| Summary: | The northern elephant seal endures a 2–3 month fast during which it depends primarily on the oxidation of fatty acids to meet its energetic demands. Plasma free fatty acid (FFA) concentration increases and is associated with the onset of insulin resistance in late‐fasted pups. Plasma FFA concentrations respond differentially to an intravenous glucose tolerance test (ivGTT) depending on fasting duration suggesting that the effects of glucose on lipid metabolism are altered. Elucidation of the mechanisms responsible for the increase in plasma FFA in late‐fasted seals is lacking. To assess the impact of fasting and glucose on lipid metabolism, adipose and plasma samples were collected before and after GTTs, performed on early (2 weeks, n=5) and late (6–8 weeks; n=8) fasted pups. Plasma triglycerides and FFAs increased post‐GTT in fasted seals. Fasting decreased adipose lipase activity by 50% and the expressions of CD36, FAS, FATP1 and PEPCK‐C 22 ‐ 43% in adipose. Fasting increased plasma lipase activity 2‐ fold. These results present the probable cause of, and reason for the onset of fasting‐induced insulin resistance in adapted mammals, as fasting leads to the altered regulation of lipolysis and reduction in tissue fatty acid uptake in late‐fasted pups, likely to ensure a constant supply of lipids in plasma, while conserving glucose for tissues which cannot metabolize lipids and sparing lean tissue. Funded by NIH HL91767
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