Keedrian I Olmstead1,2, Michael R La Frano3,4,5, Johannes Fahrmann3,6, Dmitry Grapov3, Jose A Viscarra2, John W Newman3,4, Oliver Fiehn3,7, Daniel E Crocker8, Fabian V Filipp1,2,3, Rudy M Ortiz2. 1. Systems Biology and Cancer Metabolism, Program for Quantitative Systems Biology, University of California, Merced. 2. Molecular Cell Biology, School of Natural Sciences, University of California, Merced, USA. 3. NIH West Coast Metabolomics Center, University of California, Davis. 4. Obesity and Metabolism Research Unit, USDA-Agricultural Research Service Western Human Nutrition Research Center, University of California, Davis, USA. 5. Department of Food Science and Nutrition, California Polytechnic State University, San Luis Obispo, USA. 6. Cancer Treatment Center, UT MD Anderson, Houston, USA. 7. Biochemistry Department, King Abdulaziz University, Jeddah, Saudi Arabia. 8. Biology, Sonoma State University, Rohnert Park, USA.
Abstract
INTRODUCTION: Prolonged fasting in northern elephant seals (NES) is characterized by a reliance on lipid metabolism, conservation of protein, and reduced plasma insulin. During early fasting, glucose infusion previously reduced plasma free fatty acids (FFA); however, during late-fasting, it induced an atypical elevation in FFA despite comparable increases in insulin during both periods suggestive of a dynamic shift in tissue responsiveness to glucose-stimulated insulin secretion. OBJECTIVE: To better assess the contribution of insulin to this fasting-associated shift in substrate metabolism. METHODS: We compared the responses of plasma metabolites (amino acids (AA), FFA, endocannabinoids (EC), and primary carbon metabolites (PCM)) to an insulin infusion (65 mU/kg) in early- and late-fasted NES pups (n = 5/group). Plasma samples were collected prior to infusion (T0) and at 10, 30, 60, and 120 min post-infusion, and underwent untargeted and targeted metabolomics analyses utilizing a variety of GC-MS and LC-MS technologies. RESULTS: In early fasting, the majority (72%) of metabolite trajectories return to baseline levels within 2 h, but not in late fasting indicative of an increase in tissue sensitivity to insulin. In late-fasting, increases in FFA and ketone pools, coupled with decreases in AA and PCM, indicate a shift toward lipolysis, beta-oxidation, ketone metabolism, and decreased protein catabolism. Conversely, insulin increased PCM AUC in late fasting suggesting that gluconeogenic pathways are activated. Insulin also decreased FFA AUC between early and late fasting suggesting that insulin suppresses triglyceride hydrolysis. CONCLUSION: Naturally adapted tolerance to prolonged fasting in these mammals is likely accomplished by suppressing insulin levels and activity, providing novel insight on the evolution of insulin during a condition of temporary, reversible insulin resistance.
INTRODUCTION: Prolonged fasting in northern elephant seals (NES) is characterized by a reliance on lipid metabolism, conservation of protein, and reduced plasma insulin. During early fasting, glucose infusion previously reduced plasma free fatty acids (FFA); however, during late-fasting, it induced an atypical elevation in FFA despite comparable increases in insulin during both periods suggestive of a dynamic shift in tissue responsiveness to glucose-stimulated insulin secretion. OBJECTIVE: To better assess the contribution of insulin to this fasting-associated shift in substrate metabolism. METHODS: We compared the responses of plasma metabolites (amino acids (AA), FFA, endocannabinoids (EC), and primary carbon metabolites (PCM)) to an insulin infusion (65 mU/kg) in early- and late-fasted NES pups (n = 5/group). Plasma samples were collected prior to infusion (T0) and at 10, 30, 60, and 120 min post-infusion, and underwent untargeted and targeted metabolomics analyses utilizing a variety of GC-MS and LC-MS technologies. RESULTS: In early fasting, the majority (72%) of metabolite trajectories return to baseline levels within 2 h, but not in late fasting indicative of an increase in tissue sensitivity to insulin. In late-fasting, increases in FFA and ketone pools, coupled with decreases in AA and PCM, indicate a shift toward lipolysis, beta-oxidation, ketone metabolism, and decreased protein catabolism. Conversely, insulin increased PCM AUC in late fasting suggesting that gluconeogenic pathways are activated. Insulin also decreased FFA AUC between early and late fasting suggesting that insulin suppresses triglyceride hydrolysis. CONCLUSION: Naturally adapted tolerance to prolonged fasting in these mammals is likely accomplished by suppressing insulin levels and activity, providing novel insight on the evolution of insulin during a condition of temporary, reversible insulin resistance.
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