Obesity is a significant risk factor for some of the major diseases of the last decades, such as type II
Diabetes, hypertension and some forms of cancer. Genetic predisposition is a key factor along with diet,
stage of development, physical activity and age. An important diagnostic role in the development of this
metabolic disorder is played by intestinal microbiome, which differs in the composition, above all an high
Firmicutes/Bacteroidetes ratio, between healthy and obese individuals. In particular, a decrease in the
bacteria producing butyrate (Roseburia spp. and Faecalibacterium prauznitzii) has been found in the gut
microbiota of patients with type II diabetes, compared to that of healthy individuals. The presence of F.
prauznitzii in the microbiota is normally associated to 2-Hydroxyisobutyrate (HIB), a cellular short-chain
fatty acid, also related to N-butyrate and detected at high levels in the urine of obese people. It results from
the microbial degradation of dietary proteins that escape digestion in the upper gastrointestinal tract.
Caenorhabditis elegans resulted to be a powerful model for studying the molecular mechanisms of signal
transduction pathways, such as the oxidative stress and IIS pathways, that influence several human diseases,
including diabetes. The availability of nematode mutant and transgenic strains allows analysing the pathway
involved in different disorders. High levels of reactive oxygen species (ROS) are intricately linked to obesity
and associated pathologies. The excess supply of energy substrates in obesity is believed to lead to increased
mitochondrial dysfunction and ROS signalling, which may underlie insulin resistance.
This project aims to identify the molecular and cellular mechanisms activated by the treatment of HIB
molecule in the model system C. elegans, with particular attention focused on aging process, oxidative stress
responses and lipid accumulation.
Obesity is a significant risk factor for some of the major diseases of the last decades, such as type II diabetes, hypertension and some forms of cancer (Pi-Sunyer, 2009). Genetic predisposition is a key factor along with diet, stage of development, physical activity and age. In the past years, molecular mechanisms involved in the aging process have been studied. The high homology between the genes of Caenorhabditis elegans and those implicated in human diseases makes the nematode an important model for the study of human pathologies. In C. elegans aging and lifespan are regulated by different pathways, among which the insulin/insulin-like growth factor-1 signalling. As an example, mutations in the gene encoding the DAF-2, the C. elegans homolog of the insulin/insulin-like growth factor-1 receptor, cause a prolonged lifespan in animals (Calvani et al., 2010). The signalling normally culminates with the inactivation of the transcriptional factor DAF-16. When activated, it allows the expression of genes involved in cellular stress response, metabolism and autophagy (Kim et al., 2019). Moreover, during aging free radicals, such as the reactive oxygen species (ROS), are produced in organisms, causing cellular damage. The accumulation of this damage normally correlates with lifespan. Furthermore, thanks to the transparency of C. elegans body, lipid droplets can be easily visualized through the use of fat-soluble dyes or with fluorescent compounds. It has been reported that of desaturases and elongases inactivation is associated with metabolic, physiological and behavioural phenotypes which can be a direct consequence of the alteration of the total lipid composition (Watts et al., 2000). Recent studies have suggested that the gut microbiota may have a role in obesity through the regulation of energy metabolism. Therefore, testing 2-hydroxyisobutyrate on nematodes physiology, could allow identification of molecular and cellular mechanisms, making this molecule potentially useful in the treatment of human diseases, such as diabetes. The nematode Caenorhabditis elegans is an excellent model for exploring the regulation of lipid metabolism because many human signaling, such as fats synthesis and ß-oxidation pathways, are conserved in worms.