Angiotensin II and Aldosterone Increase with Fasting in Breeding Adult Male Northern Elephant Seals (Mirounga angustirostris)

The renin‐angiotensin‐aldosterone system (RAAS) appears to contribute significantly to osmoregulation of fasting northern elephant seal (Mirounga angustirostris) pups; however, RAAS has not been characterized in fasting adult seals. Therefore, this study examined the contribution of RAAS to water turnover rates in fasting adult male northern elephant seals. Blood samples were obtained twice during their breeding fast at an interval of 6.5 wk, and water efflux rate was estimated by isotopic dilution during the same period. Serum electrolytes (Na+, K+, Cl−) and osmolality were unaltered between the two sampling periods, indicating ionic and osmotic homeostasis during the fast. Despite the lack of an increase in vasopressin, serum angiotensin II and aldosterone were increased and were significantly and positively correlated. Changes in aldosterone concentration and water efflux rate were significantly and negatively correlated, suggesting that the greater the increase in aldosterone, the smaller the loss of water. Adult male seals maintain ionic and osmotic homeostasis similar to that of fasting weaned pups, and this homeostasis appears to be mediated, at least in part, by RAAS, which probably contributes to increased water retention as well. The hormonal mechanisms by which northern elephant seals maintain water and electrolyte balance during fasting conditions appear to be similar regardless of age

Hormone and Metabolite Changes associated with Extended Breeding Fasts in Male Northern Elephant Seals (Mirounga Angustirostris)

We measured metabolic hormones and several key metabolites in breeding adult male northern elephant seals to examine the regulation of fuel metabolism during extended natural fasts of over 3 months associated with high levels of energy expenditure. Males were sampled twice, early and late in the fast, losing an average of 23% of body mass and 47% of adipose stores between measurements. Males exhibited metabolic homeostasis over the breeding fast with no changes in glucose, non-esterified fatty acids, or blood urea nitrogen. Ketoacids increased over the fast but were very low when compared to other fasting species. Changes within individuals in total triiodothyronine (tT3) were positively related to daily energy expenditure (DEE) and protein catabolism. Differences in levels of thyroid hormones relative to that observed in weaned pups and females suggest a greater deiodination of T4 to support the high DEE of breeding males. Relative levels of leptin and ghrelin were consistent with the suppression of appetite but a significant reduction in growth hormone across the fast was contrary to expectation in fasting mammals. The lack of the increase in cortisol during fasting found in conspecific weaned pups and lactating females may contribute to the ability of breeding males to spare protein despite high levels of energy expenditure. Together these findings reveal significant differences with conspecifics under varying nutrient demands, suggesting metabolic adaptation to extended high energy fasts

Insulin and GLP-1 infusions demonstrate the onset of adipose-specific insulin resistance in a large fasting mammal: potential glucogenic role for GLP-1.

Prolonged food deprivation increases lipid oxidation and utilization, which may contribute to the onset of the insulin resistance associated with fasting. Because insulin resistance promotes the preservation of glucose and oxidation of fat, it has been suggested to be an adaptive response to food deprivation. However, fasting mammals exhibit hypoinsulinemia, suggesting that the insulin resistance-like conditions they experience may actually result from reduced pancreatic sensitivity to glucose/capacity to secrete insulin. To determine whether fasting results in insulin resistance or in pancreatic dysfunction, we infused early- and late-fasted seals (naturally adapted to prolonged fasting) with insulin (0.065 U/kg), and a separate group of late-fasted seals with low (10 pM/kg) or high (100 pM/kg) dosages of glucagon-like peptide-1 (GLP-1) immediately following a glucose bolus (0.5g/kg), and measured the systemic and cellular responses. Because GLP-1 facilitates glucose-stimulated insulin secretion, these infusions provide a method to assess pancreatic insulin-secreting capacity. Insulin infusions increased the phosphorylation of insulin receptor and Akt in adipose and muscle of early and late fasted seals; however the timing of the signaling response was blunted in adipose of late fasted seals. Despite the dose-dependent increases in insulin and increased glucose clearance (high dose), both GLP-1 dosages produced increases in plasma cortisol and glucagon, which may have contributed to the glucogenic role of GLP-1. Results suggest that fasting induces adipose-specific insulin resistance in elephant seal pups, while maintaining skeletal muscle insulin sensitivity, and therefore suggests that the onset of insulin resistance in fasting mammals is an evolved response to cope with prolonged food deprivation

Transcriptome analysis of northern elephant seal (Mirounga angustirostris) muscle tissue provides a novel molecular resource and physiological insights

BackgroundThe northern elephant seal, Mirounga angustirostris, is a valuable animal model of fasting adaptation and hypoxic stress tolerance. However, no reference sequence is currently available for this and many other marine mammal study systems, hindering molecular understanding of marine adaptations and unique physiology.ResultsWe sequenced a transcriptome of M. angustirostris derived from muscle sampled during an acute stress challenge experiment to identify species-specific markers of stress axis activation and recovery. De novo assembly generated 164,966 contigs and a total of 522,699 transcripts, of which 68.70% were annotated using mouse, human, and domestic dog reference protein sequences. To reduce transcript redundancy, we removed highly similar isoforms in large gene families and produced a filtered assembly containing 336,657 transcripts. We found that a large number of annotated genes are associated with metabolic signaling, immune and stress responses, and muscle function. Preliminary differential expression analysis suggests a limited transcriptional response to acute stress involving alterations in metabolic and immune pathways and muscle tissue maintenance, potentially driven by early response transcription factors such as Cebpd.ConclusionsWe present the first reference sequence for Mirounga angustirostris produced by RNA sequencing of muscle tissue and cloud-based de novo transcriptome assembly. We annotated 395,102 transcripts, some of which may be novel isoforms, and have identified thousands of genes involved in key physiological processes. This resource provides elephant seal-specific gene sequences, complementing existing metabolite and protein expression studies and enabling future work on molecular pathways regulating adaptations such as fasting, hypoxia, and environmental stress responses in marine mammals

Elucidating Nature’s Solutions to Heart, Lung, and Blood Diseases and Sleep Disorders

Evolution has provided a number of animal species with extraordinary phenotypes. Several of these phenotypes allow species to survive and thrive in environmental conditions that mimic disease states in humans. The study of evolved mechanisms that responsible for these phenotypes may provide insights into the basis of human disease and guide the design of new therapeutic approaches. Examples include species that tolerate acute or chronic hypoxemia like deep-diving mammals and high-altitude inhabitants, as well as those that hibernate and interrupt their development when exposed to adverse environments. The evolved traits exhibited by these animal species involve modifications of common biological pathways that affect metabolic regulation, organ function, antioxidant defenses, and oxygen transport. In 2006, the National Heart, Lung, and Blood Institute (NHLBI) released a funding opportunity announcement to support studies that were designed to elucidate the natural molecular and cellular mechanisms of adaptation in species that tolerate extreme environmental conditions. The rationale for this funding opportunity is detailed in this Special Article, and the specific evolved mechanisms examined in the supported research are described. Also highlighted are past medical advances achieved through the study of animal species that have evolved extraordinary phenotypes as well as the expectations for new understanding of nature’s solutions to heart, lung, blood, and sleep disorders through future research in this area

Simultaneous angiotensin receptor blockade and glucagon-like peptide-1 receptor activation ameliorate albuminuria in obese insulin-resistant rats.

Insulin resistance increases renal oxidant production by upregulating NADPH oxidase 4 (Nox4) expression contributing to oxidative damage and ultimately albuminuria. Inhibition of the renin-angiotensin system (RAS) and activation of glucagon-like peptide-1 (GLP-1) receptor signalling may reverse this effect. However, whether angiotensin receptor type 1 (AT1) blockade and GLP-1 receptor activation improve oxidative damage and albuminuria through different mechanisms is not known. Using insulin-resistant Otsuka Long-Evans Tokushima Fatty (OLETF) rats, we tested the hypothesis that simultaneous blockade of AT1 and activation of GLP-1r additively decrease oxidative damage and urinary albumin excretion (Ualb V) in the following groups: (a) untreated, lean LETO (n = 7), (b) untreated, obese OLETF (n = 9), (c) OLETF + angiotensin receptor blocker (ARB; 10 mg olmesartan/kg/d; n = 9), (d) OLETF + GLP-1 mimetic (EXE; 10 µg exenatide/kg/d; n = 7) and (e) OLETF + ARB +exenatide (Combo; n = 6). Mean kidney Nox4 protein expression and nitrotyrosine (NT) levels were 30% and 46% greater, respectively, in OLETF compared with LETO. Conversely, Nox4 protein expression and NT were reduced to LETO levels in ARB and EXE, and Combo reduced Nox4, NT and 4-hydroxy-2-nonenal levels by 21%, 27% and 27%, respectively. At baseline, Ualb V was nearly double in OLETF compared with LETO and increased to nearly 10-fold greater levels by the end of the study. Whereas ARB (45%) and EXE (55%) individually reduced Ualb V, the combination completely ameliorated the albuminuria. Collectively, these data suggest that AT1 blockade and GLP-1 receptor activation reduce renal oxidative damage similarly during insulin resistance, whereas targeting both signalling pathways provides added benefit in restoring and/or further ameliorating albuminuria in a model of diet-induced obesity

Elucidating Nature’s Solutions to Heart, Lung, and Blood Diseases and Sleep Disorders

Evolution has provided a number of animal species with extraordinary phenotypes. Several of these phenotypes allow species to survive and thrive in environmental conditions that mimic disease states in humans. The study of evolved mechanisms that responsible for these phenotypes may provide insights into the basis of human disease and guide the design of new therapeutic approaches. Examples include species that tolerate acute or chronic hypoxemia like deep-diving mammals and high-altitude inhabitants, as well as those that hibernate and interrupt their development when exposed to adverse environments. The evolved traits exhibited by these animal species involve modifications of common biological pathways that affect metabolic regulation, organ function, antioxidant defenses, and oxygen transport. In 2006, the National Heart, Lung, and Blood Institute (NHLBI) released a funding opportunity announcement to support studies that were designed to elucidate the natural molecular and cellular mechanisms of adaptation in species that tolerate extreme environmental conditions. The rationale for this funding opportunity is detailed in this Special Article, and the specific evolved mechanisms examined in the supported research are described. Also highlighted are past medical advances achieved through the study of animal species that have evolved extraordinary phenotypes as well as the expectations for new understanding of nature’s solutions to heart, lung, blood, and sleep disorders through future research in this area

Technical Design Report for the PANDA Solenoid and Dipole Spectrometer Magnets

This document is the Technical Design Report covering the two large spectrometer magnets of the PANDA detector set-up. It shows the conceptual design of the magnets and their anticipated performance. It precedes the tender and procurement of the magnets and, hence, is subject to possible modifications arising during this process.Comment: 10 pages, 14MB, accepted by FAIR STI in May 2009, editors: Inti Lehmann (chair), Andrea Bersani, Yuri Lobanov, Jost Luehning, Jerzy Smyrski, Technical Coordiantor: Lars Schmitt, Bernd Lewandowski (deputy), Spokespersons: Ulrich Wiedner, Paola Gianotti (deputy