12:00 – 12:30 Jaime Navarro Pérez

Role of Pla2g6 in adipocytes differentiation and function

Obesity is a significant risk factor for metabolic and cardiovascular complications. While most research aims to understand why obese people develop comorbidities, our lab investigates the opposite paradigm, why some obese people are resilient to develop comorbidities. One of the most widely accepted hypotheses about adipose tissue dysfunction in obese people is the adipose tissue expandability hypothesis. During the formation of adipose tissue (adipogenesis), alterations occur in the progenitors that prevent the cells from increasing in number (hyperplasia), and therefore increase in size (hypertrophy), favouring a state of chronic inflammation and insulin resistance, which favours the development of associated comorbidities. Hence, to understand the molecular mechanisms uncoupling excess adiposity from the development of metabolic complications we will characterise the role of the candidate gene Pla2g6, previously identified in a genome-wide cross-phenotype meta-analysis of adiposity-cardiometabolic trait pairs, in adipocyte differentiation and function. To address this, firstly, we performed a gene expression profiling of Pla2g6 using the GEO repository to look at the expression levels in physiological and pathophysiological conditions. In in vitro datasets, we observed that Pla2g6 expression increases along the differentiation from preadipocytes to mature adipocytes. In a human adipose tissue dataset, its expression is significantly decreased in white adipose tissue from metabolically unhealthy human individuals vs metabolically healthy and lean controls. Similarly, in vivo, in mice, the profiling of Pla2g6 reveals its upregulation in white adipose tissue of 4-weeks ob/ob mice group (healthy obesity model); and a generalised downregulation in the white adipose tissue of a mouse model of impaired white adipose tissue expansion impairment (POKO mice) vs the wild-type group. Next, we have developed an in vitro model of adipogenesis, to study the effects of the loss of Pla2g6 in the differentiation process, using a CRISPR-Cas9 KO approach in the 3T3L1 pre-adipocyte cell line. Our findings show that Pla2g6-KO cells show a significantly reduced differentiation potential vs control. They display a decreased capability to accumulate lipids, reduced expression of adipogenic genes (i.e Pparg2 and aP2), maturation markers (i.e Plin1) as well as de novo lipogenesis genes (i.e Srebp1c, Scd1 and Fasn). The depletion of Pla2g6 also affected the proliferation and morphology of the cells which shape is different from the control ones. Altogether, our research provides a potential novel role for Pla2g6 in adipose tissue expansion and further characterization is needed to understand its exact function.

12:30 – 13:00 Blanca Escriche Navarro

New therapeutic strategies targeting senescent cells

Cellular senescence is an irreversible process of cell cycle arrest triggered by various stress signals to prevent the propagation of damaged cells. However, the persistent presence of senescent cells (SCs) can promote a dysregulated inflammatory environment that can result in tissue dysfunction, contributing to the onset and progression of multiple age-related disorders. In this context, the elimination of SCs has emerged as an effective therapeutic strategy. However, a challenging factor is that the senescent phenotype is highly heterogeneous, which hinders the discovery of a universal and robust senescence biomarker and contributes to the fact that developed senescence therapies have a highly variable response in the clinic, with off-target toxic effects. Here, we have developed two nanodevices loaded with the senolytic navitoclax and a BODIPY-based photosensitizer for selective removal of SCs targeting different biomarkers of cellular senescence, such as overexpression of the cell membrane receptor dipeptidyl peptidase-4 (DPP4), matrix metalloproteinase-3 (MMP-3) and senescence-associated β-galactosidase (SA-β-gal). In vitro and in vivo results demonstrate the potential application of the three developed systems by achieving a selective elimination of SCs with clinical relevance.