. 1 (February 1, 2003): 196–201. http://dx.doi.org/10.1042/bst0310196.
Full textAbstract:
Leptin regulates energy homoeostasis through central and peripheral mechanisms. Initial steps in leptin action include signalling through a cytokine-like receptor which activates the JAK/STAT pathway. We investigated whether the metabolic effects of leptin in muscle could be mediated by the AMP-activated protein kinase (AMP kinase). Through studies involving leptin injection intrahypothalamically or intravenously, as well as incubation of soleus muscle or cultured muscle cells with leptin, we determined that leptin stimulates fatty acid oxidation in skeletal muscle by activating AMP kinase. Leptin exerts this effect directly at the level of muscle and also through the hypothalamic sympathetic nervous system, specifically engaging α-adrenergic receptors in muscle. This represents a novel and important pathway mediating leptin's metabolic actions.