Searchable abstracts of presentations at key conferences in endocrinology

ea0049s24.1 | Obesity: Pharmacological solutions | ECE2017

MSH analogs

Kuhnen Peter

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...

ea0084ps2-09-86 | Thyroid Hormone ACTION | ETA2022

Quantification of CD5L as circulating marker of peripheral thyroid hormone action

Asaad Sabrina , Chillon Thilo , Minich Waldemar , Kuhnen Peter , Mittag Jens , Schomburg Lutz

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...

ea0092op-02-02 | Oral Session 2: Thyroid hormone action in the brain | ETA2023

Development of an image-based method for spatial registration of T3-induced changes in cell types and gene expression in human cerebral organoids

Bresser Audrey , Obermayer-Wasserscheid Benedikt , Megges Matthias , Fernandez-Vallone Valeria , Stachelscheid Harald , Kuhnen Peter , Opitz Robert

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...

ea0099ep57 | Diabetes, Obesity, Metabolism and Nutrition | ECE2024

Impact of setmelanotide on metabolic syndrome risk in patients with POMC and LEPR deficiency

Wabitsch Martin , Chung Wendy , Kuhnen Peter , Swain James , Garrison Jill , Touchot Nicolas , Argente Jesus , Clement Karine

Background: Proopiomelanocortin (POMC; including biallelic variants in PCSK1) and leptin receptor (LEPR) deficiency are associated with hyperphagia and early-onset, severe obesity. Treatment with the melanocortin-4 receptor agonist setmelanotide for 1 year results in significant and sustained improvements in weight (POMC, −25.6%; LEPR, −12.5%), hunger, and quality of life. We used the metabolic syndrome Z score based on body mass index (MetS-Z-BMI) to asse...

ea0084op-13-67 | Oral Session 13: Basic 3 | ETA2022

A single cell atlas of the T3-responsive transcriptome during early cortical neurogenesis in human cerebral organoids

Opitz Robert , Fernandez-Vallone Valeria , Megges Matthias , Amber Julie Bresser Audrey , Obermayer-Wasserscheid Benedikt , Stachelscheid Harald , Kuhnen Peter

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...

ea0084ps1-04-35 | Thyroid Hormone Transporters and Development | ETA2022

Spatiotemporal expression of the thyroid hormone transporter MCT8 during cortical neurogenesis in human cerebral organoids

Graffunder Adina , Amber Julie Bresser Audrey , Anthofer Larissa , Megges Matthias , Fernandez-Vallone Valeria , Stachelscheid Harald , Kuhnen Peter , Opitz Robert

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...

ea0090p66 | Diabetes, Obesity, Metabolism and Nutrition | ECE2023

Weight Outcomes With Setmelanotide Over 3 Years in Patients With POMC or LEPR Deficiency Obesity

Clement Karine , Wabitsch Martin , van den Akker Erica , Argente Jesus , Navarria Andrea , Srinivasan Madhura , Yuan Guojun , Malhotra Sonali , Kuhnen Peter

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...

ea0090p613 | Diabetes, Obesity, Metabolism and Nutrition | ECE2023

Long-term Body Composition in Patients With POMC or LEPR Deficiency Obesity Following Setmelanotide

Clement Karine , Wabitsch Martin , van den Akker Erica , Argente Jesus , Navarria Andrea , Srinivasan Madhura , Yuan Guojun , Malhotra Sonali , Kuhnen Peter

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...

ea0084ps2-09-81 | Thyroid Hormone ACTION | ETA2022

An experimental framework for probing molecular mechanisms of local thyroid hormone action during cortical neurogenesis in human cerebral organoids

Amber Julie Bresser Audrey , Graffunder Adina , Anthofer Larissa , Megges Matthias , Obermayer-Wasserscheid Benedikt , Rijntjes Eddy , Wiese Niklas , Fernandez-Vallone Valeria , Stachelscheid Harald , Kuhnen Peter , Opitz Robert

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...

ea0099ep5 | Diabetes, Obesity, Metabolism and Nutrition | ECE2024

4-year setmelanotide weight outcomes of patients with POMC and LEPR deficiency obesity

Chung Wendy , Swain James , Kuhnen Peter , Wabitsch Martin , van den Akker Erica , Garrison Jill , Yuan Guojun , Argente Jesus , Clement Karine , Farooqi Sadaf

Background: Patients with proopiomelanocortin (POMC; including variants in POMC or PCSK1) or leptin receptor (LEPR) deficiency due to biallelic gene variants have impaired melanocortin-4 receptor signaling that leads to hyperphagia and early-onset, severe obesity. Setmelanotide treatment in this population improved weight-related measures and hunger severity and was well tolerated. Reported here are long-term extension (LTE) outcomes after 4 years of setmelan...