Endocrine Abstracts

The leptin-melanocortin signaling pathway plays a pivotal role in the regulation of body weight within the hypothalamus. Leptin, secreted by the adipose tissue, activates the leptin receptor at the arcuate nucleus, which in turn leads to the production of proopiomelanocortin (POMC) derived peptides as melanocyte stimulating hormone (MSH). MSH activates the melanocortin 4 receptor (MC4R), regulating thereby satiety and energy expenditure. Mutations within this pathway are leadi...

The quantification of TSH from a serum or plasma sample constitutes the cornerstone of assessing the thyroid axis in the clinical routine. In addition, T4 and/or T3 levels may be determined to diagnose pathological conditions. However, these data do not necessarily reflect the local action of thyroid hormone in the target tissues and are sensitive to distortion, as best known from pregnancy when chorionic gonadotropin disturbs the regular feedback control. Recently, we identif...

Thyroid hormone (TH) signaling is essential for nervous system development. The clinical relevance of this simple statement is underscored by the severe neurological phenotypes resulting from global TH deficiency or perturbed local TH signaling during fetal development. A major aim of our research is to better understand the local action of TH during early human cortex development using cerebral organoids derived from human induced pluripotent stem cells (hiPSC) as a model sys...

Perturbation of thyroid hormone (TH) function during prenatal brain development can cause a spectrum of neurological disorders as evident in pediatric patients with untreated congenital hypothyroidism or patients with mutations in THRA and SLC16A2 genes. However, scarcity and inaccessibility of human brain tissue from early developmental stages has been a major roadblock for experimental approaches to decipher local TH action in early development. Advanced <e...

Thyroid hormones (TH) play a critical role during nervous system development and patients carrying coding variants of THRA or SLC16A2/MCT8 genes present a spectrum of neurological phenotypes presumably resulting from perturbed local TH action during early brain development. Monocarboxylate transporter MCT8 is a well-characterized TH membrane transporter and MCT8 mutations have been associated with the Allan-Herndon-Dudley Syndrome. Recent advances in stem cel...

Background: Rare variants in the melanocortin-4 receptor (MC4R) pathway are associated with early-onset, severe obesity and hyperphagia. Setmelanotide, an MC4R agonist, reduced body mass index (BMI) and decreased hunger in patients with obesity due to biallelic variants in genes encoding proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) in Phase 3 trials. The current analysis assesses the durability of setmelanotide ef...

Objective: Ideally, treatment strategies designed to reduce weight or body mass index in patients with obesity should reduce fat mass while preserving lean mass because reduced lean mass can negatively impact overall health and energy expenditure, thus favoring weight regain. In Phase 3 trials, 1 year of treatment with the melanocortin-4 receptor agonist setmelanotide led to weight reduction in patients with obesity due to biallelic variants in the genes encoding proopiomelano...

Recently, human cerebral organoids (hCOs) emerged as powerful three-dimensional in vitro models recapitulating key aspects of early human cerebral cortex development. Improved protocols for hCO generation from induced pluripotent stem cells (hiPSC) paved the way for new disease modeling approaches and enable multimodal analyses of perturbed neurogenesis resulting from manipulation of signaling pathways or gene function. These prospects prompted us to adopt this techno...