Person: Mantzoros, Christos
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Mantzoros
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Christos
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Mantzoros, Christos
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Publication Association of Adipokines with Development and Progression of Nonalcoholic Fatty Liver Disease(Korean Endocrine Society, 2018) Boutari, Chrysoula; Perakakis, Nikolaos; Mantzoros, ChristosNonalcoholic fatty liver disease (NAFLD) is a chronic liver disease affecting 30% of the general population and 40% to 70% of obese individuals. Adipose tissue plays a crucial role in its pathogenesis, as it produces and secretes pro- and anti-inflammatory cytokines called adipokines. Adiponectin and leptin have well-determined actions in terms of NAFLD pathophysiology. Adiponectin deficiency is associated with a pro-inflammatory condition, as it is observed in obesity and other metabolic disorders. On the other hand, 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 of NAFLD exert favourable effects on adipokine levels, which in turn may contribute to the improvement of liver function. This review summarizes the current knowledge and developments in the association between adipokines and NAFLD and discusses possible therapeutic implications targeting the modulation of adipokine levels as a potential tool for the treatment of NAFLD.Publication Lessons and Challenges from a 6-Month Randomized Pilot Study of Daily Ethanol Consumption: Research Methodology and Study Design(Oxford University Press, 2017) Mukamal, Kenneth; Na, Brian; Mu, Lin; Mantzoros, Christos; Manning, Warren; Mittleman, MurrayAbstract Background: Observational studies and crossover feeding studies suggest that moderate alcohol use may benefit cardiovascular risk, but we know of no long-term randomized trials that have tested this hypothesis. Objective: We evaluated the feasibility of an efficacy study of daily ethanol use in a 6-mo randomized pilot study in adults at higher cardiovascular risk. Methods: In a double-blind, randomized, controlled parallel-design trial, we screened 67 adults aged ≥55 y and randomly assigned 45 participants to consume 150 mL of an artificially sweetened beverage with or without 10% grain alcohol daily for 6 mo. Participants were asked to consume no other alcohol and returned monthly to receive the beverage and undergo measurement of HDL cholesterol, liver function tests, and complete blood counts. Results: Of the 45 randomly assigned participants, 39 completed the trial; the primary reason cited for attrition was inconvenience. None of the participants reported problem drinking or developed any serious adverse events or abnormal biochemical findings. However, we observed no differences in concentrations of HDL cholesterol, HDL lipoprotein subclasses, aspartate aminotransferase, alanine aminotransferase, γ-glutamyltransferase, mean corpuscular volume, or adiponectin between the alcohol and control arms, suggesting that adherence was poor. Every participant accurately identified their assigned beverage, most with great certainty. Conclusions: In this parallel-design pilot study of daily alcohol use, we observed none of the expected changes in markers of alcohol intake, which suggests poor adherence to this pure alcohol intervention. Our results suggest that long-term trials of alcohol consumption, if they are conducted in light drinkers similar to these, must use pragmatic designs for maximal feasibility. This study was registered at clinicaltrials.gov as NCT01377727.Publication Differential associations of leptin with adiposity across early childhood(2013) Boeke, Caroline E; Mantzoros, Christos; Hughes, Michael; Rifas-Shiman, Sheryl; Villamor, Eduardo; Zera, Chloe; Gillman, MatthewObjective: We examined associations of perinatal and 3-year leptin with weight gain and adiposity through 7 years. Design and Methods In Project Viva, we assessed plasma leptin from mothers at 26–28 weeks’ gestation (n=893), umbilical cord vein at delivery (n=540), and children at 3 years (n=510) in relation to body mass index (BMI) z-score, waist circumference, skinfold thicknesses, and dual X-ray absorptiometry body fat. Results: 50.1% of children were male and 29.5% non-white. Mean(SD) maternal, cord, and age 3 leptin concentrations were 22.9(14.2), 8.8(6.4), and 1.8(1.7) ng/mL, respectively, and 3- and 7-year BMI z-scores were 0.46(1.00) and 0.35(0.97), respectively. After adjusting for parental and child characteristics, higher maternal and cord leptin was associated with less 3- year adiposity. For example, mean 3-year BMI z-score was 0.5 lower (95%CI:−0.7,−0.2; p-trend=0.003) among children whose mothers’ leptin concentrations were in the top vs. bottom quintile. In contrast, higher age 3 leptin was associated with greater weight gain and adiposity through age 7 [e.g., change in BMI z-score from 3 to 7 years was 0.2 units (95%CI:−0.0,0.4; p-trend=0.05)]. Conclusions: Higher perinatal leptin was associated with lower 3-year adiposity, whereas higher age 3 leptin was associated with greater weight gain and adiposity by 7 years.Publication Effects of Lipid-Lowering Drugs on Irisin in Human Subjects In Vivo and in Human Skeletal Muscle Cells Ex Vivo(Public Library of Science, 2013) Gouni-Berthold, Ioanna; Berthold, Heiner K.; Huh, Joo Young; Berman, Reena; Spenrath, Nadine; Krone, Wilhelm; Mantzoros, ChristosContext and Objective The myokine irisin has been proposed to regulate energy homeostasis. Little is known about its association with metabolic parameters and especially with parameters influencing pathways of lipid metabolism. In the context of a clinical trial, an exploratory post hoc analysis has been performed in healthy subjects to determine whether simvastatin and/or ezetimibe influence serum irisin levels. The direct effects of simvastatin on irisin were also examined in primary human skeletal muscle cells (HSKMCs). Design and Participants A randomized, parallel 3-group study was performed in 72 men with mild hypercholesterolemia and without apparent cardiovascular disease. Each group of 24 subjects received a 14-day treatment with either simvastatin 40 mg, ezetimibe 10 mg, or their combination. Results: Baseline irisin concentrations were not significantly correlated with age, BMI, estimated GFR, thyroid parameters, glucose, insulin, lipoproteins, non-cholesterol sterols, adipokines, inflammation markers and various molecular markers of cholesterol metabolism. Circulating irisin increased significantly in simvastatin-treated but not in ezetimibe-treated subjects. The changes were independent of changes in LDL-cholesterol and were not correlated with changes in creatine kinase levels. In HSKMCs, simvastatin significantly increased irisin secretion as well as mRNA expression of its parent peptide hormone FNDC5. Simvastatin significantly induced cellular reactive oxygen species levels along with expression of pro- and anti-oxidative genes such as Nox2, and MnSOD and catalase, respectively. Markers of cellular stress such as atrogin-1 mRNA and Bax protein expression were also induced by simvastatin. Decreased cell viability and increased irisin secretion by simvastatin was reversed by antioxidant mito-TEMPO, implying in part that irisin is secreted as a result of increased mitochondrial oxidative stress and subsequent myocyte damage. Conclusions: Simvastatin increases irisin concentrations in vivo and in vitro. It remains to be determined whether this increase is a result of muscle damage or a protective mechanism against simvastatin-induced cellular stress. Trial Registration ClinicalTrials.gov NCT00317993 NCT00317993.Publication Leptin and Its Emerging Role in Children and Adolescents(The Japanese Society for Pediatric Endocrinology, 2006) Kelesidis, Iosif; Mantzoros, ChristosLeptin is an adipocyte-secreted hormone which plays a key role in energy homeostasis. Recent “proof of concept” studies involving leptin administration to humans support its critical role in regulating energy homeostasis, neuroendocrine and immune function as well as insulin resistance in states of energy/ caloric deprivation. Moreover, interventional studies in leptin deficient children and observational studies in normal girls and boys support a role for leptin as a permissive factor for the initiation of puberty in children. The potential clinical usefulness of leptin in several disease states in children and adolescents, including hypothalamic amenorrhea, eating disorders and syndromes of insulin resistance is still under investigation.Publication Circulating Irisin Levels Are Not Affected by Coffee Intake: A Randomized Controlled Trial(Public Library of Science, 2014) Peter, Patricia R.; Park, Kyung Hee; Huh, Joo Young; Wedick, Nicole M.; Mantzoros, ChristosIrisin, secreted by skeletal muscle and possibly fat, is hypothesized to play an important role in modulating energy expenditure, obesity and metabolism. Coffee consumption also increases energy expenditure and leads to positive metabolic effects, but whether these effects are mediated by irisin remains unknown. The objective of this study was to determine the association between baseline irisin levels and the metabolic profile in humans and to investigate whether consumption of caffeinated coffee alters irisin levels. To this end, a secondary analysis was performed investigating irisin levels at baseline and after eight weeks in 32 healthy, overweight coffee drinkers who were randomized to consumption of 5 cups per day of instant caffeinated coffee, decaffeinated coffee, or water. Spearman correlation and analysis of covariance analyses were performed to identify possible associations. Irisin levels were positively correlated with waist circumference (r = 0.41, p = 0.02), fat mass (r = 0.44, p = 0.01) and CRP (r = 0.47, p = 0.007). Though there was a trend towards increased levels of irisin over time in the caffeinated coffee group (+1.8%) when compared to the placebo group (−4%) this did not reach statistical significance (p = 0.75 for the trend). This first randomized trial failed to reveal any effects of coffee consumption on irisin levels, but a larger trial, appropriately sized on the basis of data provided by this study, is needed to conclusively investigate such a relationship. Trial Registration Clinicaltrials.gov NCT00305097Publication Omentin-1 levels are reduced by pharmacologic doses of leptin, but remain unaffected by energy deprivation and display no day-night variation(2014) Hamnvik, Ole-Petter; Thakkar, Bindiya; Chamberland, John; Aronis, Konstantinos; Schneider, Benjamin Edward; Mantzoros, ChristosObjective: To study the day-night variation of omentin-1 levels and assess whether leptin, and/or short-and long-term energy deprivation alter circulating omentin-1 levels via cytokines. Design and Methods Omentin-1 levels were measured hourly in serum samples from six healthy men to evaluate for day-night variation. To study effects of acute energy deprivation and of leptin administration, eight healthy subjects were studied in the fasting state for 72 hours with administration of either placebo or metreleptin in physiological replacement doses. We evaluated the effect of leptin in pharmacological doses on serum omentin-1 and cytokine levels, as well as on omentin-1 levels in ex vivo omental adipose tissue, in fifteen healthy volunteers. To study the effect of chronic energy deprivation and weight loss on omentin-1 levels we followed eighteen obese subjects for 12 months who underwent bariatric surgery. Results: There is no day-night variation in omentin-1 levels. Short-term and chronic energy deprivation as well as ex vivo leptin administration and physiological replacement doses of leptin do not alter omentin-1 levels, whereas pharmacologic doses of metreleptin reduce omentin-1 levels whereas levels of TNF-α receptor II and IL-6 tend to increase. Conclusions: Omentin-1 levels are reduced by pharmacological doses of metreleptin independent of effects on cytokine levels.Publication Novel Molecules Regulating Energy Homeostasis: Physiology and Regulation by Macronutrient Intake and Weight Loss(Korean Endocrine Society, 2016) Gavrieli, Anna; Mantzoros, ChristosExcess energy intake, without a compensatory increase of energy expenditure, leads to obesity. Several molecules are involved in energy homeostasis regulation and new ones are being discovered constantly. Appetite regulating hormones such as ghrelin, peptide tyrosine-tyrosine and amylin or incretins such as the gastric inhibitory polypeptide have been studied extensively while other molecules 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 been fully elucidated. This mini review focuses on the above mentioned molecules and discusses them in relation to their regulation by the macronutrient composition of the diet as well as diet-induced weight loss.Publication Lack of mature lymphocytes results in obese but metabolically healthy mice when fed a high-fat diet(Springer Science and Business Media LLC, 2015-05-21) Liu, Xiaowen; Huh, Joo Young; Gong, Huizhi; Chamberland, John; Hamnvik, Ole-Petter; Mantzoros, ChristosBackground/Objectives: Obesity is characterized by chronic inflammation and immune dysregulation, as well as insulin resistance, but the link between obesity and adaptive immunity remains to be fully studied. Methods: To elucidate the role of adaptive immunity on body composition, glucose homeostasis, and inflammation, recombination-activating gene 1 knockout (Rag1-/-) mice, without mature T lymphocytes or B-lymphocytes, were maintained on a low (LFD) or high fat diet (HFD) for 11 weeks. Results: Rag1-/- mice fed HFD gained significantly more weight and had increased body fat compared to wild type. Downregulation of energy expenditure as well as brown fat UCP-1 and UCP-3 gene expression were noticed in HFD fed Rag1-/- mice compared to LFD. HFD mice had significantly decreased energy intake compared to LFD mice, consistent with decreased AgRP and increased POMC gene expressions in the hypothalamus. Moreover, compared to wild type, Rag1-/- mice had lower IL-4 levels, a cytokine recently found to induce browning in white adipocytes, and higher IL-12 levels in HFD fed Rag1-/- mice. Despite that HFD Rag1-/- mice were more obese, they had similar glucose, insulin, and adiponectin levels, while leptin was marginally increased. Conclusions: Mice with deficiency in adaptive immunity are obese, partly due to decreased energy expenditure, but are metabolically normal, suggesting that mature lymphocytes play necessary roles in the development of obesity-related metabolic dysregulation.Publication Obese individuals with more components of the metabolic syndrome and/or prediabetes demonstrate decreased activation of reward-related brain centers in response to food cues in both the fed and fasting states: A preliminary fMRI study(2016) Farr, Olivia; Mantzoros, ChristosIt remains unknown whether obese individuals with more components of the metabolic syndrome and/or prediabetes demonstrate altered activation of brain centers in response to food cues. We examined obese prediabetics (n=26) vs. obese nondiabetics (n=11) using fMRI. We also performed regression analyses on the basis of the number of MetS components per subject. Obese individuals with prediabetes have decreased activation of the reward-related putamen in the fasting state and decreased activation of the salience- and reward-related insula after eating. Obese individuals with more components of MetS demonstrate decreased activation of the putamen while fasting. All these activations remain significant when corrected for BMI, waist circumference (WC), HbA1c and gender. Decreased activation in reward-related brain areas between obese individuals is more pronounced in subjects with prediabetes and MetS. Prospective studies are needed to quantify their contributions to the development of prediabetes/MetS and to study whether these conditions may predispose to the exacerbation of obesity and the development of comorbidities over time.
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