Rationale for Targeting Nrf2 to Reduce the Metabolic Risk: A Study in Overweight Boys and Rats Fed a Hypercaloric Diet

Excess of energy is metabolized to free fatty acids which should be stored as triglycerides (TG) otherwise they can cause inflammation, and thus a high risk for obesity-associated metabolic abnormalities. Nrf2 controls the expression of phase II/III, antioxidant and adipogenic genes. Thus, low Nrf2 expression may determine inflammation and a high metabolic risk in overweight/obesity. To test this hypothesis we performed a study in overweight children and in an experimental model of rats fed a hypercaloric diet (HCD). In a population of overweight boys (OW, n=22) and normal weight boys (NW, n=27) from San Luis City we measured clinical and biochemical parameters related to metabolic syndrome, including hypertension, insulin resistance, dyslipidemia, oxidative stress and inflammation. Compared to NW, OW boys had insulin resistance, higher atherogenic index, altered plasma lipid profile, increased markers of oxidative stress and inflammatory lipid profile. Interestingly, plasma GPx activity and GSH/GSSG ratio and leukocyte Nrf2 expression were lower in those OW children at high metabolic risk. Nrf2 expression negatively correlates with metabolic risk in OW boys. Experimentally we fed male SD rats (n=19) for 16 weeks with a normocaloric (n=7) or HCD (n=12) and found that some rats fed the HCD were obesity sensitive (OS, n=7) whereas the others were obesity resistant (OR, n=5). Compared to perirenal adipose tissue OS, OR rats showed a pattern of oxidative stress (increased NOX-2, reduced antioxidant enzymes and increased oxidative stress markers), and inflammation (increased VCAM-1, TNF-a, and lipid profile); but reduced lipogenesis (low Nrf2, PPAR-γ, lipogenic enzyme gene expression, total lipids and TG). Low Nrf2 expression determines reduced adipogenesis, but increased metabolic risk. Interventions aimed at increasing expression/activity of Nrf2 may provide a strategy to reduce metabolic risk in overweight/obese patients.