Decreased expression of adipose CD36 and FATP1 are associated with increased plasma nonesterified fatty acids during prolonged fasting in northern elephant seal pups (Mirounga angustirostris)

Authors: VISCARRA, JOSE - University Of California; VAZQUEZ-MEDINA, JOSE - University Of California; RODRIGUEZ, RUBEN - University Of California; CHAMPAGNE, CORY - University Of California; Adams, Sean; CROCKER, DANIEL - Sonoma State University; ORTIZ, RUDY - University Of California

Submitted to: Experimental Biology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/22/2011
Publication Date: 7/15/2012
Citation: Viscarra, J.A., Vazquez-Medina, J.P., Rodriguez, R., Champagne, C.D., Adams, S.H., Crocker, D.E., Ortiz, R.M. 2012. Decreased expression of adipose CD36 and FATP1 are associated with increased plasma nonesterified fatty acids during prolonged fasting in northern elephant seal pups (Mirounga angustirostris) . Experimental Biology. 215(Pt 14):2455-64.

Interpretive Summary: Emerging evidence in rodent models and in humans suggests that perturbation of proper insulin signaling, as seen in diabetes, not only impairs blood sugar control but also causes disruption of normal fat and amino acid/protein metabolism. Yet, the mechanisms underlying this phenomenon are controversial and it remains to be seen how commonplace these associations are across multiple mammalian models and taxa. Northern elephant seal pups undergo a 2-3 month post-weaning fast during which they depend primarily on the oxidation of fatty acids to meet energetic demands. The concentration of plasma free fatty acids (FFA) increases and is associated with the development of insulin resistance in late-fasted pups, which might be an adaptational response to fasting by preserving glucose. 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 contributions of plasma vs. adipose tissue activity to lipolysis during prolonged fasting in naturally fasting mammals is lacking. To assess the impact of fasting and glucose on the regulation of lipid metabolism, adipose tissue 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. Glucose administration increased plasma triglycerides and FFA concentrations in long term fasted seals, but not plasma glycerol. Fasting decreased basal adipose lipase activity by 50%. Fasting also increased plasma lipase activity 2-fold. Results suggest that long-term fasting induces shifts in the tissue-specific regulation of lipolysis and that plasma lipase activity contributes acutely to the glucose-induced increases in FFA. As seen in obese, insulin-resistant or diabetic humans and in rodent obesity animal models, naturally-developing insulin resistance in Northern elephant seal pups was marked by increased blood markers of incomplete FFA combustion and mismatched delivery of FFA vs. mitochondrial capacity (energy production site). Altogether, the consistent data when comparing disparate animals across taxonomic boundaries indicates that dysfunctional FFA oxidation and insulin resistance are a common feature in biology.

Technical Abstract: The northern elephant seal undergoes a 2-3 month post-weaning fast during which it depends primarily on the oxidation of fatty acids to meet its energetic demands. The concentration of plasma free fatty acids (FFA) increases and is associated with the development 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 contributions of plasma vs. adipose lipase activity to lipolysis during prolonged fasting in naturally fasting mammals is lacking. To assess the impact of fasting and glucose on the regulation of lipid metabolism, adipose tissue 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. Glucose administration increased plasma triglycerides and FFA concentrations in long term fasted seals, but not plasma glycerol. Fasting decreased basal adipose lipase activity by 50%. Fasting also increased plasma lipase activity 2-fold and decreased the expressions of CD36, FAS, FATP1 and PEPCK-C 22% to 43% in adipose. Results suggest that long-term fasting induces shifts in the regulation of lipolysis and that plasma lipase activity contributes acutely to the glucose-induced increases in FFA. A better understanding of changes in lipid metabolism associated with the manifestation of insulin resistance in a mammal adapted to such reliance on lipid metabolism provides a unique opportunity to assess an adaptive mechanism likely possessed by many fasting mammals.