Late offspring effects of antenatal thyroid screening.

BACKGROUND: Thyroid dysfunction in pregnancy is associated with adverse offspring outcomes and recent birth-cohort studies suggest that even mild degrees of thyroid dysfunction may be linked with a range of late cognitive and behavioural effects in childhood and adolescence. SOURCES OF DATA: This review summarizes recent literature of observational studies and critically appraises randomized controlled trials (RCTs) of antenatal thyroid screening and Levothyroxine intervention. AREAS OF AGREEMENT: Overt hypothyroidism and hyperthyroidism carry significant risks for unfavourable offspring outcomes and should be appropriately corrected in pregnancy. AREAS OF CONTROVERSY: The significance of subclinical hypothyroidism and hypothyroxinaemia is still unclear. Meta-analyses of birth-cohort studies show associations of maternal subclinical hypothyroidism and hypothyroxinaemia with intellectual deficits, attention deficit hyperactivity disorder (ADHD) and autism spectrum disorders, while hyperthyroidism and high-normal FT4 were linked with ADHD. RCTs have shown no benefits of screening on neurodevelopmental outcomes although Levothyroxine could have been initiated too late in pregnancy in these trials. GROWING POINTS: A small number of studies have shown inconsistent associations of maternal thyroid dysfunction with offspring cardiometabolic indices including blood pressure and body weight. Correction of maternal thyroid dysfunction was, however, associated with favourable long-term metabolic profiles in mothers, including lipid profiles, fat mass and body mass index. Antenatal thyroid screening may therefore present opportunities for optimizing a wider range of outcomes than envisaged. AREAS FOR DEVELOPING RESEARCH: Future trials with early antenatal thyroid screening and intervention are necessary to clarify the impact of screening on late offspring and maternal effects.

Altered Glucose Uptake in Muscle, Visceral Adipose Tissue, and Brain Predict Whole-Body Insulin Resistance and may Contribute to the Development of Type 2 Diabetes: A Combined PET/MR Study.

We assessed glucose uptake in different tissues in type 2 diabetes (T2D), prediabetes, and control subjects to elucidate its impact in the development of whole-body insulin resistance and T2D. Thirteen T2D, 12 prediabetes, and 10 control subjects, matched for age and BMI, underwent OGTT and abdominal subcutaneous adipose tissue (SAT) biopsies. Integrated whole-body 18F-FDG PET and MRI were performed during a hyperinsulinemic euglycemic clamp to asses glucose uptake rate (MRglu) in several tissues. MRglu in skeletal muscle, SAT, visceral adipose tissue (VAT), and liver was significantly reduced in T2D subjects and correlated positively with M-values (r=0.884, r=0.574, r=0.707 and r=0.403, respectively). Brain MRglu was significantly higher in T2D and prediabetes subjects and had a significant inverse correlation with M-values (r=-0.616). Myocardial MRglu did not differ between groups and did not correlate with the M-values. A multivariate model including skeletal muscle, brain and VAT MRglu best predicted the M-values (adjusted r2=0.85). In addition, SAT MRglu correlated with SAT glucose uptake ex vivo (r=0.491). In different stages of the development of T2D, glucose uptake during hyperinsulinemia is elevated in the brain in parallel with an impairment in peripheral organs. Impaired glucose uptake in skeletal muscle and VAT together with elevated glucose uptake in brain were independently associated with whole-body insulin resistance, and these tissue-specific alterations may contribute to T2D development.

SERUM ADIPONECTIN AND INSULIN-LIKE GROWTH FACTOR 1 IN PREDOMINANTLY FEMALE PATIENTS WITH THYROID CANCER: ASSOCIATION WITH THE HISTOLOGIC CHARACTERISTICS OF THE TUMOR.

OBJECTIVE: Insulin-like growth factor (IGF)-1 and adiponectin have been proposed to contribute to the pathogenesis of different malignancies. However, data regarding their association with histologic characteristics of thyroid cancer are scarce. The main aims of the present study were the comparative evaluation of IGF-1, IGF-binding protein 3 (BP3), and adiponectin serum levels between different histologic types of thyroid cancer, as well as within specific histologic characteristics of the tumors. METHODS: A total of 179 thyroid cancer patients (126 [70.4%] women) were recruited. A total of 129 (72.1%) had papillary thyroid carcinoma (including variants), 26 had follicular thyroid carcinoma (14.5%), and 24 had medullary thyroid carcinoma (13.4%). Parameters from history, physical examination, and thyroid histology were selected. Serum adiponectin, IGF-1, and IGF-BP3 were measured in fasting morning samples. RESULTS: IGF-1, IGF-BP3, and adiponectin levels were similar among different histologic types of thyroid carcinoma, with a trend towards higher IGF-1 and IGF-BP3 levels in patients with intrathyroid invasion, compared to those without. In addition, ratios of IGF-1 to adiponectin (P = .012) and IGF-1 to (adiponectin × IGF-BP3) (P = .003), as well as type 2 diabetes (P = .001), were positively associated with tumor size. CONCLUSION: Although IGF-1, IGF-BP3, and adiponectin were not separately different between groups or within specific histologic lesions, when they were combined to produce IGF-1 to adiponectin and IGF-1 to (adiponectin × IGF-BP3) ratios, they were independently associated with tumor size. Future prospective studies are needed to evaluate whether these ratios could serve as prognostic markers of thyroid tumor aggressiveness.

Endocrine Manifestations and New Developments in Mitochondrial Disease.

Mitochondrial diseases are a group of common inherited diseases causing disruption of oxidative phosphorylation. Some patients with mitochondrial disease have endocrine manifestations, with diabetes mellitus being predominant but also include hypogonadism, hypoadrenalism, and hypoparathyroidism. There have been major developments in mitochondrial disease over the past decade that have major implications for all patients. The collection of large cohorts of patients has better defined the phenotype of mitochondrial diseases and the majority of patients with endocrine abnormalities have involvement of several other systems. This means that patients with mitochondrial disease and endocrine manifestations need specialist follow-up because some of the other manifestations, such as stroke-like episodes and cardiomyopathy, are potentially life threatening. Also, the development and follow-up of large cohorts of patients means that there are clinical guidelines for the management of patients with mitochondrial disease. There is also considerable research activity to identify novel therapies for the treatment of mitochondrial disease. The revolution in genetics, with the introduction of next-generation sequencing, has made genetic testing more available and establishing a precise genetic diagnosis is important because it will affect the risk for involvement for different organ systems. Establishing a genetic diagnosis is also crucial because important reproductive options have been developed that will prevent the transmission of mitochondrial disease because of mitochondrial DNA variants to the next generation.

Serum Levels of Irisin and Omentin-1 in Breast Neoplasms and Their Association with Tumor Histology.

Breast cancer is associated with obesity, possibly due to direct effects of adipokines and myokines, such as omentin-1 and irisin. In this study, we aimed to evaluate omentin-1 and irisin levels in women with benign and/or malignant breast neoplasms vs. healthy controls. Disease-free individuals (N = 56) and patients with histologically proven benign (N = 61) or malignant tumor (N = 96; subdivided into recently diagnosed/treatment-naïve (N = 72) and chemotherapy-treated (N = 24) subgroups) were enrolled in this study. Demographic, biochemical, and tumor histological characteristics were recorded. Body composition parameters were assessed using bioelectrical impedance. Serum irisin and omentin-1 levels were quantified with ELISA kits. In adjusted models, irisin levels were higher in both benign and malignant cases compared to controls but were comparable between neoplasms. Further adjustment for omentin-1 levels showed that age (odds ratio (OR) = 1.05, 95% confidence interval (95% CI) = (1.02, 1.08), p < 0.01) and irisin levels (OR = 5.30, 95% CI = (1.24, 22.38), p=0.03) were independent predictors of the presence of malignancy. These molecules were associated with each other and with other anthropometric and demographic parameters. Irisin was associated with tumor histological characteristics including Ki67% levels, Elston-Ellis grading system, and estrogen receptors status. Omentin-1 was also associated with the Elston-Ellis grading system. In conclusion, serum irisin is increased in patients with both benign and malignant diseases of the breast. When combined with omentin-1, irisin concentration was associated with the presence of breast malignancy. This molecule's role as a potential diagnostic and/or prognostic agent in breast malignancies warrants further investigation in larger prospective studies.

Obesity and COVID-19: A jigsaw puzzle with still missing pieces.

Apart from posing various mechanical and medical issues compromising general health, obesity is a major factor for respiratory tract infections, due to specific inflammation and immunological compromise. The burden of obesity on morbidity and mortality of SARS-CoV-2 infection/COVID-19 is considerable. Herein, we aimed to search the literature and present to the readers pathophysiologic pathways that may associate obesity and COVID-19. We present potential mechanisms, which might partly explain why patients with obesity are more prone to suffer from respiratory infections in the context of COVID-19. Better understanding of these pathways could eventually guide management strategies and therapies for COVID-19 in the future.

Serum Follistatin Is Increased in Thyroid Cancer and Is Associated With Adverse Tumor Characteristics in Humans.

CONTEXT: Obesity and classical growth factors are associated with thyroid cancer (TC). However, less is known regarding novel hormones such as follistatins and activins. We hypothesized that serum follistatin but not activins would be increased in TC. OBJECTIVE: This work aimed to assess circulating levels of follistatins, activins, and growth factors in patients with a history of TC vs patients with nonmalignant thyroid diseases. METHODS: A hospital-based, unmatched case-control study was conducted with 170 thyroidectomized patients due to well-differentiated TC and 106 thyroidectomized patients without history of malignancy. Anthropometric, biochemical, and histological parameters were recorded. Serum samples were collected in the steady state 45 days after surgery. Multivariate models were used to adjust for baseline differences of the unmatched variables. Serum levels of follistatin (FST), follistatin like-3, activin A, activin B, bioactive insulin-like growth factor-1, and stanniocalcin-2 were assayed with novel, highly specific ELISA kits. RESULTS: In unmatched univariate models, TC patients had higher FST serum levels compared to cancer-free individuals, independently of histological subtype. In multivariate models adjusting for covariates, individuals in the highest tertile of FST levels were associated with an increased risk for the presence of any type of TC or specific histological subtypes, including papillary, follicular and Hürthle-cell carcinoma, and medullary TC. Higher postoperative FST concentrations were found in patients with vascular invasion and distant metastases and associated with TNM staging at diagnosis. CONCLUSION: FST serum levels are increased in TC patients and correlate with advanced tumor aggressiveness. Future longitudinal studies are needed to confirm and extend our observations.

Asymmetric Graves' Orbitopathy.

Graves' Orbitopathy (GO) is an autoimmune orbital disorder usually presenting as a sequala of autoimmune thyroid disease. The presence of GO is associated with increased psychological burden and, in severe cases may cause blindness. While most patients with GO present with bilateral disease, asymmetric or unilateral GO may affect a significant proportion of patients diagnosed with GO. Older age, male sex, active and severe disease correlate with asymmetric disease. However, the exact mechanisms causing asymmetry remain elusive. Herein, we review the literature on asymmetric GO and highlight its differences compared with bilateral GO.

Serum Levels of Activins, Follistatins, and Growth Factors in Neoplasms of the Breast: A Case-Control Study.

Context: Breast cancer is the most common malignancy in women. Noninvasive biomarkers are needed for its early diagnosis and/or prognosis. Objective: The aim of this case-control study was the comparison of serum activins, follistatins, and members of the IGF family levels in women with benign vs malignant breast neoplasms vs apparently healthy controls. Design and Patients: Women with breast benign (n = 100) or malignant tumors (n = 145) and disease-free controls (n = 100) were recruited. Women with breast cancer were subsequently subdivided into recently diagnosed/treatment-naive (n = 112) and chemotherapy-treated (n = 33). Anthropometric, demographic, biochemical, and histological data were recorded. Setting: A breast cancer clinic in Thessaloniki, Greece. Main Outcome Measures: Serum levels of activin A, activin B, follistatin, follistatin-like (FSTL)-3, total IGF-1, total and intact insulin-like growth factor binding protein (IGFBP)-4 and pregnancy-associated plasma protein-A (PAPP-A) were measured with highly specific ELISA kits. Results: In adjusted comparisons, substantial differences in FSTL-3, total and intact IGFBP-4, PAPP-A, and total IGF-1 were observed between groups. In logistic regression analysis, primarily total IGFBP-4 levels were independently associated with the overall presence of breast malignancy. FSTL-3 was the only variable that could distinguish between a benign vs malignant breast mass. In linear regression analysis, FSTL-3 was independently associated with tumor size. Conclusions: We showed that members of the IGF-1/IGFBP-4/PAPP-A axis and FSTL-3 may serve as surrogate markers in breast cancer. Future mechanistic and longitudinal studies and/or clinical trials are needed to explore the efficacy of these molecules as noninvasive biomarkers and their possible therapeutic potential in breast cancer.

Adipocytes express tissue factor and FVII and are procoagulant in a TF/FVIIa-dependent manner.

Background: Tissue factor (TF) combined with its ligand FVII initiates blood coagulation and intracellular signaling. Obese and type 2 diabetic subjects have increased TF expression in their adipose tissue and an increased risk for thrombotic complications. Here we address the role of TF/FVII on adipocyte functions. Materials and methods: Subcutaneous fat was obtained by means of needle aspiration from healthy volunteers, and adipocytes were isolated after collagenase digestion. 3T3-L1 fibroblasts kept in culture were differentiated into adipocytes by addition of IBMX, dexamethasone, rosiglitazone, and insulin to the media. Proteins and mRNA were analyzed by western blot and RT-PCR. Coagulation activity was determined by a colorimetric FX-assay. Lipolysis was measured as free glycerol using a colorimetric method. Glucose uptake was evaluated by scintillation counting of D-[U-14C] glucose. Results: In isolated human primary adipocytes we found expression of TF and FVII. TF expression was confirmed in 3T3-L1 adipocytes, and both cell types were found to be procoagulant in a TF/FVIIa-dependent manner. FXa was generated without FVIIa added to the coagulation assay, and active site-inhibited FVIIa blocked FXa formation, supporting our finding of FVII production by human primary adipocytes. There was no evidence for a role of TF in either lipolysis or glucose uptake in our experimental settings. Conclusion: Human primary adipocytes express active TF and FVII, and the TF/FVIIa complex formed on the adipocyte surface can activate substrate FX. Whether the TF/FVIIa complex conveys signaling pathways leading to biological functions and has any biological activity in adipocytes beyond coagulation remains to be elucidated.

Association between lifestyle and anthropometric parameters and thyroid nodule features.

PURPOSE: Thyroid nodularity has been associated with obesity, but data regarding associations of body composition parameters with specific ultrasound features of thyroid nodules are lacking. The aim of the present study was to assess associations between thyroid nodule ultrasound characteristics, lifestyle, and anthropometric parameters. SUBJECTS AND METHODS: This was a cross-sectional study in the general apparently healthy population of Northern Greece. Thyroid ultrasound data together with medical history, demographic, and anthropometric characteristics were individually recorded. Body composition was evaluated using bioelectrical impedance. RESULTS: Three hundred and six subjects [215 females (70.3%), aged 20-83 years] were included. Ultrasound revealed one or more thyroid nodules in 168 subjects (54.9%). Subjects with thyroid nodules were more frequently females (p = 0.033), older (p < 0.001) and had higher fat mass (p = 0.011), total body fat percentage (p < 0.001) and waist circumference (p = 0.045) than subjects without nodules. In logistic regression analyses, age and female gender were the only independent predictors of presence of thyroid nodules, as well as specific sonographic features. Additionally, total body fat percentage was positively correlated with nodule size (rho = 0.210, p = 0.006) and was the only independent predictor of hypoechoic thyroid nodule(s) and peripheral vascularity, while lack of exercise was predictive of internal vascularity. CONCLUSIONS: Body fat accumulation and lack of exercise, used as surrogate markers of sedentary lifestyle, influence thyroid nodule size and could predict some ultrasonographic characteristics, like hypoechoicity and internal vascularity. Therefore, routine thyroid examination of obese patients and promotion of active lifestyle may be warranted to prevent thyroid nodule formation and possibly progression to malignancy.

Physiological parameters regulating circulating levels of the IGFBP-4/Stanniocalcin-2/PAPP-A axis.

BACKGROUND: Insulin Growth Factor Binding Protein 4 (IGFBP-4), Stanniocalcin-2 (STC-2) and Pregnancy-Associated Plasma Protein-A (PAPP-A) have a well-documented involvement in several physiological functions in humans but predictors of their circulating levels remain largely unknown. We aimed to identify anthropometric and biochemical parameters associated with circulating levels of IGFBP-4/STC-2/PAPP-A axis (ISPa) cross-sectionally and to study their day-night variation and their regulation in response to mixed meal and exercise. METHODS: One hundred twenty two healthy individuals were evaluated cross-sectionally. Subgroups were subjected to standardized mixed meal ingestion in increasing quantities of 125mL or 250mL, or aerobic exercise for 30min, or day-night rhythm study. Main outcome measurements were circulating IGFBP-4 (total and intact), STC-2 and PAPP-A levels. RESULTS: In multivariate models, the main predictors of serum total IGFBP-4 were PAPP-A and female gender. Intact IGFBP-4 was positively associated with serum creatinine. Height was inversely and female gender and % of total body fat were positively correlated with STC-2. PAPP-A decreased after ingesting both the 125mL (p=0.03) and 250mL quantities (p=0.001), while total IGFBP-4 was reduced after the 250mL quantity (p=0.001). Exercise increased STC-2 and PAPP-A levels (p<0.001 for both). Intact, and to a lesser extent total, IGFBP-4 displayed a cortisol-like day/night variation. CONCLUSIONS: We report for the first time anthropometric and physiological modulators of ISPa serum levels in healthy humans.

Changes in Thyroid Hormone Levels Within the Normal and/or Subclinical Hyper- or Hypothyroid Range Do Not Affect Circulating Irisin Levels in Humans.

BACKGROUND: Both thyroid hormones and irisin increase energy expenditure and induce browning of adipose tissue. However, irisin physiology and regulation remain largely unknown, and existing data are mainly derived from observational studies. In this study, we aimed to elucidate whether changes in thyroid-axis hormones alter circulating irisin levels in humans, thereby exerting a direct downstream effect on serum irisin. SUBJECTS AND METHODS: Samples from a cross-sectional evaluation and two interventions were utilized, including patients who had previously undergone thyroidectomy. In the cross-sectional study, 96 consecutively enrolled subjects were divided into a euthyroid group and a subclinical hyperthyroid group, according to their serum thyrotropin (TSH) levels (TSH cutoff 0.3 mIU/L). In interventional study A, 34 patients who had undergone thyroidectomy due to thyroid cancer were withdrawn from their thyroxine replacement treatment for five weeks. In interventional study B, 13 patients underwent a recombinant human TSH stimulation protocol, and blood samples were drawn at baseline, day 3 (i.e., at least 24 hours after the second intramuscular injection), day 5, and day 10. RESULTS: Irisin concentrations were not associated with thyroid-axis hormones (i.e., TSH, free thyroxine, and free triiodiothyronine) cross-sectionally in either the overall cohort or in the euthyroid and/or subclinical hyperthyroid subgroups (p > 0.05). There was no significant difference between euthyroid and subclinical hyperthyroid subjects (p = 0.60). Levothyroxine withdrawal did not result in any changes in irisin concentrations (p = 0.33). Recombinant human TSH stimulation did not induce any significant changes in circulating irisin (p = 0.60). CONCLUSIONS: Changes in thyroid-axis hormone levels within the physiological or supraphysiological range do not affect circulating irisin levels in humans. Therefore, their metabolic effects are most likely independent of each other. Other regulators of irisin levels should be identified in the future.

Circulating irisin, omentin-1, and lipoprotein subparticles in adults at higher cardiovascular risk.

OBJECTIVE: Muscle and fat are now recognized as metabolism-regulating endocrine organs. However, muscle and adipocyte-derived novel cytokines such as irisin and omentin-1 remain understudied in relation to metabolic biomarkers that are associated with cardiovascular risk. SUBJECTS AND METHODS: Thirty-nine subjects with mean (± SD) BMI of 29.2 ± 5.4 kg/m(2) and either diabetes or two other cardiovascular risk factors were enrolled in a 6-month randomized trial of low-dose ethanol. We examined cross-sectional data at baseline, 3-month, and 6-month visits to assess (1) within-person stability of novel cytokines (irisin, omentin-1, visfatin, resistin, and soluble tumor necrosis factor receptor II) and (2) their associations with metabolic parameters, particularly lipoprotein subparticle profile. RESULTS: Repeated measures of irisin and omentin-1 were highly correlated, with intra-class correlations of 0.84 (95% CI: 0.74, 0.91; P < 0.001) and 0.81 (0.70, 0.89; P < 0.001), respectively. Irisin was negatively correlated with omentin-1 (7.4% irisin decrease per a 1-SD increment in omentin-1; 95% CI: 0.5%, 13.9%; P = 0.04). In models adjusted for age, sex, and race, irisin was negatively associated with HDL cholesterol (7.3% decrease per a 10mg/dL increment; 1.0%, 13.3%; P = 0.02) and large HDL particles (15.5% decrease per a 1-SD or 3.5-µmol/L increment; 5.2%, 24.7%; P=0.005). Omentin-1 was positively associated with mean VLDL size (3.8% increase per a 1-SD increment; 0.06%, 7.8%; P = 0.05). Adjustment for alcohol intervention, BMI, and other cytokines did not materially affect these associations. CONCLUSIONS: Irisin and omentin-1 are stable within-person, inversely associated with each other, and closely related to lipoprotein profile. These molecules may be promising markers for cardiovascular risk.

Exercise-induced irisin secretion is independent of age or fitness level and increased irisin may directly modulate muscle metabolism through AMPK activation.

CONTEXT: Irisin has been proposed to be a myokine mediating the effect of exercise on adipocyte browning. The physiology of irisin in humans is not completely understood. OBJECTIVE: To study the physiology of irisin in healthy individuals with different age and fitness levels and to explore the direct effects of irisin on muscle metabolism. DESIGN, SETTING, AND SUBJECTS: Treadmill exercise studies were conducted to measure circulating irisin at baseline and in response to exercise among old and young, physically active and sedentary individuals. Also, high- and moderate-intensity swimming was performed in adolescent men and women to study the effect of exercise intensity and the time course of irisin induction by acute bouts of exercise. Human myotubes were treated with recombinant irisin, and the effect on gene expression, cell signaling, and metabolism was examined. RESULTS: Baseline circulating irisin was lower in old (vs young) and physically active (vs sedentary) subjects. Despite differences in basal levels, the percentage increase of irisin by acute bouts of exercise was not related to age or fitness level. The time course study revealed that circulating irisin increased immediately after high-intensity interval exercise and declined 1 hour thereafter. In vitro experiments showed that irisin facilitates glucose and lipid metabolism in human muscle through AMP kinase phosphorylation. CONCLUSIONS: Despite the differences in basal irisin levels, exercise-induced irisin secretion is independent of age or fitness level. Increased irisin can directly modulate muscle metabolism through AMP kinase activation.

Effects of a 1-year exercise and lifestyle intervention on irisin, adipokines, and inflammatory markers in obese children.

OBJECTIVE: Exercise improves weight status and metabolism. Irisin, a novel myokine, may be involved in the regulation of metabolic function. The effect of an exercise and dietary lifestyle intervention for 1-year on irisin, adipokines (leptin, adiponectin, resistin) and inflammatory markers (C-reactive protein (CRP), soluble tumor necrosis factor receptor II (sTNFR-II) was evaluated, and predictors of irisin levels were characterized in obese children. METHODS: Parameters were assessed at baseline and at follow-up for 65 obese children who completed the program (7-18 years, 54%boys). Their relation to weight status and metabolic risk was analyzed. RESULTS: Anthropometric and metabolic parameters improved after completion of the program. Circulating irisin levels at baseline were 111.0 ± 8.0 ng ml(-1) and increased after the intervention by 12% [6%, 17%], P = 0.00003. There was no evidence for differences in irisin levels between genders and across age. Moreover, changes in irisin did not correlate with those in BMI-SDS, adipokines or inflammatory markers. Leptin decreased after the intervention (Δ5.3 ng ml(-1) , [3.2, 6.3], P = 10(-7) ). Anthropometric measures were significantly associated with leptin and inflammatory markers. CONCLUSIONS: A 1-year long lifestyle intervention program is associated with improvement in anthropometric and metabolic parameters and leads to an elevation in irisin levels in obese children.

Circulating irisin in healthy, young individuals: day-night rhythm, effects of food intake and exercise, and associations with gender, physical activity, diet, and body composition.

CONTEXT: The myokine irisin may increase energy expenditure and affect metabolism. OBJECTIVE: The objective of the study was to elucidate predictors of irisin and study whether circulating irisin may have day-night rhythm in humans. DESIGN: This was an observational, cross-sectional study with an additional 24-hour prospective observational arm (day-night rhythm substudy) and two prospective interventional arms (mixed meal substudy and exercise substudy). SETTING: The study was conducted at the Hellenic Military School of Medicine (Thessaloniki, Greece). PATIENTS AND INTERVENTIONS: One hundred twenty-two healthy, young individuals were subjected to anthropometric and body composition measurements, and their eating and exercise behavior profiles were assessed with validated questionnaires. Subgroups were subjected to day-night rhythm, standardized meal ingestion, and 30-minute aerobic exercise studies. MAIN OUTCOME MEASURES: Circulating irisin levels were measured. RESULTS: Ιrisin levels were lower in males than females (P = .02) after adjustment for lean body mass, which was its major determinant. Irisin levels followed a day-night rhythm (P < .001) with peak at 9:00 pm. Irisin levels were increased at the end of exercise (84.1 ± 10.0 vs 105.8 ± 14.3 ng/mL; P < .001). Irisin levels were not affected by intake of a standardized meal and were not associated with caloric intake or diet quality. CONCLUSIONS: In healthy, young individuals, circulating irisin displays a day-night rhythm, is correlated with lean body mass, and increases acutely after exercise.