Therapeutic Potential of Dimethyl Fumarate for the Treatment of High-Fat/High-Sucrose Diet-Induced Obesity

Abstract

Obesity is characterized by an imbalance between energy intake and expenditure that triggers abnormal growth of adipose tissues. Dimethyl fumarate (DMF) and its primary active metabolite, monomethyl fumarate (MMF), are Nrf2 activators and have been recognized as strategic antioxidants. This study aimed to evaluate the potential of MMF and DMF to interfere with adipogenesis and obesity, and identify the molecular mechanisms involved. The 3T3-L1 preadipocytes were incubated with differentiation medium (MIX) and simultaneously treated with different concentrations of MMF. In addition, male C57BL/6 mice were fed a standard diet or high-fat/high-sucrose diet (HFHSD) for 16 weeks, during the last 4 of which, they received oral DMF treatment. Exposure to MMF prevented the development of MIX-induced adipogenesis by reducing the expression of transcription factors that drive adipocyte differentiation and by decreasing triglyceride levels. In addition, various antioxidant and anti-inflammatory effects were observed after treatment with MMF as evidenced by the modulation of transcription factor activities and reduction in reactive oxygen species, adipokine, proinflammatory cytokine and resistin levels. In vivo treatment with DMF reduced calorie intake, body weight, and visceral and subcutaneous fat mass in HFHSD mice. Furthermore, DMF administration led to a better glycemic response as well as lower leptin and adiponectin plasma levels in these animals. Our data demonstrate that DMF and its metabolite MMF interfere with adipogenesis and prevent the key features of diet-induced obesity. Considering DMF is already a commercial drug used to treat psoriasis and multiple sclerosis, its pharmacological application for the treatment of obesity and related metabolic disorders holds promise.