• Prof. Karine Clement. (Sorbonne Université / INSERM. NutriOmique Research group. Pitié-Salpêtrière Hospital)
• Prof. Joachim Fandrey (Institut für Physiologie. Universität Duisburg-Essen) 

Toward a Precision Medicine Approach in Severe Early-Onset Obesity: Targeting the Leptin-Melanocortin Pathway

Recent advancements in understanding the genetics of obesity have brought to light monogenic forms resulting from single gene mutations. Despite their rarity, these conditions often present severe phenotypes and hyperphagia, particularly in early childhood, sometimes accompanied by additional symptoms such as endocrine deficiency. Multidisciplinary approaches are crucial for effectively managing patients with these complex disorders. A significant focus has been on the hypothalamic leptin-melanocortin pathway. Bi-allelic variants upstream of the MC4R gene particularly contribute to these early-onset and severe forms of obesity. In this context, pharmacological developments of MC4R agonists (e.g., setmelanotide) have demonstrated that pharmacologically treating patients with functional alterations of the leptin-melanocortin pathway can improve patient conditions, with significant weight loss observed, especially in those with POMC, PCSK1, and LEPR variants. Reductions in hunger scores indicate potential improvements in eating behaviors, and treated patients exhibit an improved quality of life. The indications for setmelanotide treatment have recently been extended to include Bardet Biedl syndrome (BBS) and hypothalamic obesity due to tumors. The expansion of precision treatments in this context further underscores the importance of precision medicine in addressing the challenges of genetic obesity. 

Inflammatory Hypoxia – when the bad meets the evil

Cells of the immune defense, especially leukocytes, often have to perform their function in tissue areas that are characterized by oxygen deficiency, so called hypoxia. Hypoxia significantly affects leukocyte function and controls the innate and adaptive immune response mainly through transcriptional gene regulation via the hypoxia-inducible factors (HIFs). Hypoxia is also a hallmark of inflamed tissue when malperfusion due to tissue edema, increased cellularity with higher oxygen consumption contribute to the severity of inflammatory hypoxia. Here, HIF pathway activation enables immune cells to adapt to both, hypoxic environments in physiological and inflammatory settings and modulates immune cell responses through metabolism changes and cross talk with other immune-relevant signalling pathways.