Metabolic response to a glucagon challenge varies with adiposity and life-history stage in fasting northern elephant seals Daniel E. Crocker a,⇑ , Melinda A. Fowler a,b , Cory D. Champagne a,c , Anna L. Vanderlugt a , Dorian S. Houser a,c a Sonoma State University, Rohnert Park, CA 94928, USA b Simon Fraser University, Burnaby, BC V5A 1S6, Canada c National Marine Mammal Foundation, San Diego, CA 92106, USA article info Article history: Received 11 June 2013 Revised 6 October 2013 Accepted 4 November 2013 Available online 13 November 2013 Keywords: Fasting metabolism Pinniped Glucagon Gluconeogenesis Lipolysis abstract Metabolic adaptations for extended fasting in wildlife prioritize beta-oxidation of lipids and reduced glucose utilization to support energy metabolism. The pancreatic hormone glucagon plays key roles in regulating glycemia and lipid metabolism during fasting in model species but its function in wildlife spe- cies adapted for extended fasting is not well understood. Northern elephant seals (NES) undergo natural fasts of 1–3 months while under constraints of high nutrient demands including lactation and develop- ment. We performed a glucagon challenge on lactating, molting and developing NES, early and late in their natural fasts, to examine the impact of this important regulatory hormone on metabolism. Glucagon caused increases in plasma glucose, insulin, fatty acids, ketones and urea, but the magnitude of these effects varied widely with adiposity and life-history stage. The strong impact of adiposity on glucose and insulin responses suggest a potential role for adipose derived factors in regulating hepatic metabo- lism and pancreatic sensitivity. Elevations in plasma glucose in response to glucagon were strongly asso- ciated with increases in protein catabolism, suggesting negative impacts of elevated glucagon on protein sparing. Glucagon promoted rapid ketone accumulation suggesting that low ketoacid levels in NES reflect low rates of production. These results demonstrate strong metabolic impacts of glucagon and support the idea that glucagon levels are downregulated in the context of metabolic adaptation to extended fasting. These results suggest that the regulation of carbohydrate and lipid metabolism in NES changes with adiposity, fasting duration and under various constraints of nutrient demands. Ó 2013 Published by Elsevier Inc. 1. Introduction Food deprivation is experienced by many animals, usually due to seasonal variation in food resources or life-history patterns that limit feeding opportunities during periods of reproduction or migration. Some species are adapted to fast for extended periods despite high rates of nutrient demand (Champagne et al., 2012a). Adaptations for extended fasting involve alterations in metabolism that increase reliance on beta-oxidation of stored lipids while reducing glucose utilization (Houser et al., 2012). Extended fasting requires careful management of rates of glucose disposal and production in order to minimize commitment of amino acids to gluconeogenesis, thus conserving lean tissue and preventing vital organ failure (Goodman et al., 1980). The decreased dependence on glucose oxidation in extended fasting is associated with a decreased reliance on the counter-regulatory dynamics of insulin and glucagon (Viscarra and Ortiz, 2013). In general fasting is asso- ciated with dramatic reductions in insulin levels and decreased insulin: glucagon ratios to promote lipolysis and reduce glucose utilization by tissues. However, the role that glucagon plays in ex- tended fasting is not well understood. In model species, glucagon plays a central role in regulating gly- cemia, promoting hepatic glucose synthesis and mobilization (Quesada et al., 2008). In post-absorptive animals the glucose re- sponse to glucagon is biphasic, resulting from glycogenolysis fol- lowed by gluconeogenesis. In extended fasting, glucagon promotes commitment of amino acids to gluconeogenesis (Daniel et al., 1977). Hyperglycemia from enhanced glucose production is prevented by a biphasic insulin response to glucagon (Steiner et al., 1982). The second phase insulin response is initiated prior to changes in plasma glucose levels (Cherrington et al., 2002) and is associated with binding of glucagon to receptors in pancreatic is- let cells (Kawai et al., 1995). Glucagon also promotes lipolysis in mammals (Lefebvre, 1975) and is the primary lipolytic hormone in birds (Bernard et al., 2003; Grande and Prigge, 1970). The presence of hepatic glucagon receptors is critical to the metabolic 0016-6480/$ - see front matter Ó 2013 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.ygcen.2013.11.005 ⇑ Corresponding author. Address: Dept. of Biology, Sonoma State University, 1801 E. Cotati Ave., Rohnert Park, CA 94928, USA. Fax: +1 707 664 3095. E-mail address: crocker@sonoma.edu (D.E. Crocker). General and Comparative Endocrinology 195 (2014) 99–106 Contents lists available at ScienceDirect General and Comparative Endocrinology journal homepage: www.elsevier.com/locate/ygcen