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Doctoral Thesis: “Unravelling the relevance of Plakophilin-2 and Olfactomedin-2 in obesity”

24 October 2024

This Tuesday 22/10/2024 at 11:00h  Ms. Aina Lluch Balaña, has made the reading of her doctoral thesis entitled: “Unravelling the relevance of Plakophilin-2 and Olfactomedin-2 in obesity” directed by Dr. Francisco José Ortega i el Dr. José Manuel Fernández-Real Lemos.

ABSTRACT

Obesity is a complex chronic disease linked to adipocyte dysfunction and a low-grade inflammatory condition leading to the impaired synthetic and secretory activity of hyperplastic depots of adipose tissue. As a consequence, obese subjects suffer from decreased life quality and expectancy and are more prone to metabolic disturbances. Bariatric surgery is a surgical intervention recognized for restoring metabolic homeostasis, while hampering systemic inflammation due to the loss of significant amounts of fat. In this context, the analysis of available results in human adipose tissue after surgery-induced weight loss highlighted the upregulation of two gene candidates previously unrecognized in the obesity arena: Plakophilin-2 (PKP2) and Olfactomedin-2 (OLFM2). PKP2 is a key component of desmosomes, which, when defective, is known to promote the fibro-fatty infiltration of heart muscle. OLFM2 is a pleiotropic glycoprotein with widespread but most notable expression in neural tissues, in which it is crucial for the mediation of developmental processes, also implicated in the regulation of energy homeostasis through its activity in the hypothalamus. Steaming from observations of increased PKP2 and OLFM2 in obese patients after significant weight loss, also endorsed by the analyses of additional adipose tissue samples conducted in obese and non-obese subjects, our results showed that their expression levels are inversely associated with weight. Mainly expressed in adipocytes, the steady increase observed during fat cell differentiation indicated that their presence could be crucial in the proper functioning of fat cells. As a matter of fact, adipogenesis was altered upon the partial lack of these molecules, as it happened when adipocytes were exposed to a pro-inflammatory milieu, emulating the context of obesity. Along the following pages, exhaustive analyses performed in human patient cohorts, including both longitudinal studies and cross-sectional samples, in vitro and in vivo empirical approaches, transcriptomics, proteomics and functional data are presented, unravelling a previously unknown biological role in adipose tissue and the clinical relevance of the armadillo-repeat protein PKP2 and the olfactomedin-domain containing protein OLFM2 in obesity. Defective PKP2 broke cell cycle dynamics and yielded premature senescence in adipocytes, a key rheostat for stress-induced adipose tissue dysfunction. Conversely, restoring PKP2 in inflamed adipocytes rewired E2F signalling towards the re-activation of cell cycle and decreased senescence. On the other hand, OLFM2 deficiency also conducted the downregulation of cell cycle-related genes, both in vitro an in vivo, and complementary analyses revealed the modulation of key metabolic and cellular pathways, including the regulation of citrate cycle, fatty acid degradation, axon guidance, and focal adhesion in fat cells.

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