Ulf Elbelt

Circulating levels of irisin in patients with anorexia nervosa and different stages of obesity--correlation with body mass index.

Irisin was recently identified as cleavage product of fibronectin type III domain containing 5 (FNDC5) and shown to increase energy expenditure in mice and humans and therefore was discussed as potential treatment option in obesity. However, the regulation of irisin under conditions of severely altered body weight such as anorexia nervosa and obesity remains to be investigated. We analyzed circulating irisin levels over a broad spectrum of body weight in 40 patients with anorexia nervosa (mean body mass index, BMI 12.6±0.7 kg/m(2)), normal weight controls (22.6±0.9 kg/m(2)) and obese patients with BMI of 30-40 (36.9±1.2 kg/m(2)), 40-50 (44.9±1.1 kg/m(2)) and >50 (70.1±2.7 kg/m(2), n=8/group). Correlation analyses were performed between irisin and different body indices, parameters of body composition and hormones involved in various homeostatic processes. Obese patients showed higher circulating irisin levels compared to normal weight and anorexic patients (p<0.05) resulting in a correlation of irisin with body weight (r=0.47, p<0.01) and BMI (r=0.50, p<0.001). Plasma irisin was also positively correlated with fat mass (r=0.48, p<0.01), body cell mass (r=0.45, p<0.01) and fat free mass (r=0.40, p<0.05). Insulin levels were positively correlated with irisin (r=0.45, p<0.01), whereas circulating ghrelin, cortisol, thyroid-stimulating hormone or C-reactive protein were not (p>0.05). These data indicate that circulating irisin is affected under conditions of altered BMI with highest levels in severely obese patients. The increase of irisin under conditions of obesity may indicate a physiological function to improve glucose tolerance which is often impaired in obese subjects.

Irisin as a muscle-derived hormone stimulating thermogenesis – A critical update

The recently described myokine, irisin is cleaved from fibronectin type III domain containing protein 5 (FNDC5) and has been proposed to be secreted upon exercise to promote the browning of beige fat cells in white adipose tissue that results in enhanced thermogenesis and increased energy expenditure. The initial studies suggested irisin as a treatment option for obesity and associated diseases such as type 2 diabetes mellitus and stimulated further research. However, the results of subsequent studies investigating the regulation of irisin by different types of exercise are partly conflicting and effects were only shown in highly selective patient populations so far. Moreover, other parameters like body weight or fat free mass were shown to influence irisin adding more complexity to the mechanisms regulating this hormone. The present review will describe the discovery of irisin, its potential role in adipose tissue-mediated thermogenesis, its regulation by exercise and lastly, discuss current controversies and highlight gaps of knowledge to be filled by future studies.

Molecular and Clinical Evidence for an ARMC5 Tumor Syndrome: Concurrent Inactivating Germline and Somatic Mutations Are Associated With Both Primary Macronodular Adrenal Hyperplasia and Meningioma

CONTEXT Primary macronodular adrenal hyperplasia (PMAH) is a rare cause of Cushings syndrome, which may present in the context of different familial multitumor syndromes. Heterozygous inactivating germline mutations of armadillo repeat containing 5 (ARMC5) have very recently been described as cause for sporadic PMAH. Whether this genetic condition also causes familial PMAH in association with other neoplasias is unclear. OBJECTIVE The aim of the present study was to delineate the molecular cause in a large family with PMAH and other neoplasias. PATIENTS AND METHODS Whole-genome sequencing and comprehensive clinical and biochemical phenotyping was performed in members of a PMAH affected family. Nodules derived from adrenal surgery and pancreatic and meningeal tumor tissue were analyzed for accompanying somatic mutations in the identified target genes. RESULTS PMAH presenting either as overt or subclinical Cushings syndrome was accompanied by a heterozygous germline mutation in ARMC5 (p.A110fs*9) located on chromosome 16. Analysis of tumor tissue showed different somatic ARMC5 mutations in adrenal nodules supporting a second hit hypothesis with inactivation of a tumor suppressor gene. A damaging somatic ARMC5 mutation was also found in a concomitant meningioma (p.R502fs) but not in a pancreatic tumor, suggesting biallelic inactivation of ARMC5 as causal also for the intracranial meningioma. CONCLUSIONS Our analysis further confirms inherited inactivating ARMC5 mutations as a cause of familial PMAH and suggests an additional role for the development of concomitant intracranial meningiomas.

The ghrelin activating enzyme ghrelin-O-acyltransferase (GOAT) is present in human plasma and expressed dependent on body mass index

Ghrelin is the only known peripherally produced and centrally acting peptide hormone stimulating food intake. The acylation of ghrelin is essential for binding to its receptor. Recently, the ghrelin activating enzyme ghrelin-O-acyltransferase (GOAT) was identified in mice, rats and humans. In addition to gastric mucosal expression, GOAT was also detected in the circulation of rodents and its expression was dependent on metabolic status. We investigated whether GOAT is also present in human plasma and whether expression levels are affected under different conditions of body weight. Normal weight, anorexic and obese subjects with body mass index (BMI) 30-40, 40-50 and >50 were recruited (n=9/group). In overnight fasted subjects GOAT protein expression was assessed by Western blot and ghrelin measured by ELISA. GOAT protein was detectable in human plasma. Anorexic patients showed reduced GOAT protein levels (-42%, p<0.01) whereas obese patients with BMI>50 had increased concentrations (+34%) compared to normal weight controls. Ghrelin levels were higher in anorexic patients compared to all other groups (+62-78%, p<0.001). Plasma GOAT protein expression showed a positive correlation with BMI (r=0.71, p<0.001) and a negative correlation with ghrelin (r=-0.60, p<0.001). Summarized, GOAT is also present in human plasma and GOAT protein levels depend on the metabolic environment with decreased levels in anorexic and increased levels in morbidly obese patients. These data may indicate that GOAT counteracts the adaptive changes of ghrelin observed under these conditions and ultimately contributes to the development or maintenance of anorexia and obesity as it is the only enzyme acylating ghrelin.

Differences of energy expenditure and physical activity patterns in subjects with various degrees of obesity

BACKGROUND & AIMS An imbalance of energy intake and energy expenditure leads to obesity. However, little detailed information of energy expenditure and physical activity patterns in obese subjects is available. Therefore, we assessed total energy expenditure (TEE) with its components resting energy expenditure (REE) and activity thermogenesis (AT) and the patterns of physical activity in non-obese and in subjects with different degrees of obesity. METHODS TEE and activity pattern were assessed with the SenseWear™ armband in 78 subjects (46 ± 12 years; 28 with normal weight/overweight, 13 each with obesity I° and II°, and 24 with obesity III°). In addition, REE was measured by indirect calorimetry and AT was calculated. RESULTS Although TEE (and REE) increased with increasing weight category from 2567 (1437) kcal/d in non-obese subjects to 3033 (1931) kcal/d in subjects with obesity III° (p=0.016, p<0.001, respectively) body weight adjusted TEE decreased from 33.1 to 22.1 kcal/kg/d (p<0.001). This was mainly due to decreased body weight adjusted AT (11.3-5.8 kcal/kg/d, p<0.001). AT consisted almost completely of non-exercise AT. In particular, for obese subjects exercise-related AT was negligible. CONCLUSIONS Higher degrees of obesity are associated with decreased body weight adjusted AT. These differences have to be considered for therapeutic strategies.

Irisin Levels are Not Affected by Physical Activity in Patients with Anorexia Nervosa

Irisin was recently identified as muscle-derived hormone that increases energy expenditure. Studies in normal weight and obese subjects reported an increased irisin expression following physical activity, although inconsistent results were observed. Increased physical activity in a subgroup of patients with anorexia nervosa (AN) complicates the course of the disease. Since irisin could account for differences in clinical outcomes, we investigated irisin levels in anorexic patients with high and moderate physical activity to evaluate whether irisin differs with increasing physical activity. Hospitalized female anorexic patients (n = 39) were included. Plasma irisin measured by enzyme-linked immunosorbent assay and locomotor activity were assessed at the same time. Patients were separated into two groups (n = 19/group; median excluded): moderate and high activity (6331 ± 423 vs. 13743 ± 1047 steps/day, p < 0.001). The groups did not differ in body mass index (14.2 ± 0.4 vs. 15.0 ± 0.4 kg/m2), irisin levels (558.2 ± 26.1 vs. 524.9 ± 25.2 ng/ml), and body weight-adjusted resting energy expenditure (17.6 ± 0.3 vs. 18.0 ± 0.3 kcal/kg/day, p > 0.05), whereas body weight-adjusted total energy expenditure (46.0 ± 1.4 vs. 41.1 ± 1.1 kcal/kg/day), metabolic equivalents (METs, 1.9 ± 0.1 vs. 1.7 ± 0.1 METs/day), body weight-adjusted exercise activity thermogenesis (1.8 ± 0.5 vs. 0.6 ± 0.3 kcal/kg/day), duration of exercise (18.6 ± 4.7 vs. 6.2 ± 3.1 min/day), and body weight-adjusted non-exercise activity thermogenesis (21.6 ± 1.0 vs. 18.8 ± 0.8 kcal/kg/day) were higher in the high activity compared to the moderate activity group (p < 0.05). No correlations were observed between irisin and activity parameters in the whole sample (p > 0.05). In conclusion, the current data do not support the concept of irisin being induced by exercise, at least not under conditions of severely reduced body weight like AN.

Diagnosis of Primary Hypophysitis in Germany.

CONTEXT Representative data on diagnostic findings in primary hypophysitis (PrHy) are scarce. OBJECTIVE The objective of the study was to collate consistent data on clinical features in a large series of patients with PrHy. Another objective was to gain information on current practice in a diagnostic work-up. DESIGN The Pituitary Working Group of the German Society of Endocrinology conducted a nationwide retrospective cross-sectional cohort study in Germany. PATIENTS Seventy-six patients with PrHy were identified. MAIN OUTCOME MEASURES Clinical and endocrinological features were assessed. RESULTS Headache (50%) and increase in body mass (18%) were the most frequent nonendocrine symptoms. Hypophysitis was associated with pregnancy in only 11% of the female patients. Diabetes insipidus was found in 54% of the patients at presentation. Hypogonadotropic hypogonadism was the most frequent endocrine failure (62%), whereas GH deficiency was the least frequent (37%). With 86%, thickening of the pituitary stalk was the prevailing neuroradiological sign. Compared with surgical cases, the cases without histological confirmation presented more often with suprasellar lesions and had less severe nonendocrine symptoms. Granulomatous hypophysitis was associated with more severe clinical symptoms than lymphocytic hypophysitis. Examination of cerebrospinal fluid was predominantly performed in participating neurosurgical centers, whereas thyroid antibodies were almost exclusively assessed in endocrinological centers. CONCLUSION In contrast to the literature, hypogonadism was found to be the most frequent endocrine failure in PrHy. Weight gain was identified as a clinical sign of PrHy. In the majority of patients, PrHy can be reliably identified by characteristic clinical signs and symptoms, obviating histological confirmation. The diagnostic approach should be standardized in PrHy.

Altered insulin requirement in patients with type 1 diabetes and primary adrenal insufficiency receiving standard glucocorticoid replacement therapy

OBJECTIVE Current glucocorticoid replacement regimens fail to fully mimic physiologic cortisol secretion in patients with primary adrenal insufficiency. This may lead to changes in insulin requirement in patients with primary adrenal insufficiency and type 1 diabetes. Therefore, we assessed insulin requirement in patients with autoimmune polyendocrine syndrome type 2 (APS-2). DESIGN AND SUBJECTS Ten females with primary adrenal insufficiency and type 1 diabetes (mean duration of type 1 diabetes 13+/-11 years and of primary adrenal insufficiency 11+/-9 years) were retrospectively assessed regarding insulin regimen and insulin dose adjustment. Data were compared with control patients matched for age, sex and duration of diabetes drawn from all patients with type 1 diabetes attending the diabetes outpatient clinics at the University Hospital Wuerzburg for a scheduled consultation. RESULTS Glycaemia was well controlled in both groups (mean HbA1c 6.99+/-0.81% in APS-2 patients versus 6.69+/-1.03% in control patients). The mean weight-adjusted daily dose of insulin was non-significantly higher in patients with APS-2 compared with control patients (0.69+/-0.35 IU/kg body weight versus 0.51+/-0.17 respectively). The mean insulin (IU)/carbohydrate-ratio for 10 g of carbohydrate in the morning was 1.9+/-1.0 and 1.4+/-0.5 respectively. However, the insulin/carbohydrate-ratios were significantly higher in the APS-2 patients both at noon (mean ratio 2.0+/-0.9 vs 1.1+/-0.5 in control patients) and in the evening (mean ratio 2.1+/-1.1 vs 1.3+/-0.5 respectively; P<0.05). CONCLUSIONS Glucocorticoid replacement therapy in patients with primary adrenal insufficiency and type 1 diabetes leads to significant changes in insulin requirement compared with patients with type 1 diabetes only.

Irisin: what promise does it hold?

Purpose of reviewThe recently identified myokine, irisin has raised great expectations as a potential target in the conservative treatment of obesity. This review focuses on studies exploring the effects of irisin in humans. Recent findingsPeroxisome proliferator-activated receptor &ggr; coactivator-1 &agr; expression in skeletal muscles is induced by exercise followed by expression of the membrane protein fibronectin type III domain containing 5. After cleavage from fibronectin type III domain containing 5, irisin is secreted into blood increasing thermogenesis by browning of subcutaneous white/beige adipose tissue. Although clear-cut data have been reported in rodents, the thermogenic effect of irisin in humans remains controversial. The initially reported exercise-dependent increase of irisin in humans could not be confirmed in most studies. However, a robust finding in human studies is the association of irisin with BMI. SummaryThe discovery of irisin provides more insight into exercise-induced browning of adipose tissue, and therefore leads to a better understanding of mechanisms underlying body weight regulation and further down the road possibly may lead to treatment strategies of diseases with greatly altered body weight such as obesity or anorexia nervosa.

Sex-specific regulation of NUCB2/nesfatin-1: Differential implication in anxiety in obese men and women

Nesfatin-1 is cleaved from nucleobindin2 (NUCB2) and implicated in the regulation of hunger and satiety as anorexigenic peptide hormone. Circulating NUCB2/nesfatin-1 is elevated in obesity and decreased in anorexia nervosa. In addition, a role in the regulation of stress, anxiety and depression has been demonstrated. First evidence suggested that NUCB2/nesfatin-1 might be regulated in a sex-specific manner. Thus, we investigated NUCB2/nesfatin-1 plasma levels in association with perceived stress, anxiety and depressiveness in obese men and women. We enrolled 140 inpatients (87 female, 53 male; body mass index, BMI, 30.3-81.7 kg/m(2)) hospitalized due to obesity with mental and somatic comorbidities. Perceived stress (PSQ-20), anxiety (GAD-7), and depressiveness (PHQ-9) were measured psychometrically, and at the same time NUCB2/nesfatin-1 plasma levels by ELISA. Males and females did not differ in terms of age and BMI. NUCB2/nesfatin-1 did not show a correlation with age or BMI. Mean NUCB2/nesfatin-1 levels (+25%, p<0.001) as well as mean scores for perceived stress (+26%, p < 0.01), anxiety (+54%, p < 0.001) and depressiveness (+32%, p = 0.02) were higher in females compared to males. Scores for perceived stress (r = 0.39; p < 0.001) and depressiveness (r = 0.35; p < 0.01) showed a positive correlation with NUCB2/nesfatin-1 in women, while in men no correlation was observed (p>0.19). The strongest association was observed between NUCB2/nesfatin-1 and anxiety with a positive correlation in women (r = 0.54; p < 0.001), while in men even an inverse correlation was found (r = -0.32; p = 0.03). This result was reflected in higher NUCB2/nesfatin-1 levels in women with high versus low anxiety (+51%, p<0.001) and an opposite alteration in men (-17%, p = 0.04) after a median split into two groups with high and low anxiety. In conclusion, circulating NUCB2/nesfatin-1 showed a positive correlation with anxiety, perceived stress, and depressiveness in obese women. In men, no correlation with perceived stress and depressiveness was observed, whereas the association with anxiety was inverse, pointing towards a sex-specific regulation. These results corroborate the suggestion of NUCB2/nesfatin-1 being relevantly involved in the regulation of mood and stress in a sex-specific way.