Journal articles on the topic 'Leptin signaling'
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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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Ahima, Rexford S., and Suzette Y. Osei. "Leptin signaling." Physiology & Behavior 81, no. 2 (April 2004): 223–41. http://dx.doi.org/10.1016/j.physbeh.2004.02.014.
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Zhou, Yingjiang, and Liangyou Rui. "Leptin signaling and leptin resistance." Frontiers of Medicine 7, no. 2 (April 12, 2013): 207–22. http://dx.doi.org/10.1007/s11684-013-0263-5.
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Wauman, Joris. "Leptin receptor signaling: pathways to leptin resistance." Frontiers in Bioscience 16, no. 1 (2011): 2771. http://dx.doi.org/10.2741/3885.
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Yang, Ronghua, and Lili A. Barouch. "Leptin Signaling and Obesity." Circulation Research 101, no. 6 (September 14, 2007): 545–59. http://dx.doi.org/10.1161/circresaha.107.156596.
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Foley, J. F. "ROCK Mediates Leptin Signaling." Science Signaling 5, no. 244 (October 2, 2012): ec254-ec254. http://dx.doi.org/10.1126/scisignal.2003656.
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Tian, Hai-feng, Qiao-mu Hu, Yan Meng, and Han-bing Xiao. "Molecular cloning, characterization and evolutionary analysis of leptin gene in Chinese giant salamander, Andrias davidianus." Open Life Sciences 12, no. 1 (November 23, 2017): 406–17. http://dx.doi.org/10.1515/biol-2017-0048.
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AbstractLeptin is an important hormone possessing diverse physiological roles in mammals and teleosts. However, it has been characterized only in a few amphibian species, and its evolutions are still under debate. Here, the full length of the leptin (Adlep) cDNA of Chinese giant salamander (Andrias davidianus), an early diverging amphibian species, is characterized and according to the results of the primary sequence analysis, tertiary structure reconstruction and phylogenetic analysis is confirmed to be an ortholog of mammalian leptin. An intron was identified between the coding exons of A. davidianus leptin, which indicated that the leptin is present in the salamander genome and contains a conserved gene structure in vertebrates. Adlep is widely distributed but expression levels vary among different tissues, with highest expression levels in the muscle. Additionally, the leptin receptor and other genes were mapped to three known leptin signaling pathways, suggesting that the leptin signaling pathways are present in A. davidianus. Phylogenetic topology of leptins are consistent with the generally accepted evolutionary relationships of vertebrates, and multiple leptin members found in teleosts seem to be obtained through a Cluopeocephala-specific gene duplication event. Our results will lay a foundation for further investigations into the physiological roles of leptin in A. davidianus.
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Saranac, Ljiljana, Bojko Bjelakovic, Hristina Stamenkovic, and Borislav Kamenov. "Orexitropic Signaling Proteins in Obese Children." Scientific World JOURNAL 7 (2007): 1263–71. http://dx.doi.org/10.1100/tsw.2007.218.
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Adipose tissue is not only the main organ for energy storage, but it also has endocrine properties, producing “adipokines” responsible for energy homeostasis, insulin sensitivity, and inflammation. Leptin, produced by adipocytes, is the key hormone in appetite regulation and suppression of orexigenic, hypothalamic neuropeptide Y (NPY). We wanted to establish and compare levels of leptin and NPY in different obesity types in childhood, and to investigate their correlations with auxological parameters. Twenty-one obese children (seven girls and 14 boys), divided into two groups, were compared with 14 controls. The mean age of the study group was 10.81 ± 3.69 years and the mean puberty stage was 2.21. The mean body mass index (BMI) was 32.80 kg/m2(range 23.30– 47.02) and the mean overweight 30.73 kg (range 8.00–74.00). The mean leptin level was higher in boys and in the group with central obesity, but was not significant. Leptin/NPY ratio and leptin/BMI ratio was also higher in the central obesity group and there was a more significant difference compared with controls. We found significant correlation of the leptin level with body mass (BM), body mass excess (BME), and BMI (p < 0.05). The mean leptin level in obese children was very high (36.39 ng/ml). Leptin and NPY levels showed inverse values in two different obesity types. Results are suggestive for leptin resistance rather than leptin deficiency in our group of obese children. Orexitropic signaling proteins correlated significantly with auxological parameters. Determination of the leptin and NPY concentrations provided evidence that obesity represents disease with neuroendocrine dysfunction and high leptin/NPY ratio, which could be a useful marker for central obesity.
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Metlakunta, Anantha S., Maitrayee Sahu, Hideo Yasukawa, Sandeep S. Dhillon, Denise D. Belsham, Akihiko Yoshimura, and Abhiram Sahu. "Neuronal suppressor of cytokine signaling-3 deficiency enhances hypothalamic leptin-dependent phosphatidylinositol 3-kinase signaling." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 300, no. 5 (May 2011): R1185—R1193. http://dx.doi.org/10.1152/ajpregu.00794.2010.
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Suppressor of cytokine signaling-3 (SOCS3) is thought to be involved in the development of central leptin resistance and obesity by inhibiting STAT3 pathway. Because phosphatidylinositol 3-kinase (PI3K) pathway plays an important role in transducing leptin action in the hypothalamus, we examined whether SOCS3 exerted an inhibition on this pathway. We first determined whether leptin sensitivity in the hypothalamic PI3K pathway was increased in brain-specific Socs3-deficient (NesKO) mice. In NesKO mice, hypothalamic insulin receptor substrate-1 (IRS1)-associated PI3K activity was significantly increased at 30 min and remained elevated up to 2 h after leptin intraperitoneal injection, but in wild-type (WT) littermates, the significant increase was only at 30 min. Hypothalamic p-STAT3 levels were increased up to 5 h in NesKO as opposed to 2 h in WT mice. In food-restricted WT mice with reduced body weight, leptin increased hypothalamic PI3K activity only at 30 min, and p-STAT3 levels at 30–120 min postinjection. These results suggest increased leptin sensitivity in both PI3K and STAT3 pathways in the hypothalamus of NesKO mice, which was not due to a lean phenotype. In the next experiment with a clonal hypothalamic neuronal cell line expressing proopiomelanocortin, we observed that whereas leptin significantly increased IRS1-associated PI3K activity and p-JAK2 levels in cells transfected with control vector, it failed to do so in SOCS3-overexpressed cells. Altogether, these results imply a SOCS3 inhibition of the PI3K pathway of leptin signaling in the hypothalamus, which may be one of the mechanisms behind the development of central leptin resistance and obesity.
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Groba, Claudia, Steffen Mayerl, Alies A. van Mullem, Theo J. Visser, Veerle M. Darras, Andreas J. Habenicht, and Heike Heuer. "Hypothyroidism Compromises Hypothalamic Leptin Signaling in Mice." Molecular Endocrinology 27, no. 4 (April 1, 2013): 586–97. http://dx.doi.org/10.1210/me.2012-1311.
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Abstract The impact of thyroid hormone (TH) on metabolism and energy expenditure is well established, but the role of TH in regulating nutritional sensing, particularly in the central nervous system, is only poorly defined. Here, we studied the consequences of hypothyroidism on leptin production as well as leptin sensing in congenital hypothyroid TRH receptor 1 knockout (Trhr1 ko) mice and euthyroid control animals. Hypothyroid mice exhibited decreased circulating leptin levels due to a decrease in fat mass and reduced leptin expression in white adipose tissue. In neurons of the hypothalamic arcuate nucleus, hypothyroid mice showed increased leptin receptor Ob-R expression and decreased suppressor of cytokine signaling 3 transcript levels. In order to monitor putative changes in central leptin sensing, we generated hypothyroid and leptin-deficient animals by crossing hypothyroid Trhr1 ko mice with the leptin-deficient ob/ob mice. Hypothyroid Trhr1/ob double knockout mice showed a blunted response to leptin treatment with respect to body weight and food intake and exhibited a decreased activation of phospho-signal transducer and activator of transcription 3 as well as a up-regulation of suppressor of cytokine signaling 3 upon leptin treatment, particularly in the arcuate nucleus. These data indicate alterations in the intracellular processing of the leptin signal under hypothyroid conditions and thereby unravel a novel mode of action by which TH affects energy metabolism.
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Balland, Eglantine, Weiyi Chen, Tony Tiganis, and Michael A. Cowley. "Persistent Leptin Signaling in the Arcuate Nucleus Impairs Hypothalamic Insulin Signaling and Glucose Homeostasis in Obese Mice." Neuroendocrinology 109, no. 4 (2019): 374–90. http://dx.doi.org/10.1159/000500201.
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Background: Obesity is associated with reduced physiological responses to leptin and insulin, leading to the concept of obesity-associated hormonal resistance. Objectives: Here, we demonstrate that contrary to expectations, leptin signaling not only remains functional but also is constantly activated in the arcuate nucleus of the hypothalamus (ARH) neurons of obese mice. This state of persistent response to endogenous leptin underpins the lack of response to exogenous leptin. Methods and Results: The study of combined leptin and insulin signaling demonstrates that there is a common pool of ARH neurons responding to both hormones. More importantly, we show that the constant activation of leptin receptor neurons in the ARH prevents insulin signaling in these neurons, leading to impaired glucose tolerance. Accordingly, antagonising leptin signaling in diet-induced obese (DIO) mice restores insulin signaling in the ARH and improves glucose homeostasis. Direct inhibition of PTP1B in the CNS restores arcuate insulin signaling similarly to leptin inhibition; this effect is likely to be mediated by AgRP neurons since PTP1B deletion specifically in AgRP neurons restores glucose and insulin tolerance in DIO mice. Conclusions: Finally, our results suggest that the constant activation of arcuate leptin signaling in DIO mice increases PTP1B expression, which exerts an inhibitory effect on insulin signaling leading to impaired glucose homeostasis.
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Allison, Margaret B., and Martin G. Myers. "20 YEARS OF LEPTIN: Connecting leptin signaling to biological function." Journal of Endocrinology 223, no. 1 (October 2014): T25—T35. http://dx.doi.org/10.1530/joe-14-0404.
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Hypothalamic leptin action promotes negative energy balance and modulates glucose homeostasis, as well as serving as a permissive signal to the neuroendocrine axes that control growth and reproduction. Since the initial discovery of leptin 20 years ago, we have learned a great deal about the molecular mechanisms of leptin action. An important aspect of this has been the dissection of the cellular mechanisms of leptin signaling, and how specific leptin signals influence physiology. Leptin acts via the long form of the leptin receptor LepRb. LepRb activation and subsequent tyrosine phosphorylation recruits and activates multiple signaling pathways, including STAT transcription factors, SHP2 and ERK signaling, the IRS-protein/PI3Kinase pathway, and SH2B1. Each of these pathways controls specific aspects of leptin action and physiology. Important inhibitory pathways mediated by suppressor of cytokine signaling proteins and protein tyrosine phosphatases also limit physiologic leptin action. This review summarizes the signaling pathways engaged by LepRb and their effects on energy balance, glucose homeostasis, and reproduction. Particular emphasis is given to the multiple mouse models that have been used to elucidate these functions in vivo.
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Morris, David L., and Liangyou Rui. "Recent advances in understanding leptin signaling and leptin resistance." American Journal of Physiology-Endocrinology and Metabolism 297, no. 6 (December 2009): E1247—E1259. http://dx.doi.org/10.1152/ajpendo.00274.2009.
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The brain controls energy homeostasis and body weight by integrating various metabolic signals. Leptin, an adipose-derived hormone, conveys critical information about peripheral energy storage and availability to the brain. Leptin decreases body weight by both suppressing appetite and promoting energy expenditure. Leptin directly targets hypothalamic neurons, including AgRP and POMC neurons. These leptin-responsive neurons widely connect to other neurons in the brain, forming a sophisticated neurocircuitry that controls energy intake and expenditure. The anorexigenic actions of leptin are mediated by LEPRb, the long form of the leptin receptor, in the hypothalamus. LEPRb activates both JAK2-dependent and -independent pathways, including the STAT3, PI 3-kinase, MAPK, AMPK, and mTOR pathways. These pathways act coordinately to form a network that fully mediates leptin response. LEPRb signaling is regulated by both positive (e.g., SH2B1) and negative (e.g., SOCS3 and PTP1B) regulators and by endoplasmic reticulum stress. Leptin resistance, a primary risk factor for obesity, likely results from impairment in leptin transport, LEPRb signaling, and/or the neurocircuitry of energy balance.
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Wang, Jie, Jing Ge, Haigang Cao, Xiaoyu Zhang, Yuan Guo, Xiao Li, Bo Xia, Gongshe Yang, and Xin’e Shi. "Leptin Promotes White Adipocyte Browning by Inhibiting the Hh Signaling Pathway." Cells 8, no. 4 (April 24, 2019): 372. http://dx.doi.org/10.3390/cells8040372.
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Leptin is an important secretory protein that regulates the body’s intake and energy consumption, and the functions of the Hh signaling pathway related to white adipocyte browning are controversial. It has been reported that leptin plays a critical role in adipogenesis by regulating the Hh signaling pathway, but whether there is a functional relationship between leptin, the Hh signaling pathway, and adipocyte browning is not clear. In this research, mouse white pre-adipocytes were isolated to explore the influence of the Hh signal pathway and leptin during the process described above. This showed that leptin decreased high fat diet-induced obese mice body weight and inhibited the Hh signaling pathway, which suggested that leptin and the Hh signaling pathway have an important role in obesity. After activation of the Hh signaling pathway, significantly decreased browning fat-relative gene expression levels were recorded, whereas inhibition of the Hh signaling pathway significantly up-regulated the expression of these genes. Similarly, leptin also up-regulated the expression of these genes, and increased mitochondrial DNA content, but decreased the expression of Gli, the key transcription factors of the Hh signaling pathway. In short, the results show that leptin promotes white adipocyte browning through inhibiting the Hh signaling pathway. Overall, these results demonstrate that leptin serves as a potential intervention to decrease obesity by inhibiting the Hh signaling pathway.
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Zhang, Qian, Bin Liu, Ying Cheng, Qingshu Meng, Tingting Xia, Lei Jiang, Shanghai Chen, Yong Liu, and Feifan Guo. "Leptin Signaling Is Required for Leucine Deprivation-enhanced Energy Expenditure." Journal of Biological Chemistry 289, no. 3 (December 3, 2013): 1779–87. http://dx.doi.org/10.1074/jbc.m113.528943.
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Leptin signaling in the hypothalamus is crucial in energy homeostasis. We have previously shown that dietary deprivation of the essential amino acid leucine in mice stimulates fat loss by increasing energy expenditure. The involvement of leptin signaling in this regulation, however, has not been reported. Here, we show that leucine deprivation promotes leptin signaling in mice maintained on an otherwise normal diet and restores leptin responses in mice maintained on a high fat diet, a regimen known to induce leptin resistance. In addition, we found that leucine deprivation stimulated energy expenditure, and fat loss was largely blocked in db/db mice homozygous for a mutation in leptin receptor and a knock-in mouse line Y3F with abrogation of leptin receptor Tyr1138-mediated signal transducer and activator transcript 3 signaling. Overall, our studies describe a novel link between hypothalamic leptin signaling and stimulation of energy expenditure under leucine deprivation.
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Zhang, Jiejin, and Philip J. Scarpace. "Soluble leptin receptor neutralizes leptin signaling and anorexic responses." FASEB Journal 22, S2 (April 2008): 658. http://dx.doi.org/10.1096/fasebj.22.2_supplement.658.
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Yang, Guoqing, Hongfei Ge, Anne Boucher, Xinxin Yu, and Cai Li. "Modulation of Direct Leptin Signaling by Soluble Leptin Receptor." Molecular Endocrinology 18, no. 6 (June 2004): 1354–62. http://dx.doi.org/10.1210/me.2004-0027.
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Ishida-Takahashi, Ryoko, Shigeo Uotani, Takahiro Abe, Mikako Degawa-Yamauchi, Tetsuya Fukushima, Naruhiro Fujita, Hiroyuki Sakamaki, Hironori Yamasaki, Yoshihiko Yamaguchi, and Katsumi Eguchi. "Rapid Inhibition of Leptin Signaling by Glucocorticoidsin Vitroandin Vivo." Journal of Biological Chemistry 279, no. 19 (March 1, 2004): 19658–64. http://dx.doi.org/10.1074/jbc.m310864200.
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Elevated secretion of glucocorticoids (GCs) or hypersensitivity to GCs has a permissive effect on the development of obesity and leads to abnormalities of body fat distribution. Recent studies demonstrated GCs act as antagonists of leptin in rodents. However, little is known about the interaction between GCs and leptin signaling. In the present study, we investigated the effects of GCs on leptin actionin vitroandin vivo. GCs rapidly inhibited the leptin-induced STAT3 phosphorylation in a dose- and time-dependent manner, as assayed by Western blotting using anti-phosphospecific-STAT3 in human hepatoma cell lines (Huh7) transiently expressing long form leptin receptor. GCs also inhibited the leptin-induced JAK2 tyrosine phosphorylation but unaltered the specific binding of125I-leptin to the cells. Parallel experiments, however, demonstrated that the inhibitory effects of GCs were not observed in either IL-6- or LIF-induced STAT3 phosphorylation. Furthermore, we examined the feeding behavior and hypothalamic leptin signaling following intracerebroventricular (icv) infusion of GCs prior to icv leptin infusion in Sprague-Dawley rats. The food intake after 24 h of icv leptin injection increased 3-fold in GCs-treated animals. In addition, central infusion of GCs resulted in a marked reduction of hypothalamic STAT3 phosphorylation in response to icv infusion of leptin. To clarify the molecular mechanism by which GCs rapidly reduce leptin-induced JAK/STAT signaling, we examined the intracellular signal transduction pathway potentially mediated by GCs. PD98059, a specific MEK inhibitor, blocked the inhibitory effects of GCs on leptin-induced JAK/STAT activation in Huh7 cells. These results suggest GCs antagonize leptin action by a rapid inhibition of the leptin-induced JAK/STAT pathway partly via MAPK cascade.
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Pal, Rekha, and Abhiram Sahu. "Leptin Signaling in the Hypothalamus during Chronic Central Leptin Infusion." Endocrinology 144, no. 9 (September 1, 2003): 3789–98. http://dx.doi.org/10.1210/en.2002-0148.
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Abstract Using a rat model of chronic central leptin infusion in which neuropeptide Y neurons develop leptin resistance, we examined whether leptin signal transduction mechanism in the hypothalamus is altered during central leptin infusion. Adult male rats were infused chronically into the lateral cerebroventricle with leptin (160 ng/h) or vehicle via Alzet pumps for 16 d. In the leptin-infused group, the initial decrease in food intake was followed by a recovery to their preleptin levels by d 16, although food intake remained significantly lower than in artificial cerebrospinal fluid controls; and body weight gradually decreased reaching a nadir at d 11 and remained stabilized at lower level thereafter. Phosphorylated leptin receptor and phosphorylated signal transducer and activator of transcription-3 (p-STAT3) remained elevated in association with a sustained elevation in DNA-binding activity of STAT3 in the hypothalamus throughout 16-d period of leptin infusion. However, phosphorylated Janus kinase-2 was increased during the early part of leptin infusion but remained unaltered on d 16. Although hypothalamic suppressors of cytokine signaling-3 (SOCS3) mRNA levels were increased throughout leptin infusion, SOCS3 protein levels were increased only on d 16. This study demonstrates a sustained elevation in hypothalamic leptin receptor signaling through Janus kinase-STAT pathway despite an increased expression of SOCS3 during chronic central leptin infusion. We propose that an alteration in leptin signaling in the hypothalamus through pathways other than STAT3 and/or a defect in downstream of STAT3 signaling may be involved in food intake recovery seen after an initial decrease during chronic central leptin infusion.
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Guo, Kaiying, Julie E. McMinn, Thomas Ludwig, Yi-Hao Yu, Guoqing Yang, Lulu Chen, Daniella Loh, Cai Li, Streamson Chua, and Yiying Zhang. "Disruption of Peripheral Leptin Signaling in Mice Results in Hyperleptinemia without Associated Metabolic Abnormalities." Endocrinology 148, no. 8 (August 1, 2007): 3987–97. http://dx.doi.org/10.1210/en.2007-0261.
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Although central leptin signaling appears to play a major role in the regulation of food intake and energy metabolism, the physiological role of peripheral leptin signaling and its relative contribution to whole-body energy metabolism remain unclear. To address this question, we created a mouse model (Cre-Tam mice) with an intact leptin receptor in the brain but a near-complete deletion of the signaling domain of leptin receptor in liver, adipose tissue, and small intestine using a tamoxifen (Tam)-inducible Cre-LoxP system. Cre-Tam mice developed marked hyperleptinemia (∼4-fold; P < 0.01) associated with 2.3-fold increase (P < 0.05) in posttranscriptional production of leptin. Whereas this is consistent with the disruption of a negative feedback regulation of leptin production in adipose tissue, there were no discernable changes in energy balance, thermoregulation, and insulin sensitivity. Hypothalamic levels of phosphorylated signal transducer and activator of transcription 3, neuropeptide expression, and food intake were not changed despite hyperleptinemia. The percentage of plasma-bound leptin was markedly increased (90.1–96 vs. 41.8–74.7%; P < 0.05), but plasma-free leptin concentrations remained unaltered in Cre-Tam mice. We conclude from these results that 1) the relative contribution to whole-body energy metabolism from peripheral leptin signaling is insignificant in vivo, 2) leptin signaling in adipocyte constitutes a distinct short-loop negative feedback regulation of leptin production that is independent of tissue metabolic status, and 3) perturbation of peripheral leptin signaling alone, although increasing leptin production, may not be sufficient to alter the effective plasma levels of leptin because of the counter-regulatory increase in the level of leptin binding protein(s).
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Singh, Prachi, Timothy E. Peterson, Fatima H. Sert-Kuniyoshi, Jason A. Glenn, Diane E. Davison, Abel Romero-Corral, Snigdha Pusalavidyasagar, Michael D. Jensen, and Virend K. Somers. "Leptin Signaling in Adipose Tissue." Circulation Research 111, no. 5 (August 17, 2012): 599–603. http://dx.doi.org/10.1161/circresaha.112.273656.
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White, David W., Karen K. Kuropatwinski, Rene Devos, Heinz Baumann, and Louis A. Tartaglia. "Leptin Receptor (OB-R) Signaling." Journal of Biological Chemistry 272, no. 7 (February 14, 1997): 4065–71. http://dx.doi.org/10.1074/jbc.272.7.4065.
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Ribiere, Catherine, and Charles Plut. "Nutritional regulation of leptin signaling." Current Hypertension Reports 7, no. 1 (January 2005): 11–16. http://dx.doi.org/10.1007/s11906-005-0049-5.
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Brabant, Georg, Günter Müller, Rüdiger Horn, Christian Anderwald, Michael Roden, and Heike Nave. "Hepatic leptin signaling in obesity." FASEB Journal 19, no. 8 (March 23, 2005): 1048–50. http://dx.doi.org/10.1096/fj.04-2846fje.
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Dunn-Meynell, Ambrose A., Christelle Le Foll, Miranda D. Johnson, Thomas A. Lutz, Matthew R. Hayes, and Barry E. Levin. "Endogenous VMH amylin signaling is required for full leptin signaling and protection from diet-induced obesity." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 310, no. 4 (February 15, 2016): R355—R365. http://dx.doi.org/10.1152/ajpregu.00462.2015.
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Amylin enhances arcuate (ARC) and ventromedial (VMN) hypothalamic nuclei leptin signaling and synergistically reduces food intake and body weight in selectively bred diet-induced obese (DIO) rats. Since DIO 125I-amylin dorsomedial nucleus-dorsomedial VMN binding was reduced, we postulated that this contributed to DIO ventromedial hypothalamus (VMH) leptin resistance, and that impairing VMH (ARC + VMN) calcitonin receptor (CTR)-mediated signaling by injecting adeno-associated virus (AAV) expressing a short hairpin portion of the CTR mRNA would predispose diet-resistant (DR) rats to obesity on high-fat (45%) diet (HFD). Depleting VMH CTR by 80–90% in 4-wk-old male DR rats reduced their ARC and VMN 125I-labeled leptin binding by 57 and 51%, respectively, and VMN leptin-induced phospho-signal transducer and activator of transcription 3-positive neurons by 59% vs. AAV control rats. After 6 wk on chow, VMH CTR-depleted DR rats ate and gained the equivalent amount of food and weight but had 18% heavier fat pads (relative to carcass weight), 144% higher leptin levels, and were insulin resistant compared with control AAV DR rats. After 6 wk more on HFD, VMH CTR-depleted DR rats ate the same amount but gained 28% more weight, had 60% more carcass fat, 254% higher leptin levels, and 132% higher insulin areas under the curve during an oral glucose tolerance test than control DR rats. Therefore, impairing endogenous VMH CTR-mediated signaling reduced leptin signaling and caused DR rats to become more obese and insulin resistant, both on chow and HFD. These results suggest that endogenous VMH amylin signaling is required for full leptin signaling and protection from HFD-induced obesity.
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Benomar, Yacir, Flavien Berthou, Claire-Marie Vacher, Virginie Bailleux, Arieh Gertler, Jean Djiane, and Mohammed Taouis. "Leptin But Not Ciliary Neurotrophic Factor (CNTF) Induces Phosphotyrosine Phosphatase-1B Expression in Human Neuronal Cells (SH-SY5Y): Putative Explanation of CNTF Efficacy in Leptin-Resistant State." Endocrinology 150, no. 3 (November 13, 2008): 1182–91. http://dx.doi.org/10.1210/en.2008-1097.
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Growing evidences suggest that obesity is associated with hypothalamic leptin resistance, leading to the alteration of food intake control. Alternative treatment using ciliary neurotrophic factor (CNTF) has been suggested because CNTF exerts a leptin-like effect, even in leptin-resistant states, but the mechanisms by which CNTF maintains this effect are not yet understood. Both leptin and CNTF act in the hypothalamus through similar signaling pathways including janus kinase-2/signal transducer and activator of transcription (STAT)-3 pathway. To explore the differences and interactions between leptin and CNTF signaling pathways, differentiated human neuroblastoma cells (SH-SY5Y) were exposed to either leptin or CNTF and then challenged for each cytokine. Leptin pretreatment completely abolished leptin-dependent STAT-3 and ERK 1/2 phosphorylations without affecting CNTF action. The lack of cross-desensitization between leptin and CNTF signaling pathways occurred despite the induction of suppressor of cytokine signaling-3 in response to both cytokines. Interestingly, leptin as well as insulin induced the expression of phosphotyrosine phosphatase (PTP)-1B, whereas CNTF treatment did not affect its expression. In addition, acute leptin treatment but not CNTF induced PTP-1B expression in mouse hypothalamic arcuate nucleus. Furthermore, the overexpression of human PTP-1B in SH-SY5Y cells completely abolished leptin- and insulin-dependent janus kinase-2, STAT-3, and ERK 1/2 phosphorylations, but CNTF action was not altered. Collectively, our results suggest that PTP-1B constitutes a key divergent element between leptin/insulin and CNTF signaling pathways at the neuronal level, which may constitute a possible mechanism that explains the efficacy of CNTF in leptin-resistant states. Phosphotyrosine phosphatase 1B has a critical role in the onset of neuronal leptin resistance and is unable to inhibit CNTF-dependent signaling pathways in leptin-resistant states.
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Morton, Gregory J., James E. Blevins, Francis Kim, Miles Matsen, and Dianne P. Figlewicz. "The action of leptin in the ventral tegmental area to decrease food intake is dependent on Jak-2 signaling." American Journal of Physiology-Endocrinology and Metabolism 297, no. 1 (July 2009): E202—E210. http://dx.doi.org/10.1152/ajpendo.90865.2008.
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Recent evidence suggests that leptin reduces food intake via actions in the brain circuitry of food reward, such as the ventral tegmental area (VTA), as leptin receptors are present in the VTA, and leptin injection in the VTA reduces food intake. In the hypothalamus, leptin-induced anorexia requires signaling via Janus kinase-signal transducer and activator of transcription (Jak-STAT), insulin receptor substrate (IRS)-phosphatidylinositol 3-kinase (PI 3-kinase), and mammalian target of rapamycin (mTOR). In this study, we determined whether leptin activates each of these signal transduction pathways in the VTA and whether these signaling pathways are required for VTA-leptin induced anorexia. Here, we show that pSTAT3-Tyr705, a marker of leptin activation, was induced in a midbrain region containing the VTA and substantia nigra following either intracerebroventricular leptin or direct administration of leptin to the VTA, but these interventions failed to increase levels of either pAKT-Ser473 or phospho-p70S6K-Thr389, markers of IRS-PI 3-kinase and mTOR signaling, respectively. Moreover, the effect of intra-VTA leptin administration to reduce 4- and 20-h food intake and 20-h body weight was blocked by an inhibitor of Jak-2, at a dose that had no effect on food intake or body weight by itself, but not by local inhibition of either PI 3-kinase (LY-294002) or mTOR (rapamycin) in this timeframe. Taken together, these data support the hypothesis that leptin signaling in the VTA is involved in the regulation of energy balance, but, in contrast to the leptin signaling in the hypothalamus, these effects are mediated predominantly via Jak-2 signaling rather than via the IRS-PI 3-kinase or mTOR signaling pathway.
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Shimizu, Hiroyuki, Kinji Inoue, and Masatomo Mori. "The leptin-dependent and -independent melanocortin signaling system: regulation of feeding and energy expenditure." Journal of Endocrinology 193, no. 1 (April 2007): 1–9. http://dx.doi.org/10.1677/joe-06-0144.
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The brain hypothalamus coordinates extra-hypothalamic regions to maintain energy homeostasis through the regulation of food intake and energy expenditure. A number of anorexigenic and orexigenic molecules in the hypothalamic nuclei participate in the control of energy homeostasis. Leptin and pro-opiomelanocortin (POMC)-derived α-melanocyte-stimulating hormone are key anorectic molecules, and the leptin receptor and POMC gene are both expressed in the hypothalamic arcuate nucleus. Although it has been considered that melanocortin signaling is localized downstream to leptin signaling, data have accumulated to support the concept of a leptin-independent melanocortin signaling system. We focus on and review the melanocortin signaling system that functions dependently or independently of leptin signaling in the regulation of energy homeostasis.
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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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McCowen, Karen C., Jesse C. Chow, and Robert J. Smith. "Leptin Signaling in the Hypothalamus of Normal Rats in Vivo**This work was supported in part by a Boston Obesity Nutrition Research Center Grant (to J.C.C.), NIH Grant DK-50411 (to R.J.S.), and NIH Diabetes and Endocrinology Center Grant DK-36836 (to R.J.S.)." Endocrinology 139, no. 11 (November 1, 1998): 4442–47. http://dx.doi.org/10.1210/endo.139.11.6301.
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Abstract Leptin has been shown to activate multiple signaling molecules in cultured cells, including Janus kinase-2, STAT (signal transducer and activator of transcription) proteins, and mitogen-activated protein kinase, and to stimulate the DNA-binding activity of STAT3 in mouse hypothalamus. In this study, the activation of candidate leptin signaling molecules in the hypothalamus of normal rats in vivo was investigated. Fasted male Sprague-Dawley rats were injected iv with recombinant murine leptin or vehicle. Plasma leptin concentrations were determined at defined time points, and the phosphorylation of signaling proteins was assessed in hypothalamic lysates. There was a marked increase in plasma leptin concentration at 2 min and a gradual decline by 45 min after leptin injection. Immunoblotting analysis of hypothalamic lysates with a phosphospecific STAT3 antibody demonstrated a time-dependent stimulation of STAT3 tyrosine phosphorylation. STAT3 phosphorylation was first evident at 5 min and was maximal at 30 min after leptin injection. By contrast, leptin did not increase the phosphorylation of Janus kinase proteins, mitogen-activated protein kinase, or STAT1 and -5 despite abundant expression of these signaling molecules in the hypothalamus. These results differ from findings in cultured cells and in vitro systems. It remains unclear how signaling is propagated downstream from the leptin receptor to STAT3, but this may involve novel signaling intermediates.
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Marie, Chelsea S., Hans P. Verkerke, Shom N. Paul, Aaron J. Mackey, and William A. Petri. "Leptin Protects Host Cells from Entamoeba histolytica Cytotoxicity by a STAT3-Dependent Mechanism." Infection and Immunity 80, no. 5 (February 13, 2012): 1934–43. http://dx.doi.org/10.1128/iai.06140-11.
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ABSTRACTThe adipocytokine leptin links nutritional status to immune function. Leptin signaling protects from amebiasis, but the molecular mechanism is not understood. We developed anin vitromodel of ameba-host cell interaction to test the hypothesis that leptin prevents ameba-induced apoptosis in host epithelial cells. We demonstrated that activation of mammalian leptin signaling increased cellular resistance to amebic cytotoxicity, including caspase-3 activation. Exogenous expression of the leptin receptor conferred resistance in susceptible cells, and leptin stimulation enhanced protection. A series of leptin receptor signaling mutants showed that resistance to amebic cytotoxicity was dependent on activation of STAT3 but not the Src homology-2 domain-containing tyrosine phosphatase (SHP-2) or STAT5. A common polymorphism in the leptin receptor (Q223R) that increases susceptibility to amebiasis in humans and mice was found to increase susceptibility to amebic cytotoxicity in single cells. The Q223R polymorphism also decreased leptin-dependent STAT3 activation by 21% relative to that of the wild-type (WT) receptor (P= 0.035), consistent with a central role of STAT3 signaling in protection. A subset of genes uniquely regulated by STAT3 in response to leptin was identified. Most notable were the TRIB1 and suppressor of cytokine signaling 3 (SOCS3) genes, which have opposing roles in the regulation of apoptosis. Overall apoptotic genes were highly enriched in this gene set (P< 1E−05), supporting the hypothesis that leptin regulation of host apoptotic genes via STAT3 is responsible for protection. This is the first demonstration of a mammalian signaling pathway that restricts amebic pathogenesis and represents an important advance in our mechanistic understanding of how leptin links nutrition and susceptibility to infection.
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Roujeau, Clara, Ralf Jockers, and Julie Dam. "Endospanin 1 Determines the Balance of Leptin-Regulated Hypothalamic Functions." Neuroendocrinology 108, no. 2 (October 16, 2018): 132–41. http://dx.doi.org/10.1159/000494557.
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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.
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Münzberg, Heike, Jeffrey S. Flier, and Christian Bjørbæk. "Region-Specific Leptin Resistance within the Hypothalamus of Diet-Induced Obese Mice." Endocrinology 145, no. 11 (November 1, 2004): 4880–89. http://dx.doi.org/10.1210/en.2004-0726.
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Abstract Leptin resistance in diet-induced obese (DIO) mice is characterized by elevated serum leptin and a decreased response to exogenous leptin and is caused by unknown defects in the central nervous system. Leptin normally acts on several brain nuclei, but a detailed description of leptin resistance within individual brain regions has not been reported. We first mapped leptin-responsive cells in brains from DIO mice using phospho-signal transducer and activator of transcription (P-STAT3) immunohistochemistry. After 16 wk of high-fat-diet feeding, leptin-activated P-STAT3 staining within the arcuate nucleus (ARC) was dramatically decreased. In contrast, other hypothalamic and extrahypothalamic nuclei remained leptin sensitive. Reduced leptin-induced P-STAT3 in the ARC could also be detected after 4 wk and as early as 6 d of a high-fat diet. To examine potential mechanisms for leptin-resistant STAT3 activation in the ARC of DIO mice, we measured mRNA levels of candidate signaling molecules in the leptin receptor-STAT3 pathway. We found that the level of suppressor of cytokine signaling 3 (SOCS-3), an inhibitor of leptin signaling, is specifically increased in the ARC of DIO mice. The study suggests that the ARC is selectively leptin resistant in DIO mice and that this may be caused by elevated suppressor of cytokine signaling 3 in this hypothalamic nucleus. Defects in leptin action in the ARC may play a role in the pathogenesis of leptin-resistant obesity.
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You, Jia, Yue Yu, Lei Jiang, Wenxia Li, Xinxin Yu, Lety Gonzalez, Guoqing Yang, et al. "Signaling through Tyr985 of Leptin Receptor as an Age/Diet-Dependent Switch in the Regulation of Energy Balance." Molecular and Cellular Biology 30, no. 7 (January 19, 2009): 1650–59. http://dx.doi.org/10.1128/mcb.01307-09.
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ABSTRACT Leptin regulates energy homeostasis through central activation of multiple signaling pathways mediated by Ob-Rb, the long form of leptin receptor. Leptin resistance underlies the pathogenic development of obesity, which is closely associated with environmental factors. To further understand the physiological function of leptin signaling mechanisms, we generated a knock-in line of mice (Y985F) expressing a mutant Ob-Rb with a phenylalanine substitution for Tyr985, one of the three intracellular tyrosines that mediate leptin's signaling actions. Surprisingly, whereas young homozygous Y985F animals were slightly leaner, they exhibit adult-onset or diet-induced obesity. Importantly, both age-dependent and diet-induced deterioration of energy balance was paralleled with pronounced leptin resistance, which was largely attributable to attenuation of leptin-responsive hypothalamic STAT3 activation as well as prominently elevated expression of hypothalamic SOCS3, a key negative regulator of leptin signaling. Thus, these results unmask distinct binary roles for Try985-mediated signaling in energy metabolism, acting as an age/diet-dependent regulatory switch to counteract age-associated or diet-induced obesity.
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Donato Jr., Jose, Renata Frazão, and Carol Fuzeti Elias. "The PI3K signaling pathway mediates the biological effects of leptin." Arquivos Brasileiros de Endocrinologia & Metabologia 54, no. 7 (October 2010): 591–602. http://dx.doi.org/10.1590/s0004-27302010000700002.
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The activation of the leptin receptor recruits several intracellular signaling pathways, including the phosphatidylinositol 3-kinase (PI3K) pathway. While some of the leptin-induced signaling pathways, such as the JAK2/STAT3 pathway, induce cellular responses primarily through changes in gene expression, the PI3K pathway affects cellular properties more rapidly, through post-translational changes such as protein phosphorylation. Accordingly, several studies have shown that the PI3K pathway is required for the acute effects of leptin, such as a leptin-induced decrease in food intake. Leptin signaling through PI3K also affects the electrophysiological properties of neurons, including changes in their membrane potential and firing rates. In this review, we summarize the recent advances in our understanding of the role played by the PI3K signaling pathway in controlling food intake and energy balance. In particular, we focus on the importance of the PI3K signaling pathway as a mediator of the effects of leptin on hypothalamic neurons.
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Steinberg, Gregory R., Andrew J. McAinch, Michael B. Chen, Paul E. O’Brien, John B. Dixon, David Cameron-Smith, and Bruce E. Kemp. "The Suppressor of Cytokine Signaling 3 Inhibits Leptin Activation of AMP-Kinase in Cultured Skeletal Muscle of Obese Humans." Journal of Clinical Endocrinology & Metabolism 91, no. 9 (September 1, 2006): 3592–97. http://dx.doi.org/10.1210/jc.2006-0638.
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Abstract Context: Leptin is thought to regulate whole-body adiposity and insulin sensitivity, at least in part, by stimulating fatty acid metabolism via activation of AMP-kinase (AMPK) in skeletal muscle. Human obesity is associated with leptin resistance, and recent studies have demonstrated that hypothalamic expression of the suppressors of cytokine signaling 3 (SOCS3) regulates leptin sensitivity in rodents. Objective: The objective of the study was to investigate the effects of leptin on fatty acid oxidation and AMPK signaling in primary myotubes derived from lean and obese skeletal muscle and evaluate the contribution of SOCS3 to leptin resistance and AMPK signaling in obese humans. Results: We demonstrate that leptin stimulates AMPK activity and increases AMPK Thr172 and acetyl-CoA carboxylase-β Ser222 phosphorylation and fatty acid oxidation in lean myotubes but that in obese subjects leptin-dependent AMPK signaling and fatty acid oxidation are suppressed. Reduced activation of AMPK was associated with elevated expression of IL-6 (∼3.5-fold) and SOCS3 mRNA (∼2.5-fold) in myotubes of obese subjects. Overexpression of SOCS3 via adenovirus-mediated infection in lean myotubes to a similar degree as observed in obese myotubes prevented leptin but not AICAR (5-amino-imidazole-4-carboxamide-1-β-d-ribofuranoside) activation of AMPK signaling. Conclusions: These data demonstrate that SOCS3 inhibits leptin activation of AMPK. These data suggest that this impairment of leptin signaling in skeletal muscle may contribute to the aberrant regulation of fatty acid metabolism observed in obesity and that pharmacological activation of AMPK may be an effective therapy to bypass SOCS3-mediated skeletal muscle leptin resistance for the treatment of obesity-related disorders.
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Jang, Yunseon, Jun Heo, Min Lee, Jiebo Zhu, Changjun Seo, Da Go, Sung Yoon, et al. "Angiopoietin-Like Growth Factor Involved in Leptin Signaling in the Hypothalamus." International Journal of Molecular Sciences 22, no. 7 (March 26, 2021): 3443. http://dx.doi.org/10.3390/ijms22073443.
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The hypothalamic regulation of appetite governs whole-body energy balance. Satiety is regulated by endocrine factors including leptin, and impaired leptin signaling is associated with obesity. Despite the anorectic effect of leptin through the regulation of the hypothalamic feeding circuit, a distinct downstream mediator of leptin signaling in neuron remains unclear. Angiopoietin-like growth factor (AGF) is a peripheral activator of energy expenditure and antagonizes obesity. However, the regulation of AGF expression in brain and localization to mediate anorectic signaling is unknown. Here, we demonstrated that AGF is expressed in proopiomelanocortin (POMC)-expressing neurons located in the arcuate nucleus (ARC) of the hypothalamus. Unlike other brain regions, hypothalamic AGF expression is stimulated by leptin-induced signal transducers and activators of transcription 3 (STAT3) phosphorylation. In addition, leptin treatment to hypothalamic N1 cells significantly enhanced the promoter activity of AGF. This induction was abolished by the pretreatment of ruxolitinib, a leptin signaling inhibitor. These results indicate that hypothalamic AGF expression is induced by leptin and colocalized to POMC neurons.
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Zhang, Ren, Harveen Dhillon, Huali Yin, Akihiko Yoshimura, Bradford B. Lowell, Eleftheria Maratos-Flier, and Jeffrey S. Flier. "Selective Inactivation of Socs3 in SF1 Neurons Improves Glucose Homeostasis without Affecting Body Weight." Endocrinology 149, no. 11 (July 31, 2008): 5654–61. http://dx.doi.org/10.1210/en.2008-0805.
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Suppressor of cytokine signaling 3 (Socs3) has been identified as a mediator of central leptin resistance, but the identity of specific neurons in which Socs3 acts to suppress leptin signaling remains elusive. The ventromedial hypothalamus (VMH) was recently shown to be an important site for leptin action because deleting leptin receptor within VMH neurons causes obesity. To examine the role of VMH Socs3 in leptin resistance and energy homeostasis, we generated mice lacking Socs3 specifically in neurons positive for steroidogenic factor 1 (SF1), which is expressed abundantly in the VMH. These mice had increased phosphorylation of signal transducer and activator of transcription-3 in VMH neurons, suggesting improved leptin signaling, and consistently, food intake and weight-reducing effects of exogenous leptin were enhanced. Furthermore, on either chow or high-fat diets, these mice had reduced food intake. Unexpectedly, energy expenditure was reduced as well. Mice lacking Socs3 in SF1 neurons, despite no change in body weight, had improved glucose homeostasis and were partially protected from hyperglycemia and hyperinsulinemia induced by high-fat diets. These results suggest that Socs3 in SF1 neurons negatively regulates leptin signaling and plays important roles in mediating leptin sensitivity, glucose homeostasis, and energy expenditure.
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Lee, Jennifer K., Jung-Heun Ha, Do-Kyun Kim, JaeHee Kwon, Young-Eun Cho, and In-Sook Kwun. "Depletion of Zinc Causes Osteoblast Apoptosis with Elevation of Leptin Secretion and Phosphorylation of JAK2/STAT3." Nutrients 15, no. 1 (December 23, 2022): 77. http://dx.doi.org/10.3390/nu15010077.
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Zinc (Zn) has been reported to mediate leptin secretion, and thus leptin can be an important candidate molecule linking Zn with bone formation. The present study investigated whether zinc deficiency induces leptin secretion by activating a JAK2/STAT3 signaling pathway and leads to osteoblastic apoptosis. MC3T3-E1 cells were incubated for 24 h in normal osteogenic differentiation medium (OSM) or OSM treated with either 1 μM (Low Zn) or 15 μM (High Zn) of ZnCl2 containing 5 μM TPEN (Zn chelator). Our results demonstrated that low Zn stimulated extracellular leptin secretion and increased mRNA and protein expression of leptin in osteoblastic MC3T3-E1 cells. The OB-Rb (long isoform of leptin receptor) expressions were also elevated in osteoblasts under depletion of Zn. Leptin-signaling proteins, JAK2 and p-JAK2 in the cytosol of low Zn osteoblast conveyed leptin signaling, which ultimately induced higher p-STAT3 expression in the nucleus. Apoptotic effects of JAK2/STAT3 pathway were shown by increased caspase-3 in low Zn osteoblasts as well as apoptotic morphological features observed by TEM. Together, these data suggest that low Zn modulates leptin secretion by activating JAK2/STAT3 signaling pathway and induces apoptosis of osteoblastic MC3T3-E1 cells.
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Israel, Davelene D., Sharone Sheffer-Babila, Carl de Luca, Young-Hwan Jo, Shun Mei Liu, Qiu Xia, Daniel J. Spergel, Siok L. Dun, Nae J. Dun, and Streamson C. Chua. "Effects of Leptin and Melanocortin Signaling Interactions on Pubertal Development and Reproduction." Endocrinology 153, no. 5 (March 9, 2012): 2408–19. http://dx.doi.org/10.1210/en.2011-1822.
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Leptin and melanocortin signaling control ingestive behavior, energy balance, and substrate utilization, but only leptin signaling defects cause hypothalamic hypogonadism and infertility. Although GnRH neurons do not express leptin receptors, leptin influences GnRH neuron activity via regulation of immediate downstream mediators including the neuropeptides neuropeptide Y and the melanocortin agonist and antagonist, α-MSH, agouti-related peptide, respectively. Here we show that modulation of melanocortin signaling in female db/db mice through ablation of agouti-related peptide, or heterozygosity of melanocortin 4 receptor, restores the timing of pubertal onset, fertility, and lactation. Additionally, melanocortin 4 receptor activation increases action potential firing and induces c-Fos expression in GnRH neurons, providing further evidence that melanocortin signaling influences GnRH neuron activity. These studies thus establish melanocortin signaling as an important component in the leptin-mediated regulation of GnRH neuron activity, initiation of puberty and fertility.
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Dunn, Sarah L., Marie Björnholm, Sarah H. Bates, Zhibin Chen, Matthew Seifert, and Martin G. Myers. "Feedback Inhibition of Leptin Receptor/Jak2 Signaling via Tyr1138 of the Leptin Receptor and Suppressor of Cytokine Signaling 3." Molecular Endocrinology 19, no. 4 (April 1, 2005): 925–38. http://dx.doi.org/10.1210/me.2004-0353.
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Abstract Leptin is an adipocyte-derived hormone that communicates the status of body energy stores to the brain to regulate feeding and energy balance. The inability of elevated leptin levels to adequately suppress feeding in obesity suggests attenuation of leptin action under these conditions; the activation of feedback circuits due to high leptin levels could contribute to this leptin resistance. Using cultured cells exogenously expressing the long form of the leptin receptor (LRb) or an erythropoietin receptor/LRb chimera, we show that chronic stimulation results in the attenuation of LRb signaling and the establishment of a state in which the receptor is refractory to reactivation. Mutation of LRb Tyr1138 (the site that recruits signal transducer and activator of transcription 3) alleviated this feedback inhibition, suggesting that signal transducer and activator of transcription 3 mediates the induction of a feedback inhibitor, such as suppressor of cytokine signaling 3 (SOCS3), during chronic LRb stimulation. Indeed, manipulation of the expression or activity of the LRb-binding tyrosine phosphatase, SH2-domain containing phosphatase-2, by overexpression of wild-type and dominant negative isoforms or RNA interference-mediated knockdown did not alter the attenuation of LRb signals. In contrast, SOCS3 overexpression repressed LRb signaling, whereas RNA interference-mediated knockdown of SOCS3 resulted in increased LRb signaling that was not attenuated during chronic ligand stimulation. These data suggest that Tyr1138 of LRb and SOCS3 represent major effector pathways for the feedback inhibition of LRb signaling. Furthermore, we show that mice expressing an LRb isoform mutant for Tyr1138 display increased activity of the leptin-dependent growth and immune axes, suggesting that Tyr1138-mediated feedback inhibition may regulate leptin sensitivity in vivo.
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Madiehe, Abram M., Ling Lin, Christy White, H. Doug Braymer, George A. Bray, and David A. York. "Constitutive activation of STAT-3 and downregulation of SOCS-3 expression induced by adrenalectomy." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 281, no. 6 (December 1, 2001): R2048—R2058. http://dx.doi.org/10.1152/ajpregu.2001.281.6.r2048.
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Removal of adrenal steroids by adrenalectomy (ADX) slows or reverses the development of many forms of obesity in rodents, including those that are leptin or leptin receptor deficient. Obesity is associated with hyperleptinemia and leptin resistance. We hypothesized that glucocorticoids impair leptin receptor signaling and that removal thereof would activate the Janus kinase (JAK)-signal transducers and activators of transcription (STAT) signaling pathway. The inhibitory effect of leptin (2.5 μg icv) on food intake was enhanced in ADX rats. A combination of ribonuclease protection assays, RT-PCR, Western blots, and mobility shift assays was used to evaluate the leptin signaling pathway in whole hypothalami from sham-operated, ADX and corticosterone-replaced ADX (ADX-R) Sprague-Dawley rats that were treated acutely with either saline vehicle or leptin intracerebroventricularly. ADX increased the expression of leptin receptor mRNA, increased STAT-3 mRNA and protein levels, induced constitutive STAT-3 phosphorylation and DNA binding activity, and also reduced suppressor of cytokine signaling-3 (SOCS-3) mRNA and protein levels. ADX and leptin treatment increased STAT-3 phosphorylation, but with no concomitant increase in DNA binding activity. Leptin and ADX decreased NPY mRNA expression, but their combination did not further decrease NPY mRNA. Corticosterone supplementation of ADX rats partially reversed many of these effects. In conclusion, ADX through activation of STAT-3 and inhibition of SOCS-3 activates the JAK-STAT signaling pathway. These effects most probably explain the ability to prevent the development of obesity by removal of adrenal steroids.
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Roy, A. F., Y. Benomar, V. Bailleux, C. M. Vacher, A. Aubourg, A. Gertler, J. Djiane, and M. Taouis. "Lack of cross-desensitization between leptin and prolactin signaling pathways despite the induction of suppressor of cytokine signaling 3 and PTP-1B." Journal of Endocrinology 195, no. 2 (November 2007): 341–50. http://dx.doi.org/10.1677/joe-07-0321.
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Hyperprolactinemia and hyperleptinemia occur during gestation and lactation with marked hyperphagia associated with leptin resistance. Prolactin (PRL) induces the expression of orexigenic neuropeptide Y (NPY) through the activation of JAK-2/STAT-3 signaling pathway in hypothalamic paraventricular nucleus (PVN) leading to hyperphagia. PRL may also act through the inhibition of anorexigenic effect of leptin via induction of suppressor of cytokine signaling 3 (SOCS-3). This paper aimed to co-localize PRL (PRL-R) and leptin (ObRb) receptors in the hypothalamus of female rats and investigate the possible cross-desensitization between PRL-R and ObRb. We showed that: 1) PRL-R and ObRb are expressed in the PVN and co-localized in the same neurons; 2) in lactating females leptin failed to activate JAK-2/STAT-3 signaling pathway; 3) in Chinese Hamster Ovary (CHO) stably co-expressing PRL-R and ObRb, overexposure to PRL did not affect leptin signaling but totally abolished PRL-dependent STAT-5 phosphorylation. The overexposure to leptin produces similar results with strong alteration of leptin-dependent STAT-3 phosphorylation, whereas PRL-dependent STAT-5 was not affected; and 4) CHO-ObRb/PRL-R cells overexposure to leptin or PRL induces the expression of negative regulators SOCS-3 and PTP-1B. Thus, we conclude that these negative regulators affect specifically the inducer signaling pathway; for instance, SOCS-3 induced by PRL will affect PRL-R signaling but not ObRb signaling and vice versa. Finally, the lack of cross-desensitization between PURL-R and ObRb suggests that hyperphagia observed during gestation and lactation may be attributed to a direct effect of PRL on NPYexpression, and is most likely exacerbated by the physiological leptin resistance state.
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Ferrer-Donato, Agueda, Ana Contreras, Laura M. Frago, Julie A. Chowen, and Carmen M. Fernandez-Martos. "Alterations in Leptin Signaling in Amyotrophic Lateral Sclerosis (ALS)." International Journal of Molecular Sciences 22, no. 19 (September 24, 2021): 10305. http://dx.doi.org/10.3390/ijms221910305.
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Leptin has been suggested to play a role in amyotrophic lateral sclerosis (ALS), a fatal progressive neurodegenerative disease. This adipokine has previously been shown to be associated with a lower risk of ALS and to confer a survival advantage in ALS patients. However, the role of leptin in the progression of ALS is unknown. Indeed, our understanding of the mechanisms underlying leptin’s effects in the pathogenesis of ALS is very limited, and it is fundamental to determine whether alterations in leptin’s actions take place in this neurodegenerative disease. To characterize the association between leptin signaling and the clinical course of ALS, we assessed the mRNA and protein expression profiles of leptin, the long-form of the leptin receptor (Ob-Rb), and leptin-related signaling pathways at two different stages of the disease (onset and end-stage) in TDP-43A315T mice compared to age-matched WT littermates. In addition, at selected time-points, an immunoassay analysis was conducted to characterize plasma levels of total ghrelin, the adipokines resistin and leptin, and metabolic proteins (plasminogen activator inhibitor type 1 (PAI-1), gastric inhibitory peptide (GIP), glucagon-like peptide 1 (GLP-1), insulin and glucagon) in TDP-43A315T mice compared to WT controls. Our results indicate alterations in leptin signaling in the spinal cord and the hypothalamus on the backdrop of TDP-43-induced deficits in mice, providing new evidence about the pathways that could link leptin signaling to ALS.
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Vilariño-García, Teresa, Antonio Pérez-Pérez, Esther Santamaría-López, Nicolás Prados, Manuel Fernández-Sánchez, and Víctor Sánchez-Margalet. "Sam68 mediates leptin signaling and action in human granulosa cells: possible role in leptin resistance in PCOS." Endocrine Connections 9, no. 6 (June 2020): 479–88. http://dx.doi.org/10.1530/ec-20-0062.
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Introduction Polycystic ovary syndrome (PCOS) is a complex metabolic disorder associated with ovulatory dysfunction, hyperandrogenism, obesity, and insulin resistance, that leads to subfertility. Sam68 is an RNA-binding protein with signaling functions that is ubiquitously expressed, including gonads. Sam68 is recruited to leptin signaling, mediating different leptin actions. Objective We aimed to investigate the role of Sam68 in leptin signaling, mediating the effect on aromatase expression in granulosa cells and the posible implication of Sam68 in the leptin resistance in PCOS. Materials and methods Granulosa cells were from healthy donors (n = 25) and women with PCOS (n = 25), within the age range of 20 to 40 years, from Valencian Infertility Institute (IVI), Seville, Spain. Sam68 expression was inhibited by siRNA method and overexpressed by expression vector. Expression level was analysed by qPCR and immunoblot. Statistical significance was assessed by ANOVA followed by different post-hoc tests. A P value of <0.05 was considered statistically significant. Results We have found that leptin stimulation increases phosphorylation and expression level of Sam68 and aromatase in granulosa cells from normal donors. Downregulation of Sam68 expression resulted in a lower activation of MAPK and PI3K pathways in response to leptin, whereas overexpression of Sam68 increased leptin stimulation of signaling, enhancing aromatase expression. Granulosa cells from women with PCOS presented lower expression of Sam68 and were resistant to the leptin effect on aromatase expression. Conclusions These results suggest the participation of Sam68 in leptin receptor signaling, mediating the leptin effect on aromatase expression in granulosa cells, and point to a new target in leptin resistance in PCOS.
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Metlakunta, Anantha S., Maitrayee Sahu, and Abhiram Sahu. "Hypothalamic Phosphatidylinositol 3-Kinase Pathway of Leptin Signaling Is Impaired during the Development of Diet-Induced Obesity in FVB/N Mice." Endocrinology 149, no. 3 (November 29, 2007): 1121–28. http://dx.doi.org/10.1210/en.2007-1307.
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Phosphatidylinositol 3-kinase (PI3K) pathway of leptin signaling plays an important role in transducing leptin action in the hypothalamus. Obesity is usually associated with resistance to the effect of leptin on food intake and energy homeostasis. Although central leptin resistance is thought to be involved in the development of diet-induced obesity (DIO), the mechanism behind this phenomenon is not clearly understood. To determine whether DIO impairs the effect of leptin on hypothalamic PI3K signaling, we fed 4-wk-old FVB/N mice a high-fat diet (HFD) or low-fat diet (LFD) for 19 wk. HFD-fed mice developed DIO in association with hyperleptinemia, hyperinsulinemia, and impaired glucose and insulin tolerance. Leptin (ip) significantly increased hypothalamic PI3K activity and phosphorylated signal transducer and activator of transcription 3 (p-STAT3) levels in LFD-fed mice but not in DIO mice. Immunocytochemical study confirmed impaired p-STAT3 activation in various hypothalamic areas, including the arcuate nucleus. We next tested whether both PI3K and STAT3 pathways of leptin signaling were impaired during the early period of DIO. Leptin failed to increase PI3K activity in DIO mice that were on a HFD for 4 wk. However, leptin-induced p-STAT3 activation in the hypothalamus measured by Western blotting and immunocytochemistry remained comparable between LFD- and HFD-fed mice. These results suggest that the PI3K pathway but not the STAT3 pathway of leptin signaling is impaired during the development of DIO in FVB/N mice. Thus, a defective PI3K pathway of leptin signaling in the hypothalamus may be one of the mechanisms of central leptin resistance and DIO.
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Carlo, A. S., M. Pyrski, C. Loudes, A. Faivre-Baumann, J. Epelbaum, L. M. Williams, and W. Meyerhof. "Leptin Sensitivity in the Developing Rat Hypothalamus." Endocrinology 148, no. 12 (December 1, 2007): 6073–82. http://dx.doi.org/10.1210/en.2007-0822.
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In adults, the adipocyte-derived hormone, leptin, regulates food intake and body weight principally via the hypothalamic arcuate nucleus (ARC). During early postnatal development, leptin functions to promote the outgrowth of neuronal projections from the ARC, whereas a selective insensitivity to the effects of leptin on food intake appears to exist. To investigate the mechanisms underlying the inability of leptin to regulate food intake during early development, leptin signaling was analyzed both in vitro using primary cultures of rat embryonic ARC neurones and in vivo by challenging early postnatal rats with leptin. In neuronal cultures, despite the presence of key components of the leptin signaling pathway, no detectable activation of either signal transducer and activator of transcription 3 or the MAPK pathways by leptin was detected. However, leptin down-regulated mRNA levels of proopiomelanocortin and neuropeptide Y and decreased somatostatin secretion. Leptin challenge in vivo at postnatal d (P) 7, P14, P21, and P28 revealed that, in contrast to adult and P28 rats, mRNA levels of neuropeptide Y, proopiomelanocortin, agouti-related peptide and cocaine- and amphetamine-regulated transcript were largely unaffected at P7, P14, and P21. Furthermore, leptin stimulation increased the suppressor of cytokine signaling-3 mRNA levels at P14, P21, and P28 in several hypothalamic nuclei but not at P7, indicating that selective leptin insensitivity in the hypothalamus is coupled to developmental shifts in leptin receptor signaling. Thus, the present study defines the onset of leptin sensitivity in the regulation of energy homeostasis in the developing hypothalamus.
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Cui, Qi, Yingmei Zhang, Ning Tian, Jiaxin Yang, Dongshan Ya, Wenjing Xiang, Zixian Zhou, et al. "Leptin Promotes Angiogenesis via Pericyte STAT3 Pathway upon Intracerebral Hemorrhage." Cells 11, no. 17 (September 3, 2022): 2755. http://dx.doi.org/10.3390/cells11172755.
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Angiogenesis is a vital endogenous brain self-repair processes for neurological recovery after intracerebral hemorrhage (ICH). Increasing evidence suggests that leptin potentiates angiogenesis and plays a beneficial role in stroke. However, the proangiogenic effect of leptin on ICH has not been adequately explored. Moreover, leptin triggers post-ICH angiogenesis through pericyte, an important component of forming new blood vessels, which remains unclear. Here, we reported that exogenous leptin infusion dose-dependent promoted vascular endothelial cells survival and proliferation at chronic stage of ICH mice. Additionally, leptin robustly ameliorated pericytes loss, enhanced pericytes proliferation and migration in ICH mice in vivo, and in ICH human brain microvascular pericytes (HBVPC) in vitro. Notably, we showed that pericytes-derived pro-angiogenic factors were responsible for enhancing the survival, proliferation and tube formation followed leptin treatment in human brain microvascular endothelial cells (HCMEC/D3)/HBVPC co-culture models. Importantly, considerable improvements in neurobehavioral function and hostile microenvironment were observed in leptin treatment ICH mice, indicating that better vascular functionality post ICH improves outcome. Mechanistically, this study unveiled that leptin boost post-ICH angiogenesis potentially through modulation of leptin receptor (leptinR)/Signal Transducer and Activator of Transcription 3 (STAT3) signaling pathway in pericyte. Thus, leptin may be a lucrative option for the treatment of ICH.
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Jayaram, Bhavaani, Weihong Pan, Yuping Wang, Hung Hsuchou, Aurelien Mace, Germaine G. Cornelissen-Guillaume, Pramod K. Mishra, Robert A. Koza, and Abba J. Kastin. "Astrocytic leptin-receptor knockout mice show partial rescue of leptin resistance in diet-induced obesity." Journal of Applied Physiology 114, no. 6 (March 15, 2013): 734–41. http://dx.doi.org/10.1152/japplphysiol.01499.2012.
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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.
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Lipsey, Crystal C., Adriana Harbuzariu, Robert W. Robey, Lyn M. Huff, Michael M. Gottesman, and Ruben R. Gonzalez-Perez. "Leptin Signaling Affects Survival and Chemoresistance of Estrogen Receptor Negative Breast Cancer." International Journal of Molecular Sciences 21, no. 11 (May 27, 2020): 3794. http://dx.doi.org/10.3390/ijms21113794.
Full textAbstract:
Estrogen-receptor-negative breast cancer (BCER−) is mainly treated with chemotherapeutics. Leptin signaling can influence BCER− progression, but its effects on patient survival and chemoresistance are not well understood. We hypothesize that leptin signaling decreases the survival of BCER− patients by, in part, inducing the expression of chemoresistance-related genes. The correlation of expression of leptin receptor (OBR), leptin-targeted genes (CDK8, NANOG, and RBP-Jk), and breast cancer (BC) patient survival was determined from The Cancer Genome Atlas (TCGA) mRNA data. Leptin-induced expression of proliferation and chemoresistance-related molecules was investigated in triple-negative BC (TNBC) cells that respond differently to chemotherapeutics. Leptin-induced gene expression in TNBC was analyzed by RNA-Seq. The specificity of leptin effects was assessed using OBR inhibitors (shRNA and peptides). The results show that OBR and leptin-targeted gene expression are associated with lower survival of BCER− patients. Importantly, the co-expression of these genes was also associated with chemotherapy failure. Leptin signaling increased the expression of tumorigenesis and chemoresistance-related genes (ABCB1, WNT4, ADHFE1, TBC1D3, LL22NC03, RDH5, and ITGB3) and impaired chemotherapeutic effects in TNBC cells. OBR inhibition re-sensitized TNBC to chemotherapeutics. In conclusion, the co-expression of OBR and leptin-targeted genes may be used as a predictor of survival and drug resistance of BCER− patients. Targeting OBR signaling could improve chemotherapeutic efficacy.