Northern elephant seal (Mirounga angustirostris) pups rely on the oxidation of fat stores as their primary source of energy during their 8- to 12-wk postweaning fast; however, potential endocrine mechanisms involved with this increased fat metabolism have yet to be examined. Therefore, 15 pups were serially blood sampled in the field during the first 7 wk of their postweaning fast to examine the changes in plasma concentrations of cortisol and thyroid hormones (TH), which are involved in fat metabolism in other mammals. Cortisol increased, indicating that it contributed to an increase in lipolysis. Increased total triiodothyronine (tT(3)) and thyroxine (tT(4)) may not reflect increased thyroid gland activity, but rather alterations in hormone metabolism. tT(3)-to-tT(4) ratio decreased, suggesting a decrease in thyroxine (T(4)) deiodination, whereas the negative correlation between total proteins and free T(4) suggests that the increase in free hormone is attributed to a decrease in binding globulins. Changes in TH are most similar to those observed during hibernation than starvation in mammals, suggesting that the metabolic adaptations to natural fasting are more similar to hibernation despite the fact these animals remain active throughout the fasting period.
Northern elephant seals endure a 2–3 month fast characterized by sustained hyperglycemia, hypoinsulinemia and increased plasma cortisol and free fatty acids, conditions often seen in insulin resistant humans. We previously showed that adipose Glut4 expression and AMP kinase (AMPK) activity increase and plasma glucose decreases in fasting seals suggesting that AMPK activity contributes to glucose regulation during insulin resistant conditions. To address the hypothesis that AMPK activity increases during fasting-induced insulin resistance, we performed glucose tolerance tests (GTT) on early (n=5) and late (n=8) fasted seal pups and compared adipose tissue expression of insulin signaling proteins, PPARγ, and AMPK, in addition to plasma adiponectin, leptin, cortisol, insulin and non-esterified fatty acids (NEFA) levels. Fasting was associated with decreased glucose clearance, plasma insulin and adiponectin, and intracellular insulin signaling, as well as increased plasma cortisol and NEFAs, supporting the suggestion that seals develop insulin resistance late in the fast. Expression of Glut4 and VAMP2 increased (52% and 63%, respectively) with fasting but did not change significantly during the GTT. PPARγ and phosphorylated AMPK did not change in early fasted seals, but increased significantly (73% and 50%, respectively) in late fasted seals during the GTT. Increased AMPK activity along with the reduction in the activity of insulin-signaling proteins supports our hypothesis that AMPK activity is increased following the onset of insulin resistance. The association between increased AMPK activity and Glut4 expression suggests that AMPK plays a greater role in regulating glucose metabolism in mammals adapted to prolonged fasting than in non-fasting mammals.
SUMMARYElephant seals are naturally adapted to survive up to three months of absolute food and water deprivation (fasting). Prolonged food deprivation in terrestrial mammals increases reactive oxygen species (ROS) production, oxidative damage and inflammation that can be induced by an increase in the renin-angiotensin system (RAS). To test the hypothesis that prolonged fasting in elephant seals is not associated with increased oxidative stress or inflammation, blood samples and muscle biopsies were collected from early (2-3 weeks post-weaning) and late (7-8 weeks post-weaning) fasted seals. Plasma levels of oxidative damage, inflammatory markers and plasma renin activity (PRA), along with muscle levels of lipid and protein oxidation, were compared between early and late fasting periods. Protein expression of angiotensin receptor 1 (AT 1 ), pro-oxidant (Nox4) and antioxidant enzymes (CuZn-and Mn-superoxide dismutases, glutathione peroxidase and catalase) was analyzed in muscle. Fasting induced a 2.5-fold increase in PRA, a 50% increase in AT 1 , a twofold increase in Nox4 and a 70% increase in NADPH oxidase activity. By contrast, neither tissue nor systemic indices of oxidative damage or inflammation increased with fasting. Furthermore, muscle antioxidant enzymes increased 40-60% with fasting in parallel with an increase in muscle and red blood cell antioxidant enzyme activities. These data suggest that, despite the observed increases in RAS and Nox4, an increase in antioxidant enzymes appears to be sufficient to suppress systemic and tissue indices of oxidative damage and inflammation in seals that have fasted for a prolonged period. The present study highlights the importance of antioxidant capacity in mammals during chronic periods of stress to help avoid deleterious systemic consequences.
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