Dottorato in BIOLOGIA CELLULARE E DELLO SVILUPPO

Titolo della tesi: 2-hydroxyisobutyric acid (2-HIBA) modulates ageing and fat deposition in C.elegans animal model

2-hydroxyisobutyric acid (2-HIBA) is a metabolite found in human urine. Recent studies have shown that 2-HIBA levels increased in patients with obesity and hepatic steatosis, suggesting that it could potentially be involved in clinical conditions. 2-HIBA is associated with reduced bacterial diversity and the presence of F. prausnitzii in obese gut microbiota. We investigated how treatment with 2-HIBA affected the physiology of the model organism Caenorhabditis elegans, in both standard and High-Glucose Diet (HGD) growth conditions, by targeted transcriptomic, metabolomic analyses, Coherent Anti-Stokes Raman Scattering (CARS) and two-photon fluorescence microscopy. 2-HIBA in both conditions resulted particularly effective to extend the lifespan, delay ageing processes and stimulate the oxidative stress resistance in wild type nematodes through the activation of insulin/IGF-1 signaling (IIS), and p38 MAPK pathways. Lifespan extension was mediated by activation of SKN-1 transcriptional factor and moreover by peptide transporter PEP-2. 2-HIBA pro-longevity effect on C. elegans, appeared to be correlated to increase in tryptophan levels as a consequence of a reduced expression of 2,3-dioxygenase (TDO) in treated animals. On the other hand, 2-HIBA influenced lipid metabolism in independently manner; in No-GD worms 2-HIBA induced an increase in lipid droplets which instead decreased in HGD conditions suggesting the activation of different pathways. Therefore, this study represents a first step in understanding the impact of 2-HIBA on C.elegans animal model.