Rationale for Targeting Nrf2 to Reduce theMetabolic Risk: A Study in OverweightBoys and Rats Fed a Hypercaloric Diet

SANTILLAN, LUCAS; OLIVERA VARGAS, JA; GOMEZ MEJIBA, SE; SIEWERT, SUSANA; GIMENEZ, MARIA SOFIA; RAMIREZ, DARIO

BALTIMORE

Congreso; SFRBM 2017; 2017

SFRBM 2017

Rationale for Targeting Nrf2 to Reduce theMetabolic Risk: A Study in OverweightBoys and Rats Fed a Hypercaloric DietLucas D Santillan1, Jorge A Olivera Vargas1, Sandra EGomez Mejiba1, Maria S Gimenez1, Susana E Siewert2, andDario C. Ramirez11CONICET-UNSL, San Luis, Argentina2UNSL, San Luis, ArgentinaExcess of energy is metabolized to free fatty acids whichshould be stored as triglycerides (TG) otherwise they cancause inflammation, and thus a high risk for obesityassociatedmetabolic abnormalities. Nrf2 controls theexpression of phase II/III, antioxidant and adipogenic genes.Thus, low Nrf2 expression may determine inflammation anda high metabolic risk in overweight/obesity. To test thishypothesis we performed a study in overweight children andin an experimental model of rats fed a hypercaloric diet(HCD). In a population of overweight boys (OW, n=22) andnormal weight boys (NW, n=27) from San Luis City wemeasured clinical and biochemical parameters related tometabolic syndrome, including hypertension, insulinresistance, dyslipidemia, oxidative stress and inflammation.Compared to NW, OW boys had insulin resistance, higheratherogenic index, altered plasma lipid profile, increasedmarkers of oxidative stress and inflammatory lipid profile.Interestingly, plasma GPx activity and GSH/GSSG ratio andleukocyte Nrf2 expression were lower in those OW childrenat high metabolic risk. Nrf2 expression negatively correlateswith metabolic risk in OW boys. Experimentally we fed maleSD rats (n=19) for 16 weeks with a normocaloric (n=7) orHCD (n=12) and found that some rats fed the HCD wereobesity sensitive (OS, n=7) whereas the others were obesityresistant (OR, n=5). Compared to perirenal adipose tissueOS, OR rats showed a pattern of oxidative stress (increasedNOX-2, reduced antioxidant enzymes and increasedoxidative stress markers), and inflammation (increasedVCAM-1, TNF-a, and lipid profile); but reduced lipogenesis (low Nrf2, PPAR-γ, lipogenic enzyme gene expression, totallipids and TG). Low Nrf2 expression determines reducedadipogenesis, but increased metabolic risk. Interventionsaimed at increasing expression/activity of Nrf2 may providea strategy to reduce metabolic risk in overweight/obesepatients.Supported by: PICT-2014-3369, PROICO-23214 & PIP-916(to DCR and SEGM)DOI: 10.1016/j.freeradbiomed.2017.10.237