Oxylipin responses to fasting and insulin infusion in a large mammalian model of fasting-induced insulin resistance, the northern elephant seal

Authors: WRIGHT, DANA - California Polytechnic State University; KATUNDU, KONDWANI - University Of Malawi; VISCARRA, JOSE - University Of California; CROCKER, DANIEL - Sonoma State University; Newman, John; LA FRANO, MICHAEL - California Polytechnic State University; ORTIZ, RUDY - University Of California

Submitted to: American Journal of Physiology - Regulatory Integrative & Comparative Physiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/2/2021
Publication Date: 9/23/2021
Citation: Wright, D.N., Katundu, K.G., Viscarra, J.A., Crocker, D.E., Newman, J.W., La Frano, M.R., Ortiz, R.M. 2021. Oxylipin responses to fasting and insulin infusion in a large mammalian model of fasting-induced insulin resistance, the northern elephant seal. American Journal of Physiology - Regulatory Integrative & Comparative Physiology. 321(4):R537-R546. https://doi.org/10.1152/ajpregu.00016.2021.
DOI: https://doi.org/10.1152/ajpregu.00016.2021

Interpretive Summary: The prolonged, post-weaning fast of Northern elephant seal (Mirounga angustirostris) pups is characterized by a reliance on lipid metabolism and reversible, fasting-induced insulin resistance. Therefore, this natural process in these animals provide a unique model to examine the effects of insulin on lipid metabolism. In previous studies, we have shown that acute insulin infusion shifts fatty acid metabolism associated with energy demand dependent on fasting duration. This study complements the previous study by examining the effects of fasting duration and insulin infusion on circulating levels of oxylipins, the bioactive fatty acid metabolites which are important regulators of insulin-dependent metabolism, vascular function and inflammation. Northern elephant seal pups were studied at two post-weaning periods (n =5/period): early fasting (1–2 weeks post-weaning; 127 ± 1 kg) and late fasting (6–7 weeks post-weaning; 93 ± 4 kg). Different cohorts of pups were weighed, sedated, and infused with insulin (65 mU/kg). Plasma was collected prior to infusion (T0), and at 10, 30, 60, and 120 minutes after infusion. The oxylipin profile was analyzed by UPLC-ESI-MS/MS. Nine oxylipins changed between early and late fasting, decrease in prostaglandin F2-alpha (PGF2a), and increase in 14,15-dihydroxyeicosatrienoic (DiHETrE) acid, 20-hydroxyeicosatetraenoic acid (20-HETE), and 4-hydroxydocosahexaenoic acid (4-HDoHE; p <0.05), while insulin infusions decreased PGF2a and increased decreased 14,15-DiHETrE, 20-HETE and 4-HDoHE during the 2hr post-infusion period. In addition, 12-hydroperoxyeicosatetraenoic acid and 12- hydroxyeicosatetraenoic acid decreased with fasting and response to insulin, respectively. Ultimately, oxylipins with putative roles in insulin regulation were altered with prolonged fasting and found to be sensitive to insulin infusion, suggesting that they may contribute to the manifestation of insulin resistance and participate in the metabolic regulation of these conditions.

Technical Abstract: The prolonged, post-weaning fast of Northern elephant seal (Mirounga angustirostris) pups is characterized by a reliance on lipid metabolism and reversible, fasting-induced insulin resistance providing a unique model to examine the effects of insulin on lipid metabolism. We have previously shown that acute insulin infusion induced a shift in fatty acid metabolism dependent on fasting duration. This study complements the previous study by examining the effects of fasting duration and insulin infusion on circulating levels of oxylipins, bioactive metabolites derived from the oxygenation of polyunsaturated fatty acids. Northern elephant seal pups were studied at two post-weaning periods (n = 5/period): early fasting (1–2 weeks post-weaning; 127 ± 1 kg) and late fasting (6–7 weeks post-weaning; 93 ± 4 kg). Different cohorts of pups were weighed, sedated, and infused with 65 mU/kg of insulin. Plasma was collected prior to infusion (T0), and at 10, 30, 60, and 120 min post-infusion. A profile of ~80 oxylipins were analyzed by UPLC-ESI-MS/MS. Nine oxylipins changed between early and late fasted seals. Fasting decreased PGF2a and increased 14,15-DiHETrE, 20-HETE, and 4-HDoHE (p<0.05), while insulin reversed these responses. In addition, 12-HpETE and 12-HETE decreased with fasting and response to insulin, respectively. Oxylipins altered during fasting and shown to be sensitive to insulin infusion may contribute to the manifestation of insulin resistance and may participate in the metabolic regulation of these conditions.