- USING NITRONE COMPOUNDS TO IMPROVE INSULIN SENSITIVITY IN A MOUSE MODEL OF DIET-INDUCED OBESITY

CHACON I DEL V ; GUZMAN CF; BARRERA FS; RAMIREZ JM; GARRO JC; RIVERO L; MORALES I; BARBIERI, S; COSTA P; COSTA D; RAMIREZ DC; GOMEZ MEJIBA S

san luis

Congreso; SBC; 2024

USING NITRONE COMPOUNDS TO IMPROVE INSULIN SENSITIVITY IN A MOUSE MODEL OF DIET-INDUCED OBESITYChacon I del V 1, Guzman CF. 1, Barrera FS. 2, Ramirez JM. 1,2, Garro JC3, Rivero L 4, Morales I 4, Barbieris S 4, Costa P5, Costa D5, Ramirez DC. 1, Gomez Mejiba SE. 21Laboratory of Experimental and Translational Medicine IMIBIO-SL CONICET, 2Laboratory of Nutrition and Experimental Therapeutics IMIBIO-SL CONICET, 3Laboratory of Medicinal Chemistry, 4Laboratory of Bromatology. CCT-San Luis-National University of San Luis, San Luis, 5700 San Luis, 5Universidad Federativa de Rio de Janeiro, Rio de Janiero, Brazil. E-mail:inachacon55@gmail.comObesity 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. Together with 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 and insulin resistance (IR), respectively, in obesity. Nitrone compounds can act as agonists of 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 certain specific biological activity, thus guiding experimental research. In this research, we aimed to screen using in silico methods, synthetic nitrone compounds that can activate the Nrf2 signaling pathway. Interestingly, our in silico studies predicted that the nitrone LQB122 has a similar Nrf2 agonist activity to sulforaphane—a well-known Nrf2 signaling agonist. Our in vitro studies showed that LQB122 did not cause toxicity in 3T3.L1 cells. Then, we aimed to test the compound in a diet-induced obesity mouse model for its anti-inflammatory and insulin-sensitizing effects. To achieve this goal, we fed male C57 mice with a control (CoD, rodent chow, and tap water) 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 the LQB122 nitrone (0.125nmol/50ul/g) for the remaining week of the dietary regime. The nitrone did not cause significant oxido-inflammatory or metabolic changes in CoD mice, however, LQB122 reduced hepatic neutrophilic inflammation and systemic inflammation, and improved insulin sensitivity in the ObD mice. LQB122 can serve as a structural platform for the design of novel mechanism-based drugs to reduce IR and maybe other obesity-associated metabolic abnormalities