Cacace, Giuseppe (2021) Understanding obesity: new insights from ANKRD26. [Tesi di dottorato]

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Mounting evidence sustains the role of DNA methylation in determining obesity as well as the down-stream adverse responses to increased BMI. Thus, identifying new players and mechanisms relevant to obesity and its related endo-phenotypes and understanding whether and how DNA methylation changes may affect these targets is of particular importance. My colleagues and I have recently recognized the Ankyrin repeat domain 26 (Ankrd26) gene as an interesting and proper target to study. This work aims to i. provide clearer evidence in humans of the cause-effect relationship between ANKRD26 gene expression and DNA methylation and investigate the correlation of these changes to obesity-related endo-phenotypes, unhealthy metabolic states and cardio-metabolic risk. Also, I aim to ii. establish in vitro the obesity-induced hypothalamic regulation of Ankrd26 gene in terms of DNA methylation changes, and clarify the role of the Ankrd26 protein on the hypothalamic regulation of anorexigenic signals in vitro. i. Hyper-methylation at three specific CpG sites within the ANKRD26 promoter causes down-regulation of its gene expression and represents a common abnormality in obese patients, particularly if metabolically unhealthy. Furthermore, these mRNA and DNA methylation changes of ANKRD26 gene correlate to increased Body Mass Index (BMI), and raised levels of both pro-inflammatory molecules and cardio-metabolic risk-related factors in humans. ii. Down-regulation of Ankrd26 mRNA and protein expression occur in the hypothalamus of diet-induced obese mice compared to lean control mice. These changes are associated to hyper-methylation of a specific CpG site in the gene promoter. Furthermore, Ankrd26 protein is up-regulated by the treatments with both the hormones, insulin and leptin, and the drug Exendin-4 in murine hypothalamic mHypoE-N46 cells. Also, over-expression of Ankrd26 modulates MAPK signaling and neuropeptide gene expression, by increasing the mRNA of the anorexigenic POMC and CART and decreasing the mRNA of the orexigenic AgRP, in mHypoE-N46-Ankrd26 cells. In conclusion, the results showed in my PhD thesis demonstrated that down-regulation of the ANKRD26 gene and hyper-methylation at specific CpGs of its promoter are common abnormalities in obesity and mark adverse health outcomes. Also, my data demonstrate that Ankrd26 protein might play a pivotal role in the regulation of energy homeostasis in vitro, acting as down-stream effector of anorexigenic signals in hypothalamic neuronal cells.

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