Glut4 is upregulated despite decreased insulin signaling during prolonged fasting in northern elephant seal pups

Abstract

Viscarra JA, Vázquez-Medina JP, Crocker DE, Ortiz RM. Glut4 is upregulated despite decreased insulin signaling during prolonged fasting in northern elephant seal pups. Am J Physiol Regul Integr Comp Physiol 300: R150 -R154, 2011. First published October 27, 2010 doi:10.1152/ajpregu.00478.2010.-Postprandial cellular glucose uptake is dependent on an insulin-signaling cascade in muscle and adipose tissue, resulting in the translocation of the insulindependent glucose transporter 4 (Glut4) into the plasma membrane. Additionally, extended food deprivation is characterized by suppressed insulin signaling and decreased Glut4 expression. Northern elephant seals are adapted to prolonged fasts characterized by high levels of plasma glucose. To address the hypothesis that the fastinginduced decrease in insulin is associated with reduced insulin signaling in prolonged fasted seals, we compared the adipose protein levels of the cellular insulin-signaling pathway, Glut4 and plasma glucose, insulin, cortisol, and adiponectin concentrations between Early (n ϭ 9; 2-3 wks postweaning) and Late (n ϭ 8; 6 -8 wks postweaning) fasted seals. Plasma adiponectin (230 Ϯ 13 vs. 177 Ϯ 11 ng/ml), insulin (2.7 Ϯ 0.4 vs. 1.0 Ϯ 0.1 U/ml), and glucose (9.8 Ϯ 0.5 vs. 8.0 Ϯ 0.3 mM) decreased, while cortisol (124 Ϯ 6 vs. 257 Ϯ 30 nM) doubled with fasting. Glut4 increased (31%) with fasting despite the significant decreases in the cellular content of phosphatidylinositol 3-kinase as well as phosphorylated insulin receptor, insulin receptor substrate-1, and Akt2. Increased Glut4 may have contributed to the decrease in plasma glucose, but the decrease in insulin and insulin signaling suggests that Glut4 is not insulin-dependent in adipose tissue during prolonged fasting in elephant seals. The reduction of plasma glucose independent of insulin may make these animals an ideal model for the study of insulin resistance. elephant seal; glucocorticoids; glucose transporter; hyperglycemia; insulin resistance REGARDLESS OF AGE OR gender, the northern elephant seal (Mirounga angustirostris) endures a 2-3 mo fast twice a year as a natural component of its life history (21, 24). Unlike hibernators, which can experience similar bouts of food deprivation but conserve energy by lowering their metabolic rate and core body temperature (26), fasting seals remain normothermic and metabolically active during their prolonged fasts (8,35). Fasting seals remain physically active as well, with males using their time on land to form and defend harems, with females giving birth to and nursing newborn pups, and with postweaning pups developing the diving ability they will need when they go out to sea, all the while completely abstaining from food or water.Fasting elephant seals rely primarily on the oxidation of their extensive fat stores to meet ϳ90 -95% of their energy requirements and maintain high levels of plasma glucose (5, 21) during their fast. Such reliance on lipid oxidation results in elevated circulating free fatty acids levels (4, 32

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).…”

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

“…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.…”

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.…”