The Role of the Nrf2 Signaling in Obesity and Insulin Resistance

Abstract

Obesity, a metabolic disorder characterized by excessive accumulation of adipose tissue, has globally become an increasingly prevalent disease. Extensive studies have been conducted to elucidate the underlying mechanism of the development of obesity. In particular, the close association of inflammation and oxidative stress with obesity has become increasingly evident. Obesity has been shown to exhibit augmented levels of circulating proinflammatory cytokines, which have been associated with the activation of pathways linked with inflammation-induced insulin resistance, a major pathological component of obesity and several other metabolic disorders. Oxidative stress, in addition to its role in stimulating adipose differentiation, which directly triggers obesity, is considered to feed into this pathway, further aggravating insulin resistance. Nuclear factor E2 related factor 2 (Nrf2) is a basic leucine zipper transcription factor that is activated in response to inflammation and oxidative stress, and responds by increasing antioxidant transcription levels. Therefore, Nrf2 has emerged as a critical new target for combating insulin resistance and subsequently, obesity. However, the effects of Nrf2 on insulin resistance and obesity are controversial. This review focuses on the current state of research on the interplay of inflammation and oxidative stress in obesity, the role of the Nrf2 pathway in obesity and insulin resistance, and the potential use of Nrf2 activators for the treatment of insulin resistance.

Redox regulation of the insulin signalling pathway

“…Prolonged activation of NRF2 may also result in metabolic changes as NADPH-generating enzymes are targets of NRF2. Therefore, NRF2 acts as a direct link between redox homeostasis and energy metabolism [ 137 ]. NRF2 tightly controls GSH biosynthesis by regulating the expression of two GCL subunits, which catalyses the rate-limiting step of GSH biosynthesis, namely the reaction of glutamate with cysteine [ 138 ].…”

The Good and Bad of Nrf2: An Update in Cancer and New Perspectives in COVID-19

“…A recent study has demonstrated that the inhibition of Nrf2 signalling could significantly promote the incidence of type I diabetes mellitus, and, on the other hand, its reactivation reduces oxidative stress in pancreatic β-cells [ 143 ]. At the same time, the absence of Nrf2 protects from insulin resistance in long-term high-fat diet feeding by decreasing adipose tissue inflammation [ 144 , 145 ].…”

A Role of Stress Sensor Nrf2 in Stimulating Thermogenesis and Energy Expenditure

“…Recently, it was described that Nrf2 plays a role in controlling adipogenesis [ 73 , 81 , 82 , 83 , 84 , 85 , 86 ]. Several studies have shown that mice lacking Nrf2 can be protected from high fat diet induced obesity despite similar food intake [ 81 , 82 , 87 , 88 ].…”