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Christos S Mantzoros - One of the best experts on this subject based on the ideXlab platform.
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Leptin therapy alters appetite and neural responses to food stimuli in brain areas of Leptin sensitive subjects without altering brain structure
The Journal of Clinical Endocrinology and Metabolism, 2014Co-Authors: Olivia M Farr, Mary Brinkoetter, Christina G. Fiorenza, Panagiotis Papageorgiou, Florencia Ziemke, Bangbon Koo, Rafael Rojas, Christos S MantzorosAbstract:Context: Leptin is a key regulator of energy intake and expenditure. Individuals with congenital Leptin Deficiency demonstrate structural and functional brain changes when given Leptin. However, whether acquired Leptin Deficiency may operate similarly is unclear. Objective: We set out to determine whether the brains of individuals with acquired Leptin Deficiency may react to Leptin in a similar manner. Design: We used functional magnetic resonance imaging before and after short- and long-term metreLeptin treatment in three Leptin-sensitive patients with acquired hypoLeptinemia. Nine healthy women were scanned as normoLeptinemic controls. Setting: The setting was an academic medical center. Patients or Other Participants: The participants were 3 hypoLeptinemic women and nine normoLeptinemic, matched women. Interventions: We used metreLeptin, recombinant Leptin, therapy for 24 weeks in hypoLeptinemic women only. Main Outcome Measure: We measured neural changes in response to viewing food as compared to nonf...
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Leptin in human physiology and pathophysiology
American Journal of Physiology-endocrinology and Metabolism, 2011Co-Authors: Christos S Mantzoros, Faido Magkos, Mary Inkoette, Elizabeth Sienkiewicz, Tina Dardeno, Sangyong Kim, Olepette R Hamnvik, Anastasia KoniarisAbstract:Leptin, discovered through positional cloning 15 years ago, is an adipocyte-secreted hormone with pleiotropic effects in the physiology and pathophysiology of energy homeostasis, endocrinology, and metabolism. Studies in vitro and in animal models highlight the potential for Leptin to regulate a number of physiological functions. Available evidence from human studies indicates that Leptin has a mainly permissive role, with Leptin administration being effective in states of Leptin Deficiency, less effective in states of Leptin adequacy, and largely ineffective in states of Leptin excess. Results from interventional studies in humans demonstrate that Leptin administration in subjects with congenital complete Leptin Deficiency or subjects with partial Leptin Deficiency (subjects with lipoatrophy, congenital or related to HIV infection, and women with hypothalamic amenorrhea) reverses the energy homeostasis and neuroendocrine and metabolic abnormalities associated with these conditions. More specifically, in women with hypothalamic amenorrhea, Leptin helps restore abnormalities in hypothalamic-pituitary-peripheral axes including the gonadal, thyroid, growth hormone, and to a lesser extent adrenal axes. Furthermore, Leptin results in resumption of menses in the majority of these subjects and, in the long term, may increase bone mineral content and density, especially at the lumbar spine. In patients with congenital or HIV-related lipoatrophy, Leptin treatment is also associated with improvements in insulin sensitivity and lipid profile, concomitant with reduced visceral and ectopic fat deposition. In contrast, Leptin's effects are largely absent in the obese hyperLeptinemic state, probably due to Leptin resistance or tolerance. Hence, another emerging area of research pertains to the discovery and/or usefulness of Leptin sensitizers. Results from ongoing studies are expected to further increase our understanding of the role of Leptin and the potential clinical applications of Leptin or its analogs in human therapeutics.
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narrative review the role of Leptin in human physiology emerging clinical applications
Annals of Internal Medicine, 2010Co-Authors: Theodore Kelesidis, Iosif Kelesidis, Sharon H Chou, Christos S MantzorosAbstract:Leptin is a hormone secreted by adipose tissue in direct proportion to amount of body fat. The circulating Leptin levels serve as a gauge of energy stores, thereby directing the regulation of energy homeostasis, neuroendocrine function, and metabolism. Persons with congenital Deficiency are obese, and treatment with Leptin results in dramatic weight loss through decreased food intake and possible increased energy expenditure. However, most obese persons are resistant to the weight-reducing effects of Leptin. Recent studies suggest that Leptin is physiologically more important as an indicator of energy Deficiency, rather than energy excess, and may mediate adaptation by driving increased food intake and directing neuroendocrine function to converse energy, such as inducing hypothalamic hypogonadism to prevent fertilization. Current studies investigate the role of Leptin in weight-loss management because persons who have recently lost weight have relative Leptin Deficiency that may drive them to regain weight. Leptin Deficiency is also evident in patients with diet- or exercise-induced hypothalamic amenorrhea and lipoatrophy. Replacement of Leptin in physiologic doses restores ovulatory menstruation in women with hypothalamic amenorrhea and improves metabolic dysfunction in patients with lipoatrophy, including lipoatrophy associated with HIV or highly active antiretroviral therapy. The applications of Leptin continue to grow and will hopefully soon be used therapeutically.
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drug insight the role of Leptin in human physiology and pathophysiology emerging clinical applications
Nature Clinical Practice Endocrinology & Metabolism, 2006Co-Authors: Aoife M Brennan, Christos S MantzorosAbstract:Leptin is an adipocyte-secreted hormone with a key role in energy homeostasis. Studies in animal models, in humans with congenital complete Leptin Deficiency, and observational and interventional studies in humans with relative Leptin Deficiency (lower than normal Leptin levels) have all indicated that Leptin regulates multiple physiological functions, primarily in states of energy Deficiency. This information led to proof-of-concept clinical trials involving Leptin administration to individuals with relative or complete Leptin Deficiency. These conditions include congenital complete Leptin Deficiency, due to mutations in the Leptin gene, and states of relative Leptin Deficiency including lipoatrophy and some forms of hypothalamic amenorrhea. Leptin, in replacement doses, normalizes neuroendocrine, metabolic and immune function in patients with these conditions, but further clinical studies are required to determine its long-term efficacy and safety. Management of Leptin-deficient states with replacement doses of Leptin holds promise as a therapeutic option. In addition, elucidation of the mechanisms underlying Leptin resistance, which characterizes hyperLeptinemic states such as human obesity and diabetes, might provide novel therapeutic targets for these prevalent clinical problems.
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the emerging clinical significance of Leptin in humans with absolute or relative Leptin Deficiency
Current Opinion in Internal Medicine, 2005Co-Authors: Stergios J Moschos, Christos S MantzorosAbstract:Purpose of reviewThis article summarizes recent clinical investigations involving Leptin administration in a variety of human disease states and presents new information regarding the role of Leptin in the neuroendocrine control of energy homeostasis, reproduction, and immune function in humans.Rece
Julio Licinio - One of the best experts on this subject based on the ideXlab platform.
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Dynamics of plasma proteome during Leptin-replacement therapy in genetically based Leptin Deficiency
The Pharmacogenomics Journal, 2011Co-Authors: V P Andreev, Gilberto Paz-filho, R C Dwivedi, O V Krokhin, M-l Wong, J A Wilkins, Julio LicinioAbstract:The effects of Leptin-replacement therapy on the plasma proteome of three unique adults with genetically based Leptin Deficiency were studied longitudinally during the course of recombinant human Leptin-replacement treatment. Quantitative proteomics analysis was performed in plasma samples collected during four stages: before Leptin treatment was initiated, after 1.5 and 6 years of Leptin-replacement treatment, and after 7 weeks of temporary interruption of Leptin-replacement therapy. Of 500 proteins reliably identified and quantitated in those four stages, about 100 were differentially abundant twofold or more in one or more stages. Synchronous dynamics of abundances of about 90 proteins was observed reflecting both short- and long-term effects of Leptin-replacement therapy. Pathways and processes enriched with overabundant synchronous proteins were cell adhesion, cytoskeleton remodeling, cell cycle, blood coagulation, glycolysis, and gluconeogenesis. Plausible common regulators of the above synchronous proteins were identified using transcription regulation network analysis. The generated network included two transcription factors (c-Myc and androgen receptor) that are known to activate each other through a double-positive feedback loop, which may represent a potential molecular mechanism for the long-term effects of Leptin-replacement therapy. Our findings may help to elucidate the effects of Leptin on insulin resistance.
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human Leptin Deficiency caused by a missense mutation multiple endocrine defects decreased sympathetic tone and immune system dysfunction indicate new targets for Leptin action greater central than peripheral resistance to the effects of Leptin and s
The Journal of Clinical Endocrinology and Metabolism, 1999Co-Authors: Metin Ozata, I C Ozdemir, Julio LicinioAbstract:We have previously demonstrated that genetically based Leptin Deficiency due to a missense Leptin gene mutation in a highly consanguineous extended Turkish pedigree is associated with morbid obesity and hypogonadism. We have now performed detailed assessments of endocrine, sympathetic, and immune function. We have also identified a new adult female homozygous patient in this extended family who is severely obese and amenorrheic. In this family all wild-type and heterozgous individuals have normal body weight. Seven obese members of this family, whom we presume to have been Leptin deficient, died during childhood. There are several findings that indicate potentially novel targets for Leptin action in humans. Four homozygous patients (1 adult male, 2 adult females, and 1 child) have sympathetic system dysfunction, whereas all heterozygous subjects have normal sympathetic system function. Despite sympathetic system dysfunction and postural hypotension, 1 of 3 homozygous adult patients has impaired renin-aldosterone function. The patients also exhibit alterations in GH and PTH-calcium function, and 1 of them has decreased bone mineral density. Despite their obesity, these patients do not have risk factors for cardiovascular disease, such as hypertension, impairments in lipid metabolism, or hyperLeptinemia [corrected]. These data support the hypothesis that the obese may have central, but not peripheral, resistance to the effects of Leptin and that hyperLeptinemia [corrected] may mediate the cardiovascular morbidity of the obese who are not Leptin deficient. Furthermore, these data indicate that there may be several new targets for Leptin action in human physiology. Such new targets may lead to novel pharmacological strategies for the use of Leptin agonists and antagonists in the treatment of human disease. All 19 normal weight individuals in this family are alive, whereas 7 of 11 obese individuals died in childhood after infections. The odds ratio for mortality in the context of this obesity phenotype is 25.4, indicating that this mutation severely impairs key biological functions during childhood, negatively impacting on survival. We found that only the obese child in this family had thyroid function abnormalities. The oldest homozygous female patient started to menstruate, albeit with a luteal phase defect, 7 months ago, after a delay of over 20 yr, whereas the younger adult subjects are still hypogonadic. Thus, we conclude that due to their long life span, humans who survive the negative effects of Leptin Deficiency during childhood can, in contrast to ob/ob mice, over decades compensate some of the effects of Leptin Deficiency on immunity and endocrine function through mechanisms that remain to be elucidated.
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human Leptin Deficiency caused by a missense mutation multiple endocrine defects decreased sympathetic tone and immune system dysfunction indicate new targets for Leptin action greater central than peripheral resistance to the effects of Leptin and s
The Journal of Clinical Endocrinology and Metabolism, 1999Co-Authors: Metin Ozata, I C Ozdemir, Julio LicinioAbstract:We have previously demonstrated that genetically based Leptin Deficiency due to a missense Leptin gene mutation in a highly consanguineous extended Turkish pedigree is associated with morbid obesity and hypogonadism. We have now performed detailed assessments of endocrine, sympathetic, and immune function. We have also identified a new adult female homozygous patient in this extended family who is severely obese and amenorrheic. In this family all wild-type and heterozygous individuals have normal body weight. Seven obese members of this family, whom we presume to have been Leptin deficient, died during childhood. There are several findings that indicate potentially novel targets for Leptin action in humans. Four homozygous patients (1 adult male, 2 adult females, and 1 child) have sympathetic system dysfunction, whereas all heterozygous subjects have normal sympathetic system function. Despite sympathetic system dysfunction and postural hypotension, 1 of 3 homozygous adult patients has impaired renin-ald...
Jean L Chan - One of the best experts on this subject based on the ideXlab platform.
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recombinant methionyl human Leptin administration activates signal transducer and activator of transcription 3 signaling in peripheral blood mononuclear cells in vivo and regulates soluble tumor necrosis factor α receptor levels in humans with relati
The Journal of Clinical Endocrinology and Metabolism, 2005Co-Authors: Jean L Chan, Barbara B Kahn, Stergios J Moschos, John Bullen, Kathleen Heist, Xian Li, Christos S MantzorosAbstract:Studies of congenital complete Leptin Deficiency in animals and humans support a role for Leptin in regulating immune function. Whether acquired relative Leptin Deficiency affects immunological parameters in healthy humans remains unknown. We thus used experimental models of relative Leptin Deficiency and recombinant methionyl human Leptin (r-metHuLeptin) administration in humans to investigate whether r-metHuLeptin would activate signaling pathways in peripheral blood mononuclear cells (PBMCs) and whether acquired relative Leptin Deficiency and/or increasing circulating Leptin levels into the physiologic range would change PBMC subpopulations and cytokines important in the T-helper cell and systemic immune responses. We found that r-metHuLeptin administration to healthy humans activates signal transducer and activator of transcription-3 signaling in PBMCs in vivo. Neither short-term Leptin Deficiency, induced by 3-d complete fasting, nor physiologic r-metHuLeptin replacement for the same period of time h...
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recombinant methionyl human Leptin administration activates signal transducer and activator of transcription 3 signaling in peripheral blood mononuclear cells in vivo and regulates soluble tumor necrosis factor α receptor levels in humans with relative Leptin Deficiency
The Journal of Clinical Endocrinology and Metabolism, 2005Co-Authors: Jean L Chan, Barbara B Kahn, Stergios J Moschos, Kathleen Heist, John W Bullen, Youngbum Kim, Christos S MantzorosAbstract:Studies of congenital complete Leptin Deficiency in animals and humans support a role for Leptin in regulating immune function. Whether acquired relative Leptin Deficiency affects immunological parameters in healthy humans remains unknown. We thus used experimental models of relative Leptin Deficiency and recombinant methionyl human Leptin (r-metHuLeptin) administration in humans to investigate whether r-metHuLeptin would activate signaling pathways in peripheral blood mononuclear cells (PBMCs) and whether acquired relative Leptin Deficiency and/or increasing circulating Leptin levels into the physiologic range would change PBMC subpopulations and cytokines important in the T-helper cell and systemic immune responses. We found that r-metHuLeptin administration to healthy humans activates signal transducer and activator of transcription-3 signaling in PBMCs in vivo. Neither short-term Leptin Deficiency, induced by 3-d complete fasting, nor physiologic r-metHuLeptin replacement for the same period of time had a major effect on PBMC subpopulations or serum cytokines in healthy men. In contrast, normalizing serum Leptin levels over 8 wk in lean women with relative Leptin Deficiency for 5.1 +/- 1.4 yr (mean +/- se) due to chronic energy deficit increased soluble TNFalpha receptor levels, indicating activation of the TNFalpha system. These findings suggest that relative Leptin Deficiency due to more long-term energy deprivation is associated with defects in immunological parameters that may be corrected with exogenous r-metHuLeptin administration. Further studies are warranted to assess the implications of acquired relative hypoLeptinemia and/or r-metHuLeptin administration on the immunosuppression associated with energy- and Leptin-deficient states in humans.
Phillip Gorden - One of the best experts on this subject based on the ideXlab platform.
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MetreLeptin for injection to treat the complications of Leptin Deficiency in patients with congenital or acquired generalized lipodystrophy
Expert review of clinical pharmacology, 2015Co-Authors: Cristina Adelia Meehan, Elaine Cochran, Rebecca J. Brown, Andrea Kassai, Phillip GordenAbstract:The lipodystrophies represent a class of diseases characterized by Leptin Deficiency. Leptin Deficiency is associated with a severe form of the metabolic syndrome characterized by dyslipidemia, insulin resistance, diabetes, and ovarian dysfunction. MetreLeptin is the pharmaceutical derived product that has been approved by the Food and Drug Administration (FDA) to treat the severe metabolic abnormalities of the generalized forms of lipodystrophy. Herein we describe the properties of metreLeptin, its use in patients, which includes the administration of the drug and how it may be acquired by medical professionals as well as its safety, tolerability, and properties. Finally, we speculate on future uses and development of metreLeptin.
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effect of Leptin replacement on pituitary hormone regulation in patients with severe lipodystrophy
The Journal of Clinical Endocrinology and Metabolism, 2002Co-Authors: Emin Argun Oral, Elaine Ruiz, Alex M Depaoli, Alexa Andewelt, Nancy G Sebring, Anthony J Wagner, Phillip GordenAbstract:Leptin is important in regulating energy homeostasis. Severe lipodystrophy is associated with Leptin Deficiency and insulin resistance, hypertriglyceridemia, and hepatic steatosis. Leptin Deficiency is also associated with abnormalities of the pituitary hormones in rodent models and patients with congenital absence of Leptin. We inquired whether similar abnormalities are seen in patients with lipodystrophy and whether replacement of Leptin will make an impact on the regulation of pituitary hormones. Seven female patients (aged 15–42 yr, all diabetic) with lipodystrophy and serum Leptin levels less than 4 mg/liter were treated with recombinant methionyl-human Leptin (recombinant Leptin) in physiological doses in an open-labeled study. The following parameters were evaluated before and at 4 months of Leptin treatment: menstrual history, pelvic ultrasonogram, LHRH, TRH, and CRH tests. While on recombinant Leptin, mean serum Leptin concentration increased from 1.3 ± 0.3 mg/liter to 11.1 ± 2.5 mg/liter. Only o...
Stergios J Moschos - One of the best experts on this subject based on the ideXlab platform.
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the emerging clinical significance of Leptin in humans with absolute or relative Leptin Deficiency
Current Opinion in Internal Medicine, 2005Co-Authors: Stergios J Moschos, Christos S MantzorosAbstract:Purpose of reviewThis article summarizes recent clinical investigations involving Leptin administration in a variety of human disease states and presents new information regarding the role of Leptin in the neuroendocrine control of energy homeostasis, reproduction, and immune function in humans.Rece
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recombinant methionyl human Leptin administration activates signal transducer and activator of transcription 3 signaling in peripheral blood mononuclear cells in vivo and regulates soluble tumor necrosis factor α receptor levels in humans with relati
The Journal of Clinical Endocrinology and Metabolism, 2005Co-Authors: Jean L Chan, Barbara B Kahn, Stergios J Moschos, John Bullen, Kathleen Heist, Xian Li, Christos S MantzorosAbstract:Studies of congenital complete Leptin Deficiency in animals and humans support a role for Leptin in regulating immune function. Whether acquired relative Leptin Deficiency affects immunological parameters in healthy humans remains unknown. We thus used experimental models of relative Leptin Deficiency and recombinant methionyl human Leptin (r-metHuLeptin) administration in humans to investigate whether r-metHuLeptin would activate signaling pathways in peripheral blood mononuclear cells (PBMCs) and whether acquired relative Leptin Deficiency and/or increasing circulating Leptin levels into the physiologic range would change PBMC subpopulations and cytokines important in the T-helper cell and systemic immune responses. We found that r-metHuLeptin administration to healthy humans activates signal transducer and activator of transcription-3 signaling in PBMCs in vivo. Neither short-term Leptin Deficiency, induced by 3-d complete fasting, nor physiologic r-metHuLeptin replacement for the same period of time h...
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recombinant methionyl human Leptin administration activates signal transducer and activator of transcription 3 signaling in peripheral blood mononuclear cells in vivo and regulates soluble tumor necrosis factor α receptor levels in humans with relative Leptin Deficiency
The Journal of Clinical Endocrinology and Metabolism, 2005Co-Authors: Jean L Chan, Barbara B Kahn, Stergios J Moschos, Kathleen Heist, John W Bullen, Youngbum Kim, Christos S MantzorosAbstract:Studies of congenital complete Leptin Deficiency in animals and humans support a role for Leptin in regulating immune function. Whether acquired relative Leptin Deficiency affects immunological parameters in healthy humans remains unknown. We thus used experimental models of relative Leptin Deficiency and recombinant methionyl human Leptin (r-metHuLeptin) administration in humans to investigate whether r-metHuLeptin would activate signaling pathways in peripheral blood mononuclear cells (PBMCs) and whether acquired relative Leptin Deficiency and/or increasing circulating Leptin levels into the physiologic range would change PBMC subpopulations and cytokines important in the T-helper cell and systemic immune responses. We found that r-metHuLeptin administration to healthy humans activates signal transducer and activator of transcription-3 signaling in PBMCs in vivo. Neither short-term Leptin Deficiency, induced by 3-d complete fasting, nor physiologic r-metHuLeptin replacement for the same period of time had a major effect on PBMC subpopulations or serum cytokines in healthy men. In contrast, normalizing serum Leptin levels over 8 wk in lean women with relative Leptin Deficiency for 5.1 +/- 1.4 yr (mean +/- se) due to chronic energy deficit increased soluble TNFalpha receptor levels, indicating activation of the TNFalpha system. These findings suggest that relative Leptin Deficiency due to more long-term energy deprivation is associated with defects in immunological parameters that may be corrected with exogenous r-metHuLeptin administration. Further studies are warranted to assess the implications of acquired relative hypoLeptinemia and/or r-metHuLeptin administration on the immunosuppression associated with energy- and Leptin-deficient states in humans.