Leptin in Relation to the Lipodystrophy-Associated Metabolic Syndrome

Christos S. Mantzoros 대한당뇨병학회 2012 Diabetes and Metabolism Journal Vol.36 No.3

Leptin, an adipocyte-secreted hormone, regulates energy homeostasis as well as reproductive, neuroendocrine, immune and metabolic functions. Subjects with decreased amounts of fat in their adipose tissue, i.e., lipoatrophy, have low leptin levels. In the context of open-label, uncontrolled studies leptin administration, in physiological replacement doses, has been shown to have metabolically salutary effects in the rare patients with the syndrome of congenital lipodystrophy accompanied by leptin deficiency. Much more patients with lipodystrophy suffer from lipodystrophy and the metabolic syndrome associated with the use of highly active antiretroviral therapy. In this so called highly active antiretroviral therapy (HAART)-associated lipodystrophy and metabolic syndrome, patients demonstrate fat maldistribution with dyslipidemia, insulin resistance, and other metabolic complications. Leptin administration has been shown to decrease central fat mass and to improve fasting insulin/glucose levels and insulin sensitivity in human immunodeficiency virus-infected hypoleptinemic patients with HAART induced lipodystrophy and the metabolic syndrome. By contrast, the results of leptin treatment in leptin replete or hyperleptinemic obese individuals with glucose intolerance and diabetes mellitus have been minimal or null, presumably due to leptin tolerance or resistance that impairs leptin action. In this review, we present the emerging clinical applications and potential therapeutic uses of leptin in humans with lipodystrophy and the metabolic syndrome. Leptin, an adipocyte-secreted hormone, regulates energy homeostasis as well as reproductive, neuroendocrine, immune and metabolic functions. Subjects with decreased amounts of fat in their adipose tissue, i.e., lipoatrophy, have low leptin levels. In the context of open-label, uncontrolled studies leptin administration, in physiological replacement doses, has been shown to have metabolically salutary effects in the rare patients with the syndrome of congenital lipodystrophy accompanied by leptin deficiency. Much more patients with lipodystrophy suffer from lipodystrophy and the metabolic syndrome associated with the use of highly active antiretroviral therapy. In this so called highly active antiretroviral therapy (HAART)-associated lipodystrophy and metabolic syndrome, patients demonstrate fat maldistribution with dyslipidemia, insulin resistance, and other metabolic complications. Leptin administration has been shown to decrease central fat mass and to improve fasting insulin/glucose levels and insulin sensitivity in human immunodeficiency virus-infected hypoleptinemic patients with HAART induced lipodystrophy and the metabolic syndrome. By contrast, the results of leptin treatment in leptin replete or hyperleptinemic obese individuals with glucose intolerance and diabetes mellitus have been minimal or null, presumably due to leptin tolerance or resistance that impairs leptin action. In this review, we present the emerging clinical applications and potential therapeutic uses of leptin in humans with lipodystrophy and the metabolic syndrome.

Decreasing Lean Body Mass with Age: Challenges and Opportunities for Novel Therapies

Chrysoula Boutari,Christos S. Mantzoros 대한내분비학회 2017 Endocrinology and metabolism Vol.32 No.4

Novel Molecules Regulating Energy Homeostasis: Physiology and Regulation by Macronutrient Intake and Weight Loss

Anna Gavrieli,Christos S. Mantzoros 대한내분비학회 2016 Endocrinology and metabolism Vol.31 No.3

Excess energy intake, without a compensatory increase of energy expenditure, leads to obesity. Several molecules are involved inenergy homeostasis regulation and new ones are being discovered constantly. Appetite regulating hormones such as ghrelin, peptidetyrosine-tyrosine and amylin or incretins such as the gastric inhibitory polypeptide have been studied extensively while othermolecules such as fibroblast growth factor 21, chemerin, irisin, secreted frizzle-related protein-4, total bile acids, and heme oxygenase-1 have been linked to energy homeostasis regulation more recently and the specific role of each one of them has not beenfully elucidated. This mini review focuses on the above mentioned molecules and discusses them in relation to their regulation bythe macronutrient composition of the diet as well as diet-induced weight loss.

Leptin as a Modulator of Neuroendocrine Function in Humans

Sami M. Khan,Christos S. Mantzoros,Ole-Petter R. Hamnvik,Mary Brinkoetter 연세대학교의과대학 2012 Yonsei medical journal Vol.53 No.4

Leptin, a peptide hormone secreted by adipocytes in proportion of the amount of energy stored in fat, plays a central role in regulating human energy homeostasis. In addition, leptin plays a significant permissive role in the physiological regulation of several neuroendocrine axes, including the hypothalamic-pituitary-gonadal, -thyroid, -growth hormone, and -adrenal axes. Decreased levels of leptin, also known as hypoleptinemia, signal to the brain a state of energy deprivation. Hypoleptinemia can be a congenital or acquired condition, and is associated with alterations of the aforementioned axes aimed at promoting survival. More specifically, gonadotropin levels decrease and become less pulsatile under conditions of energy deprivation, and these changes can be at least partially reversed through leptin administration in physiological replacement doses. Similarly, leptin deficiency is associated with thyroid axis abnormalities including abnormal levels of thyrotropin-releasing hormone, and leptin administration may at least partially attenuate this effect. Leptin deficiency results in decreased insulin-like growth factor 1 levels which can be partially ameliorated through leptin administration, and leptin appears to have a much more pronounced effect on the growth of rodents than that of humans. Similarly, adrenal axis function is regulated more tightly by low leptin in rodents than in humans. In addition to congenital leptin deficiency, conditions that may be associated with decreased leptin levels include hypothalamic amenorrhea, anorexia nervosa, and congenital or acquired lipodystrophy syndromes. Accumulating evidence from proof of concept studies suggests that leptin administration, in replacement doses, may ameliorate neuroendocrine abnormalities in individuals who suffer from these conditions.

Association of Adipokines with Development and Progression of Nonalcoholic Fatty Liver Disease

Chrysoula Boutari,Nikolaos Perakakis,Christos S. Mantzoros 대한내분비학회 2018 Endocrinology and metabolism Vol.33 No.1

Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease affecting 30% of the general population and 40% to 70% ofobese individuals. Adipose tissue plays a crucial role in its pathogenesis, as it produces and secretes pro- and anti-inflammatory cytokinescalled adipokines. Adiponectin and leptin have well-determined actions in terms of NAFLD pathophysiology. Adiponectin deficiencyis associated with a pro-inflammatory condition, as it is observed in obesity and other metabolic disorders. On the otherhand, increased leptin levels, above the normal levels, act as a pro-inflammatory stimulus. Regarding other adipokines (resistin, visfatin,chemerin, retinol-binding protein 4, irisin), data about their contribution to NAFLD pathogenesis and progression are inconclusive. In addition, pharmacological agents like thiazolidinediones (pioglitazone and rosiglitazone), that are used in the management ofNAFLD exert favourable effects on adipokine levels, which in turn may contribute to the improvement of liver function. This reviewsummarizes the current knowledge and developments in the association between adipokines and NAFLD and discusses possibletherapeutic implications targeting the modulation of adipokine levels as a potential tool for the treatment of NAFLD.

ELSEVIER : Irisin in response to acute and chronic whole-body vibration exercise in humans

( Joo Young Huh ),( Vassilis Mougios ),( Athanasios Skraparlis ),( Athanasios Kabasakalis ),( Christos S Mantzoros ) 전남대학교 약품개발연구소 2014 약품개발연구지 Vol.23 No.-

Objective. Irisin is a recently identified myokine, suggested to mediate the beneficial effects of exercise by inducing browning of white adipocytes and thus increasing energy expenditure. In humans, the regulation of irisin by exercise is not completely understood. We investigated the effect of acute and chronic whole-body vibration exercise, a moderateintensity exercise that resembles shivering, on circulating irisin levels in young healthy subjects. MaterialslMethods. Healthy untrained females participated in a 6-week program of wholebody vibration exercise training. Blood was drawn before and immediately after an acute bout of exercise at baseline (week 0) and after 6 weeks of training. Results. The resting irisin levels were not different at baseline (week 0) and after 6 weeks of training. At both 0 and 6 weeks of training, an acute bout of vibration exercise significantly elevated circulating irisin levels by 9.5% and 18.1%, respectively (p = 0.05 for the percent change of irisin levels). Conclusions. Acute bouts of whole-body vibration exercise are effective in increasing circulating irisin levels but chronic training does not change levels of baseline irisin levels in humans. @ 2014 Elsevier Inc. All rights reserved.

Irisin in Response to Exercise in Humans With and Without Metabolic Syndrome

( Joo Young Huh ),( Aikaterina Siopi ),( Vassilis Mougios ),( Kyung Hee Park ),( Christos S. Mantzoros ) 전남대학교 약품개발연구소 2015 약품개발연구지 Vol.24 No.-

Context: Irisin is a recently identified exercise-induced myokine. However, the circulating levels of irisin in response to different types of exercise in subjects with metabolic syndrome are unknown. Objective: This study aimed to study the levels of irisin in healthy males and subjects with metabolic syndrome at baseline and in response to exercise. Design: Each individual completed high-intensity interval exercise (HIIE), continuous moderateintensity exercise (CME), and resistance exercise (RE) sessions in a random, crossover design. Percentage change in circulating irisin levels was examined. Two different irisin assays were used to compare the results of the RE study. Results: Circulating irisin increased immediately after HIIE, CME, and RE and declined 1 hour later. The increase was greater in response to resistance compared with either high-intensity intermittent exercise orCME. Change in irisin in response to exercise did not differ between individuals with and without metabolic syndrome. Conclusions: Exercise is able to increase circulating irisin levels in individuals with the metabolic syndrome as well as healthy individuals. Whether this increase may contribute to the beneficial effects of exercise on patients with the metabolic syndrome remains to be studied further. (J Clin Endocrinol Metab 100: E453-E457, 2015)

Levels of circulating selenoprotein P, fibroblast growth factor (FGF) 21 and FGF23 in relation to the metabolic syndrome in young children

Ko, B-J,Kim, S M,Park, K H,Park, H S,Mantzoros, C S Macmillan Publishers Limited 2014 International Journal of Obesity Vol.38 No.12

Background/objectives:Circulating selenoprotein P (SeP), fibroblast growth factor (FGF) 21 and FGF23 have been associated with metabolic syndrome (MetS) in adults but not in children. We sought to evaluate the association among SeP, FGF21, FGF23 and MetS in young children.Subjects/methods:A cross-sectional study conducted during a school health examination on 210 children aged 9 years. We measured serum SeP, FGF21 and FGF23 levels, and assessed anthropometric and cardiometabolic variables. MetS was defined as the presence of ⩾3 of the following five criteria: high blood pressure, low high-density lipoprotein cholesterol (HDL-C), high triglyceride, high fasting glucose and abdominal obesity.Results:SeP was correlated positively with HDL-C and negatively with body mass index, waist circumference (WC), blood pressure, transaminases, triglyceride and homeostasis model assessment of insulin resistance (HOMA-IR). FGF21 was directly correlated with WC, triglyceride and HOMA-IR, and FGF23 was inversely correlated with fasting glucose and alanine aminotransferase. Children with MetS had lower SeP and FGF23 levels and higher HOMA-IR than children without MetS. The highest tertile of SeP had decreased odds for MetS (odds ratio 0.05, 95% confidence interval (CI) 0.00–0.96, P  for trend=0.042), whereas FGF21 and FGF23 did not relate to the risk for MetS after controlling for confounders.Conclusions:Elevated SeP concentrations are independently associated with a reduced risk of MetS in children. The associations between FGF21, FGF23 and metabolic parameters are not of comparable significance.

Irisin stimulates muscle growth-related genes and regulates adipocyte differentiation and metabolism in humans

( Jy Huh ),( F Din Cer ),( E Mesfum ),( Cs Mantzoros ) 전남대학교 약품개발연구소 2014 약품개발연구지 Vol.23 No.-

BACKGROUND: Irisin is a recently identified exercise-induced myokine suggested to induce browning of white adipocytes. Deficiency of myostatin, and thus stimulation of muscle growth, has also been reported to induce irisin and its precursor FNOC5 expression in muscle and drive the browning of white ;ldipocytes in mice, implying that irisin may be rel;lted to muscle growth in addition to its beneficial effects in ;ldipocytes. In humans, the effect of irisin in muscle hypertrophy as well as adipocyte met;lbolism has not been fully investigated. METHODS: Primary cultured human myocytes/adipocytes and 3T3-L 1 cells were used to examine irisin-regulated gene/protein expression. Lipid accumulation, ATP content, glycolysis, lipolysis and metabolite profile were measured in control and irisin-treated (10 and 50 nM) adipocytes. RESULTS: In human myocytes, FNDC5 mRNA and irisin secretion were increased during myogenic differentiation, along with PGC10 and myogenin expression. Irisin treatment significantly increased insulin-like growth factor 1 and decreased myostatin gene expression through ERK pathway. PGC104, a newly discovered PGCla isoform specifically related to muscle hypertrophy, was also upregulated. In human adipocytes, irisin induced uncoupling protein 1 and consequently increased adipocyte energy expenditure, expression of metabolic enzymes nd metabolite intermediates, resulting in inhibition of lipid accumulation. Irisin and FNDC5 treatment also reduced preadipocyte differentiation, suggesting an additional mechanism in suppressing fat mass. CONCLUSIONS: These results suggest that irisin/FNOC5 has a pleiotropic role in muscle and improvement of adipocyte metabolism in humans. International Journal of Obesity (2014) 38, 1538-1544; doi:l0.l038/ijo.2014.42

Identification and Saturable Nature of Signaling Pathways Induced by Metreleptin in Humans: Comparative Evaluation of In Vivo, Ex Vivo, and In Vitro Administration

( Hyun-seuk Moon ),( Joo Young Huh ),( Fadime Dincer ),( Benjamin E. Schneider ),( Per-olof Hasselgren ),( Christos S. Mantzoros ) 전남대학교 약품개발연구소 2015 약품개발연구지 Vol.24 No.-

Signaling pathways activated by leptin in metabolically important organs have largely been studied only in animal and/or cell culture studies. In this study, we examined whether leptin has similar effects in human peripheral tissues in vivo, ex vivo, and in vitro and whether the response would be different in lean and obese humans. For in vivo leptin signaling, metreleptin was administered and muscle, adipose tissue, and peripheral blood mononuclear cells were taken for analysis of signal activation. Experiments were also done ex vivo and with primary cultured cells in vitro. The signal activation was compared between male versus female and obese versus lean humans. Acute in vivo, ex vivo, and/or in vitro metreleptin administration similarly activated STAT3, AMPK, ERK1/2, Akt, mTOR, NF-κB, and/or IKKα/β without any differences between male versus female and obese versus lean subjects. All signaling pathways were saturable at ~30-50 ng/mL, consistent with the clinical evidence showing no additional effect(s) in obese subjects who already have high levels of leptin. Our data provide novel information on downstream effectors of metreleptin action in humans that may have therapeutic implications.