👤 E Blond

Obesity is a multifactorial disease with a strong genetic component. It is imperative to enhance the identification of genetic variations in their early and severe manifestations in order to facilitate the development of personalized therapeutic strategies, informed clinical care, and the facilitation of genetic counseling. The objective of the study was to provide a comprehensive description of rare variations identified by next generation sequencing of a panel of genes. From 2018 to 2023, a panel of 22 genes was genotyped in 1066 probands (499 children and 567 adults) with severe early-onset obesity. The genetic study led to a molecular diagnosis in 34 probands (3.2%) and revealed variants of unknown significance (VUS) in 10.3% of cases. In the pediatric cohort, a genetic diagnosis was established in 19 probands (3.8%) and a VUS was identified in 67 (13.4%). A total of 152 rare single-nucleotides variants (SNVs) were identified, of which 34 were classified as pathogenic, predominantly within the Early genetic screening in severe obesity provides valuable diagnostic insights and identifies candidates for personalized treatment. The integration of genetics into clinical practice is imperative for the enhancement of care pathways and the facilitation of targeted therapeutic strategies. Show less

Type 2 diabetes mellitus (T2DM), characterized by hyperglycemia and dyslipidemia, leads to nonproliferative diabetic retinopathy (NPDR). NPDR is associated with blood-retina barrier disruption, plasma exudates, microvascular degeneration, elevated inflammatory cytokine levels, and monocyte (Mo) infiltration. Whether and how the diabetes-associated changes in plasma lipid and carbohydrate levels modify Mo differentiation remains unknown. Here, we show that mononuclear phagocytes (MPs) in areas of vascular leakage in DR donor retinas expressed perilipin 2 (PLIN2), a marker of intracellular lipid load. Strong upregulation of PLIN2 was also observed when healthy donor Mos were treated with plasma from patients with T2DM or with palmitate concentrations typical of those found in T2DM plasma, but not under high-glucose conditions. PLIN2 expression correlated with the expression of other key genes involved in lipid metabolism (ACADVL, PDK4) and the DR biomarkers ANGPTL4 and CXCL8. Mechanistically, we show that lipid-exposed MPs induced capillary degeneration in ex vivo explants that was inhibited by pharmaceutical inhibition of PPARγ signaling. Our study reveals a mechanism linking dyslipidemia-induced MP polarization to the increased inflammatory cytokine levels and microvascular degeneration that characterize NPDR. This study provides comprehensive insights into the glycemia-independent activation of Mos in T2DM and identifies MP PPARγ as a target for inhibition of lipid-activated MPs in DR. Show less