Prolonged Fasting Increases Nrf2 Nuclear Accumulation and DNA Binding Ability in Postweaned Northern Elephant Seals

Abstract

Northern elephant seals naturally experience prolonged periods of absolute food and water deprivation (fasting) while breeding, molting and weaning. Prolonged fasting in elephant seals promotes insulin resistance, activates the renin‐angiotensin system and increases NADPH oxidase activity and protein expression without increasing oxidative damage or inflammation. Prolonged fasting also stimulates the antioxidant system of the elephant seal likely resulting in the prevention of oxidative damage. The redox‐senstive transcription factor Nrf2 is the main regulator of the adaptive response to oxidative stress. Nrf2 translocates into the nucleus and increases the transcription of antioxidant genes in response to intracellular oxidant production. To test the hypothesis that Nrf2 is activated in response to prolonged fasting in elephant seals, angiotensin II (Ang II) and TGF‐β circulating concentrations, along with NADPH oxidase 4 (Nox4) mRNA expression and Nrf2 nuclear content and DNA binding ability, were measured in blood and muscle samples collected from seals fasting for 1, 3, 5 and 7 weeks. Ang II and TGF‐β increased gradually through the fasting and where 40‐fold (Ang II) and 2‐fold (TGF‐β) higher at wk 7 than at wk 1. Nox4 was 5‐fold higher at wk 7 than at wk 1 while Nrf2 nuclear content and DNA binding ability were 2‐fold higher. Results show that prolonged fasting activates the adaptive response to oxidative stress in elephant seals and suggest that Ang II and TGF‐β stimulate Nox4, which may potentially mediate a hormetic protective response in fasting seals.