Fiona Gribble: Incretins

Professor Fiona Gribble from the University of Cambridge opened the event with a comprehensive talk on the role of gut hormones in metabolism regulation and their therapeutic potential. She emphasized the incretin effect, where active GLP-1 is released by intestinal L-cells but not by pancreatic alpha cells, which release glucagon. This distinction is crucial for understanding different treatments for diabetes and obesity, including:

• Semaglutide: A GLP-1 agonist used to treat obesity and diabetes.
• Tirzepatide (Eli Lilly, Mounjaro): GLP1R/GIPR agonists that show better effects on body weight loss and HbA1c levels.
• Retatrutide: A GLP-1/GIP/glucagon triple agonist, currently in clinical trials, showing promising efficiency.

Prof. Gribble also discussed the role of enteroendocrine cells, which secrete GLP-1 and other hormones depending on their location in the gut. She highlighted the importance of SLC5A1 expression in L cells and the use of SGLT1 knockout mice organoids to demonstrate the glucose-sensing function of SGLT1. Additionally, she noted that bile acids are absorbed by enterocytes and sensed by endocrine cells at the basolateral membrane, rather than being directly absorbed by the endocrine cells. This mechanism is crucial for understanding how hormones like INSL5 are regulated.

Marta Korbonits: Genes and giants

Professor Marta Korbonits from Queen Mary University of London explored the genetic causes of pituitary neuroendocrine tumors (PitNETS) and their link to gigantism. She detailed the role of AIP gene mutations in acromegaloid giantism, noting that most mutations are loss-of-function. Korbonits explained that AIP genes are highly conserved, and when knocked out in fruit flies, the flies are non-viable. However, this can be rescued by adding human AIP gene expression, making it a valuable model for analyzing human mutations.

Prof. Korbonits also discussed X-linked acrogigantism caused by GPR101 gene duplication and the use of Pegvisomant to treat overgrowth. She highlighted the presence of R304 stop mutations in GPR101 in multiple families in Northern Ireland.

Ali Abbara: Kisspeptin

Dr. Ali Abbara from Imperial College London presented his research on kisspeptin and its role in puberty and reproductive health. He explained how kisspeptin stimulates GnRH secretion, influencing LH levels and ovulation. Kisspeptin has potential in differentiating functional and genetic hypogonadism. He also discussed the development of MVT-602, a long-lasting kisspeptin-10, and its potential applications.

Grigorios Panigiotou: Remote metabolic monitoring

Dr. Grigorios Panigiotou discussed the development of remote metabolic monitoring tools, recommending anthropometry over BMI for body composition measurement. He introduced a new app for body composition analysis, highlighting its potential for improving metabolic monitoring. Dr Panigiotou emphasized the importance of accurate body composition measurement in managing metabolic health.

Miguel Ruiz-Cruz: miRNA biomarkers for pediatric obesity

Dr. Miguel Ruiz-Cruz shared his research on miRNA as biomarkers for pediatric obesity, identifying correlations between different miRNA and metabolic markers.

Sofia Aliotta: GLP1R agonists

Dr. Sofia Aliotta focused on the effects of GLP1R agonists on hormone levels and gastrointestinal symptoms in treated patients. She emphasized the role of motilin and its gastrointestinal effects, providing insights into how GLP1R agonists can be used to manage these symptoms.

Johannes Kohl: Hormonal control of neuronal circuits and behavior

Dr. Johannes Kohl from the Francis Crick Institute discussed hormonal control of neuronal circuits during pregnancy and its impact on maternal behavior. Studies have revealed that mouse mothers exhibit maternal behavior from day 14 of pregnancy until day 50, indicating that this behavior is not solely hormone-driven. MRI scans of pregnant vs non-pregnant mice have shown region-specific brain volume changes during pregnancy. FISH analysis has implicated Esr1 in the onset of parenting; knocking out Esr1 from the MPOA region abolishes parenting onset.

David Gershlick: Membrane trafficking defects of leptin variants

Dr. David Gershlick from the University of Cambridge discussed membrane trafficking defects in leptin variants. He explained the use of RUSH (Retention Using Selective Hooks) to synchronize ER exports and analyze leptin mutations. Gershlick highlighted the impact of misfolding and degradation on leptin secretion, noting that some mutations lead to decreased expression due to mRNA degradation. He discussed the S141C mutation, which results in slower leptin secretion compared to wild-type or other mutants, and how this can be recovered with an alanine substitution (S141A).