We show that irisin levels are affected by age, sex, obesity, and particularly muscle mass, whereas diurnal rhythm and meals do not contribute to the variation in irisin levels. Short bouts of intensive exercise but not long-term elevations in physical activity, acutely and transiently increase serum irisin levels in children and adults.

Recent studies suggested the persistence of brown adipocytes in adult humans, as opposed to being exclusively present in infancy. In this study, we investigated the presence of brown-like adipocytes in adipose tissue (AT) samples of children and adolescents aged 0 to 18 years and evaluated the association with age, location, and obesity. For this, we analysed AT samples from 131 children and 23 adults by histological, immunohistochemical and expression analyses. We detected brown-like and UCP1 positive adipocytes in 10.3% of 87 lean children (aged 0.3 to 10.7 years) and in one overweight infant, whereas we did not find brown adipocytes in obese children or adults. In our samples, the brown-like adipocytes were interspersed within white AT of perirenal, visceral and also subcutaneous depots. Samples with brown-like adipocytes showed an increased expression of UCP1 (>200fold), PRDM16 (2.8fold), PGC1α and CIDEA while other brown/beige selective markers, such as PAT2, P2RX5, ZIC1, LHX8, TMEM26, HOXC9 and TBX1 were not significantly different between UCP1 positive and negative samples. We identified a positive correlation between UCP1 and PRDM16 within UCP1 positive samples, but not with any other brown/beige marker. In addition, we observed significantly increased PRDM16 and PAT2 expression in subcutaneous and visceral AT samples with high UCP1 expression in adults. Our data indicate that brown-like adipocytes are present well beyond infancy in subcutaneous depots of non-obese children. The presence was not restricted to typical perirenal locations, but they were also interspersed within WAT of visceral and subcutaneous depots.

Adequate androgen receptor (AR) function is crucial for male sex development and maintenance of secondary male characteristics. Mutations in the AR lead to androgen insensitivity syndrome (AIS) characterized by an end-organ resistance to androgens. The clinical appearance of individuals with 46,XY karyotype and an AR mutation varies widely from normal male to the ultimate completely female phenotype of complete androgen insensitivity syndrome (CAIS). We have analyzed the androgen receptor missense mutations P723S, P904S, and H917R, clinically associated with CAIS, which were described to have a normal maximum androgen binding (Bmax) but elevated equilibrium dissociation constants (Kd’s) and compared their properties with the F916X deletion mutant, leading to the loss of the last four amino acids of the AR. Functional analysis allowed a quantitative and qualitative discrimination of these mutants in transactivation, amino-terminal/carboxy-terminal (N/C)-interaction, and coactivation capacity, varying widely with each distinct mutation. We conclude that mutations in the AR have to be characterized meticulously, not only to prove any quantitative functional deficit as a proof of consequence, but also to gain knowledge on qualitative functional properties. This is necessary as a possible link to genotype-phenotype correlation in AIS, but also with respect to medical decision making in CAIS.

Nicotinamide phosphoribosyl transferase (NAMPT) is an inflammatory adipocytokine shown to interact in immune modulation in chronic inflammatory diseases, acute respiratory distress syndrome, sepsis, cancer and obesity in adulthood. It is, however, not clear whether this association reflects a chronic elevation or acute inflammatory response. We analyzed NAMPT concentrations in distinct states of inflammation in 102 children and found consistently significantly increased NAMPT levels in subjects with acute infections. NAMPT concentrations in children with stable chronic inflammatory diseases were not significantly different, whereas in patients with acute relapse of chronic disease NAMPT was significantly higher than in children in remission or healthy controls. In states of low-grade inflammation (children with atopic disease or obesity) we did not detect alterations in NAMPT serum levels. NAMPT correlated positively with inflammatory markers such as CRP. The most predictive factor for NAMPT serum concentrations was leucocyte count and therein the neutrophil count. Furthermore, systemic circulating NAMPT levels were closely associated with NAMPT release from corresponding cultured PBMCs. In conclusion, NAMPT is selectively increased in states of acute but not chronic inflammation in children. The close relationship between systemic circulating NAMPT with leucocyte counts and release indicate that leucocytes most probably are the source of inflammation related NAMPT levels.

Infants born small for gestational age (SGA) are at risk to develop metabolic complications. Insulin-like growth factor 1 (IGF-1) resistance due to IGF-1 receptor (IGF1R) mutations is a rare genetic condition that causes proportionate growth retardation. The contribution of an impaired IGF1R function to the development of comorbidities such as disturbed glucose homeostasis is not well understood. Genetic analysis and detailed auxological, endocrine and psychological investigations in two male SGA siblings were performed. The two patients and their father bear a novel heterozygous mutation (p.Cys1248Tyr) in the IGF1R gene. Both brothers displayed very similar growth pattern before and during recombinant human growth hormone treatment, whereas oral glucose tolerance tests showed variable manifestations of progressive impaired glucose tolerance. The father had already developed type 2 diabetes mellitus. Growth retardation in our patients is likely caused by the IGF1R mutation that might predispose to disturbances of carbohydrate homeostasis. Therefore, a close metabolic monitoring of affected patients is indicated, particularly if growth hormone therapy is commenced.