Regulation of oxidative stress response by Nrf2 target genes. The Nrf2-regulated gene product is indicated by the blue circle. Reactive oxygen species and electrophiles are indicated in red. Antioxidants and other chemicals were indicated as blue and yellow diamonds, respectively. Cystine/glutamate transporter (xCT) and glutamate-cysteine ligase (GCL) are involved in glutathione synthesis, and glutathione reductase recycles oxidized glutathione (GSSG) to reduced glutathione (GSH). GSH is used as an antioxidant, conjugation of electrophile by glutathione S-transferase (GST) to excrete via multidrug resistance-associated protein (MRP1), and reduction of H
O by glutathione peroxidase (GPX). H
•) dismutase (SOD) and is eliminated by the catalase and peroxiredoxin (PRX)/thioredoxin (TRX) systems. Free heme is degraded by heme oxygenase-1 (HO-1), and the degradation product bilirubin functions as an antioxidant. Released ferrous iron (Fe
into a hydroxyl radical (OH•) as known as the Fenton reaction. Fe
) by the ferritin heavy chain (FTH) and stored inactively. Glucose-6-phosphate (G6P) dehydrogenase (G6PD) and malic enzyme 1 (ME1) produce NADPH, which is used for reactions by GR, TRX reductase (TRXRD), and NAD(P)H Quinone oxidoreductase 1 (NQO1). G6PD is a pentose phosphate pathway enzyme that produces 6-phosphogluconolactone (6PGL).
4.2. The Role of Nrf2 Activation in WAT and Obesity
Several studies have examined how Nrf2 could affect obesity or IR using systemic
Nrf2 or
Keap1 knockdown (KD) mice (i.e., constitutive Nrf2 activation model). Both mice are reportedly resistant to HFD-induced obesity, with some contradicting results in the case of the former
[32][67]. As Nrf2 in adipocytes and preadipocytes contributes to lipid metabolism, differentiation, and adipogenesis conducted by C/EBPβ and RXRα, Nrf2 is expectably involved in adipogenesis in response to HFD
[33][34][66,68]. Although Nrf2 is generally required for HFD-induced obesity, as mentioned, constitutive Nrf2 activation by
Keap1 KD also inhibited HFD-induced obesity by decreasing PPARγ and C/EBPα
[35][69]. As
Nrf2 KO affects HFD-induced obesity, the role of HFD-induced IR is impossible to analyze using this model without negating the effect of obesity. However, tissue-specific
Nrf2 KO in adipocytes, but not in hepatocytes, exacerbated HFD-induced IR
[36][70].
4.3. The Role of Nrf2 in Pancreatic β-Cells
Pancreatic β-cells are known to be susceptible to oxidative stress due to the low-level expression of antioxidant enzymes and high ROS production coupled with glucose metabolism and insulin biosynthesis
[37][38][74,75]. Baumel-Alterzon et al. showed that Nrf2 is activated by high glucose in
ex vivo islet β-cells and also in mice fed HFD for 1 week [
77]. β-cell-specific
Nrf2 KO mice fed HFD exhibited increased oxidative stress, decreased β-cell mass, and worsened glucose tolerance. In contrast, either β-cell-specific
Keap1 KO or administration of Nrf2 activator conferred resistance to β-cell dysfunction by HFD, implicating that Nrf2 pathway contributes to the protection and therapeutic prevention of β-cells from oxidative stress [
77].
4.4. The Role of Nrf2 in Mitochondrial Function
Nrf2 target genes mainly act in the protection of cytoplasmic oxidative stress, although certain target genes such as
HO-1,
NQO1, and
Pink1 might directly modify oxidative stress in the mitochondria
[39][78] (
Figure 4). On the other hand, excess mtROS, such as H
2O
2, might diffuse and cause oxidative stress in the cytoplasm. On this occasion, Nrf2 may protect against oxidative stress via the generation of GSH and upregulation of ROS detoxifying enzymes such as GPXs. However, excess ROS in some cases reduce Nrf2 translation, and therefore the Nrf2-mediated stress response is limited
[40][79].
4.5. Insulin Resistance Alleviation upon Nrf2 Activation
Nrf2 activation by Keap1 knockdown improves glucose intolerance by enhancing glycogen branching
[41][84]. Indeed, SFN improves IR in HFD-fed mice
[42][43][85,86]. Xirouchaki et al. demonstrated that NADPH oxidase 4 (NOX4) is induced by moderate or intense acute stress or exercise training in mice and humans that precedes
NOX2 induction when it occurs
[44][87]. They demonstrated that skeletal muscle-specific
NOX4 decreases Nrf2, mitochondrial biogenesis-related genes, including PPARα, and mitochondrial biogenesis itself in in vitro cultured myotubes.
4.6. The Effect of Aging on T2D Etiology
Aging accelerates multiple age-related diseases, including T2D. Aging reportedly downregulates various cytoprotective factors, including the above-mentioned coenzyme Q
[45][88] and Nrf2
[46][89]. Importantly, aging deteriorates mitochondrial function, as described in Harman’s free radical theory of aging. Among others, aging particularly deteriorates Complex I or IV activities. As Complex I mostly consists of nuclear- and mitochondrial-encoded subunits, reasonably efficient Complex I function is susceptible to aging.
5. Conclusions
Various results obtained in IR models support the importance of mtROS overproduction in IR and WAT metabolic abnormalities in disease progression toward other tissues and T2D (
Figure 67). Although the functional role of Nrf2 in IR remains controversial based on studies of
Nrf2-deficient animals, Nrf2 activation by SFN and other inducers is concordantly beneficial for IR in insulin-sensitive tissues, including WAT. As the accumulation of BCAA and its metabolites in the blood reflects mitochondrial metabolism in the muscles and WAT in the case of obesity, the administration of Nrf2 inducers might provide a potential preventive intervention strategy against IR and T2D.
Figure 67. Insulin resistance progression and its prevention by Nrf2 inducers. The occurrence and progression of insulin resistance are affected both by genetic predisposition and environmental factors, including obesity and aging. IR is triggered by mitochondrial dysfunction and ROS overproduction, associated with ceramide accumulation. As IR in one tissue could propagate to other tissues, IR in the WAT and unhealthy obesity increase circulating free fatty acid levels, leading to depositions in the liver and muscles or conversion into ceramides, worsening the conditions that lead to type-2 diabetes. Defects in mitochondrial BCAA catabolism result in BCAA metabolite accumulation in the blood. Nrf2 inducer administration could improve IR through gene expression involved in antioxidant systems, mitochondrial function, and lipid metabolism.