In silico screening and in vivo testing of nitrone compounds to reduce insulin resistance in a mouse model of diet-induced obesity

INALEN CHACON ; CARLA FLORENCIA GUZMAN; FLORENCIA BARRERA; CRISTOFER MARTÍN LOPEZ ; JONATHAN M. RAMIREZ ; LUCILA RIVEROS; IVANA MORALES; SONIA ESTHER BARBERIS; JUAN GARRO; AYRES GUIMARAES DIAS; DÉBORA DE SOUZA DOS SANTOS COSTA; DARIO C RAMIREZ; GOMEZ MEJIBA, SANDRA;

Congreso; SOCIETY OF FREE RADICAL BIOLOGY AND MEDICINE; 2024

Obesity is the result of a chronic-positive energy balance that results in circulating free fatty acids(FFAs) which can activate macrophages, triggering adipose tissue (AT) inflammation. Togetherwith AT and muscle, the liver is one of the main organs that control systemic insulin sensitivity.Both, FFAs and AT-derived inflammation mediators are responsible for systemic inflammation andinsulin resistance (IR), respectively, in obesity. Nitrone compounds can act as agonists of the Nrf2pathway, facilitating the storage of FFAs as triglycerides, thus reducing AT- andsystemic-inflammation and thus improving IR. Computational chemistry can predict leadingstructures of a certain specific biological activity, thus guiding experimental research. In thisresearch, we aimed to screen, using in silico methods, synthetic nitrone compounds that can activatethe Nrf2 signaling pathway. Interestingly, our in silico studies predicted that the nitrone LQB122has a similar Nrf2 agonist activity to sulforaphane—a well-known Nrf2 signaling agonist. Our invitro studies showed that LQB122 did not cause toxicity in 3T3.L1 cells. Then, we aimed to test thecompound in a diet-induced obesity mouse model for its anti-inflammatory and insulin-sensitizingeffects. To achieve this goal, we fed male C57 mice with a control (CoD, rodent chow, and tapwater) or an obesogenic (ObD, 22% bovine fat + 10% fructose in drinking water) diet for 24 weeks.At 23 weeks, a group of CoD and ObD were injected (i.p.) with either saline or saline containing theLQB122 nitrone (0.125nmol/50ul/g body weight) for the remaining week of the dietary regime. Thenitrone did not cause significant oxido-inflammatory or metabolic changes in CoD mice, however,LQB122 reduced hepatic neutrophilic inflammation and systemic inflammation, and improvedinsulin sensitivity in the ObD mice. LQB122 can serve as a structural platform for the design ofnovel mechanism-based drugs to reduce IR and other obesity-associated metabolic abnormalities