IN SILICO SCREENING AND IN VIVO TESTING OF NITRONE COMPOUNDS TO REDUCE INSULIN RESISTANCE IN A MOUSE MODEL OF DIET-INDUCED OBESITY

INALEN DEL V. CHACON,; CARLA F. GUZMAN1, ; FLORENCIA S. BARRERA; CRISTOFER M. LOPEZ; JONATHAN M. RAMIREZ; JUAN GARRO; LUCILA RIVERO; IVANA MORALE; SONIA BARBIERIS4,; PAULO COSTA; DEBORA COSTA; DARIO C. RAMIREZ,[B, C]; SANDRA E. GOMEZ MEJIBA

Congreso; SAIC; 2024

Obesity is the result of a chronic positive energy balance that resultsin circulating free fatty acids (FFAs) which can activate macrophagestriggering adipose tissue (AT) inflammation. Together with AT andmuscle, the liver is one of the main organs that control systemicinsulin sensitivity. Both, FFAs and AT-derived inflammation mediatorsare responsible for systemic inflammation and insulin resistance(IR), respectively, in obesity. Nitrone compounds can act as agonistsof the Nrf2 pathway facilitating the storage of FFAs as triglycerides,thus reducing AT- and systemic-inflammation and thus improving IR.Computational chemistry can predict leading structures of a certainspecific biological activity, thus guiding experimental research. Inthis research, we aimed to screen using in silico methods, syntheticnitrone compounds that can activate the Nrf2 signaling pathway.Interestingly, our in silico studies predicted that the nitrone LQB122has a similar Nrf2 agonist activity to sulforaphane—a well-knownNrf2 signaling agonist. Our in vitro studies showed that LQB122did not cause toxicity in 3T3.L1 cells. Then, we aimed to test thecompound in a diet-induced obesity mouse model for its anti-inflammatoryand insulin-sensitizing effects. To achieve this goal, we fedmale C57 mice with a control (CoD, rodent chow, and tap water) oran obesogenic (ObD, 22% bovine fat + 10% fructose in drinking water)diet for 24 weeks. At 23 weeks, a group of CoD and ObD wereinjected (i.p.) with either saline or saline containing the LQB122 nitrone(0.125nmol/50ul/g) for the remaining week of the dietary regime.The nitrone did not cause significant oxido-inflammatory ormetabolic changes in CoD mice, however, LQB122 reduced hepaticneutrophilic inflammation and systemic inflammation, and improvedinsulin sensitivity in the ObD mice. LQB122 can serve as a structuralplatform for the design of novel mechanism-based drugs to reduceIR and maybe other obesity-associated metabolic abnormalities.