Enhanced Nrf2 Activity Worsens Insulin Resistance, Impairs Lipid Accumulation in Adipose Tissue, and Increases Hepatic Steatosis in Leptin-Deficient Mice

Abstract

The study herein determined the role of nuclear factor erythoid 2–related factor 2 (Nrf2) in the pathogenesis of hepatic steatosis, insulin resistance, obesity, and type 2 diabetes. Lepob/ob-Keap1-knockdown (KD) mice, which have increased Nrf2 activity, were generated. Markers of obesity and type 2 diabetes were measured in C57Bl/6J, Keap1-KD, Lepob/ob, and Lepob/ob-Keap1-KD mice. Lepob/ob-Keap1-KD mice exhibited less lipid accumulation, smaller adipocytes, decreased food intake, and reduced lipogenic gene expression. Enhanced Nrf2 activity impaired insulin signaling, prolonged hyperglycemia in response to glucose challenge, and induced insulin resistance in Lepob/ob background. Nrf2 augmented hepatic steatosis and increased lipid deposition in liver. Next, C57Bl/6J and Keap1-KD mice were fed a high-fat diet (HFD) to determine whether Keap1 and Nrf2 impact HFD-induced obesity. HFD-induced obesity and lipid accumulation in white adipose tissue was decreased in Keap1-KD mice. Nrf2 activation via Keap1-KD or sulforaphane suppressed hormone-induced differentiation and decreased peroxisome proliferator–activated receptor-γ, CCAAT/enhancer–binding protein α, and fatty acid–binding protein 4 expression in mouse embryonic fibroblasts. Constitutive Nrf2 activation inhibited lipid accumulation in white adipose tissue, suppressed adipogenesis, induced insulin resistance and glucose intolerance, and increased hepatic steatosis in Lepob/ob mice.

Dose-dependent deleterious and salutary actions of the Nrf2 inducer dh404 in chronic kidney disease

“…In contrast, excessive or unrestrained activity of Nrf2 system has been shown to have adverse consequences. For instance unrestrained activation of Nrf2 pathway leads to post-natal mortality in Keap1knock out mice [50] and worsening of insulin resistance, adipose tissue contraction, weight loss, and hepatic steatosis in Keap1 knock down leptin-deficient mice [51] Nrf2 is held in the cell cytoplasm as an inactive complex by Keap1 (Kelch-like ECH-associated protein 1) a repressor molecule which mediates Nrf2 degradation by serving as an adaptor for Cul3 Rbx1 E3 ligase complex. Keap1 molecule contains a number of reactive cysteine residues that serve as sensors of the intra-cellular redox state.…”

Increased Energy Expenditure, Ucp1 Expression, and Resistance to Diet-induced Obesity in Mice Lacking Nuclear Factor-Erythroid-2-related Transcription Factor-2 (Nrf2)

“…However, it is worth noting that in addition to the protective effects of Nrf2, the same group also found that mice lacking Nrf2 demonstrate decreased serum glucose levels compared with control mice, which correlates with data from our model of Nrf2 deficiency. In mice doubly deficient in Keap1 and leptin, there was a resistance to high fat diet-induced obesity and a decrease in adipose tissue weight that was also associated with impaired insulin signaling, hyperglycemia, and glucose intolerance (80). Additional studies utilizing the ob/ob genetic model of obesity have yielded varied results.…”

Degradation of Keap1 activates BH3-only proteins Bim and PUMA during hepatocyte lipoapoptosis

“…The role of Keap1-Nrf2 in the context of fatty liver disease remains to be clarified. Some studies have reported that Keap1 deletion increases insulin resistance and hepatocyte steatosis in murine models of steatohepatitis, 20,21 and whether silencing of Keap1 also increases hepatocyte injury by high-fat diet feeding merits further investigation.…”

“…19 Although genetic deficiency in Keap1 rendered mice more resistant to APAPinduced hepatotoxicity, loss of Keap1 compromised the longterm survival of these animals without increasing their risk of tumor formation. 18 Also, recent studies suggest that Keap1 deletion worsened insulin resistance and increased hepatocyte steatosis in diet-induced 20 and genetic obesity 21 in mice, implying a possible protective role of Keap1 regarding these parameters. Previous studies indicate that Keap1 regulates apoptosis by modulating the expression of the anti-apoptotic bcl2-family members Bcl-x L 22,23 and Bcl-2.…”