2-hydroxyisobutyric acid (2-HIBA) modulates ageing and fat deposition in Caenorhabditis elegans

Emily Schifano; Giorgia Conta; Adele Preziosi; Carino Ferrante; Giovanni Batignani; Patrizia Mancini; Alberta Tomassini; Fabio Sciubba; Tullio Scopigno; Daniela Uccelletti; Alfredo Miccheli

doi:10.3389/fmolb.2022.986022

2-hydroxyisobutyric acid (2-HIBA) modulates ageing and fat deposition in Caenorhabditis elegans

Front Mol Biosci. 2022 Nov 23:9:986022. doi: 10.3389/fmolb.2022.986022. eCollection 2022.

Authors

Emily Schifano¹, Giorgia Conta^{2

3}, Adele Preziosi¹, Carino Ferrante^{4

5}, Giovanni Batignani^{4

5}, Patrizia Mancini⁶, Alberta Tomassini^{2

3}, Fabio Sciubba^{2

3}, Tullio Scopigno^{4

5}, Daniela Uccelletti¹, Alfredo Miccheli^{2

3}

Affiliations

¹ Department of Biology and Biotechnology "C. Darwin", Sapienza University of Rome, Rome, Italy.
² Department of Environmental Biology, Sapienza University of Rome, Rome, Italy.
³ NMR-based Metabolomics Laboratory of Sapienza (NMLab), Sapienza University of Rome, Rome, Italy.
⁴ Department of Physics, Sapienza University of Rome, Rome, Italy.
⁵ Center for Life Nano- and Neuro-science, Istituto Italiano di Tecnologia, Rome, Italy.
⁶ Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.

Abstract

High levels of 2-hydroxyisobutyric acid (2-HIBA) were found in urines of patients with obesity and hepatic steatosis, suggesting a potential involvement of this metabolite in clinical conditions. The gut microbial origin of 2-HIBA was hypothesized, however its actual origin and role in biological processes are still not clear. 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 and metabolomic analyses, Coherent Anti-Stokes Raman Scattering (CARS) and two-photon fluorescence microscopy. In standard conditions, 2-HIBA 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 and, consequently, through a reduction of ROS levels. Moreover, variations of lipid accumulation observed in treated worms correlated with transcriptional levels of fatty acid synthesis genes and with the involvement of peptide transporter PEP-2. In HGD conditions, the effect of 2-HIBA on C. elegans resulted in a reduction of the lipid droplets deposition, accordingly with an increase of acs-2 gene transcription, involved in β-oxidation processes. In addition, the pro-longevity effect appeared to be correlated to higher levels of tryptophan, which may play a role in restoring the decreased viability observed in the HGD untreated nematodes.

Keywords: 2-hydroxyisobutyric acid; CARS; Caenorhabditis elegans; ageing; high-glucose diet; lipid metabolism; metabolomics; oxidative stress.