5′AMP-activated protein kinase activity is increased in adipose tissue of northern elephant seal pups during prolonged fasting-induced insulin resistance

Abstract

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.

Activation of systemic, but not local, renin-angiotensin system is associated with up-regulation of TNF-α during prolonged fasting in northern elephant seal pups

“…While activation of systemic RAS may result from food deprivation to help regulate osmotic homeostasis (Ortiz et al, 2000;Ortiz et al, 2002;Ortiz et al, 2006), the effects of this increase in RAS on cellular functions in seals have not been examined. Given that these animals present with an IR-like condition during prolonged fasting (Fowler et al, 2008;Viscarra et al, 2011a;Viscarra et al, 2011b), this study suggests that the activation of systemic RAS, not local RAS, is most likely contributing to the IRlike condition observed in fasting seal pups. In humans and rodents, excess TNF-α in muscle can disrupt the tyrosine-phosphorylation of IRS (Plomgaard et al, 2005) and suppress fatty acid oxidation by suppressing AMPK signaling (Steinberg et al, 2006), which can contribute to impaired wholebody insulin sensitivity because muscle is responsible for the majority of glucose uptake in vivo.…”

“…For the maintenance of circulating glucose levels, fasting pups rely on lipid oxidation and efficient glucose recycling (Champagne et al, 2005;Champagne et al, 2012;Costa and Ortiz, 1982;Tavoni et al, 2013), coupled with insulin resistance (IR)-like conditions (Fowler et al, 2008;Viscarra et al, 2011a;Viscarra et al, 2011b). These adapted mechanisms allow pups to meet their energetic burdens during prolonged fasting.…”

Prolonged fasting increases purine recycling in post-weaned northern elephant seals

“…Plasma HGPRT and XO activities increased (P<0.05) at each week across the fasting over the 7week measurement period (Fig.4C,D). cortisol, non-esterified fatty acids and promoting insulin resistance (Ortiz et al, 2000;Ortiz et al, 2001;Ortiz et al, 2003;Ortiz et al, 2006;Vázquez-Medina et al, 2010;Viscarra et al, 2011a;Viscarra et al, 2011b). Unfortunately, the molecular and physiological mechanisms adopted by seals to cope with prolonged fasting are not fully elucidated.…”

“…In humans, rats and mice, prolonged fasting increases oxidant production, oxidative damage and inflammation (Crescimanno et al, 1989;Di Simplicio et al, 1997;Grattagliano et al, 2000;Kondoh et al, 2003;Mårtensson, 1986;Sorensen et al, 2006;Souza Rocha et al, 2008;Wu et al, 2004). In elephant seals, prolonged fasting does not induce oxidative damage or inflammation despite promoting the chronic activation of the renin-angiotensin system (RAS) and increasing circulating cortisol, NADPH oxidase activity, Nox4 protein expression and insulin resistance (Ortiz et al, 2000;Ortiz et al, 2002;Vázquez-Medina et al, 2010;Viscarra et al, 2011a;Viscarra et al, 2011b).…”

Hormone and metabolite changes associated with extended breeding fasts in male northern elephant seals (Mirounga angustirostris)

“…During this period, males have low rates of water flux and spare protein efficiently (Ortiz et al, 2006;Crocker et al, 2012). Studies in fasting and lactating female elephant seals have suggested reduced insulin response and sensitivity (Fowler et al, 2008;Viscarra et al, 2011aViscarra et al, , 2011b. To date, no studies have examined the hormone regulation of metabolism in adult male pinnipeds during natural breeding fasts.…”