Neural control of feeding by malonyl-CoA using Caenorhabditis elegans as a model system

GARNERO, M.P; DE MENDOZA, D; MANSILLA, MC

Valparaiso

Congreso; Third Latin American Worm meeting; 2023

Obesity is an increasingly serious problem worldwide, and the few drugs available to treat and prevent the disease have severe side effects. Therefore, it is of great interest to elucidate the mechanisms that control appetite and body weight, to develop new therapies.In mammals, changes in hypothalamic malonyl-CoA concentration have been postulated to contribute to regulation of appetite control. To determine if a similar behavior occurs in worms, we modified malonyl-CoA concentration using the mycotoxin cerulenin or RNAi knockdowns. Malonyl-CoA is a precursor of fatty acid biosynthesis, so the inhibition of Fatty Acid Synthase (FAS) increases its concentration. Cerulenin binds covalently to a cysteine residue in the active site of the eukaryotic FAS I ketoacyl synthase domain, blocking the interaction of the enzyme with malonyl-CoA. We have shown that cerulenin affects the development of C. elegans, causing the arrest of the worms in early larval stages. To determine if the feeding behavior of the worms responds to concentrations of malonyl-CoA, we evaluated their rate of food intake by measuring the pharyngeal pumping of young adult worms treated with different concentrations of the mycotoxin. In all cases we observed lower rates of pharyngeal pumping in treated worms than in untreated ones. Furthermore, RNAi assays to block neuronal FAS I expression showed a similar decrease in pump rates.These results suggest that an increase in neuronal malonyl-CoA leads to a decreased feeding rate, indicating that this nematode could be a valuable model to contribute to the understanding of homologous processes in mammals.