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

Abstract

SUMMARYThe northern elephant seal pup (Mirounga angustirostris) 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 non-esterified fatty acids (NEFAs) increases and is associated with the development of insulin resistance in late-fasted pups. Furthermore, plasma NEFA 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. However, elucidation of the lipolytic mechanisms including lipase activity during prolonged fasting in mammals is scarce. To assess the impact of fasting and glucose on the regulation of lipid metabolism, adipose tissue and plasma samples were collected before and after ivGTTs performed on early (2weeks, N5) and late (6-8weeks; N8) fasted pups. Glucose administration increased plasma triglycerides and NEFA concentrations in late-fasted seals, but not plasma glycerol. Fasting decreased basal adipose lipase activity by 50%. Fasting also increased plasma lipase activity twofold and decreased the expressions of CD36, FAS, FATP1 and PEPCK-C by 22-43% in adipose tissue. Plasma acylcarnitine profiling indicated that late-fasted seals display higher incomplete LCFA -oxidation. Results suggest that long-term fasting induces shifts in the regulation of lipolysis and lipid metabolism associated with the onset of insulin resistance in northern elephant seal pups. Delineation of the mechanisms responsible for this shift in regulation during fasting can contribute to a more thorough understanding of the changes in lipid metabolism associated with dyslipidemia and insulin resistance in mammals.

Prolonged food deprivation increases mRNA expression of deiodinase 1 and 2, and thyroid hormone receptor β-1 in a fasting-adapted mammal

“…The fasting metabolism of seals is primarily dependent on lipid oxidation (Crocker et al, 1998;Pramfalk et al, 2011; Crocker et al, 2012a; Crocker et al, 2012b;van Heyningen and Glaysher, 2012;Houser et al, 2012;Viscarra et al, 2012). Lipid metabolism in fasting pups is characterized by reduced adipose NEFA uptake and increased triglyceride hydrolysis, which contribute to the maintenance of elevated NEFA during the fast .…”

“…Because our hypothesis focused on the changes in the deiodinases and the TH receptor, these proteins were given priority. Protein expression was quantified by standard western blot as previously described (Vázquez-Medina et al, 2011;Viscarra et al, 2011a;Viscarra et al, 2011b;Vázquez-Medina et al, 2012;Soñanez-Organis et al, 2012;Viscarra et al, 2012). The primary antibodies for DI1 and DI2, THrβ1, TATA binding protein, histone H3 and β-actin (Santa Cruz Biotechnology, Santa Cruz, CA) were diluted 1:500 to 1:5000.…”

“…cryptically hyperthyroid) (Magnus and Henderson, 1988a;Magnus and Henderson, 1988b). Such variability in the regulation of TH levels and function in food-deprived mammals demonstrates the diversity of TH physiology during periods of acute or chronic food deprivation, and highlights the necessity to perform more comprehensive studies into the functional relevance of these differences.Northern elephant seals, Mirounga angustirostris (Gill 1866), naturally fast from food and water for up to 3 months while on land (Ortiz et al, 1978; Crocker et al, 1998;Le Boeuf and Laws, 1994), and during the post-weaning fast, oxidation of non-esterified fatty acids (NEFAs) accounts for approximately 95% of the pup's metabolic rate (Ortiz et al, 1978;Viscarra et al, 2012). The fasting metabolism of seals is primarily dependent on lipid oxidation (Crocker et al, 1998;Pramfalk et al, 2011; Crocker et al, 2012a; Crocker et al, 2012b;van Heyningen and Glaysher, 2012;Houser et al, 2012;Viscarra et al, 2012).…”

“…These cellular responses to fasting duration suggest that upregulation of TH-mediated cellular activity contributes, at least in part, to the sustained lipid-based metabolism of these animals (Ortiz et al, 1978;Houser and Costa, 2001;Noren et al, 2003;Houser et al, 2012;Viscarra et al, 2012). This apparent paradox suggests that an increase in TH activity is partially responsible for the maintenance of the relatively high metabolic rates observed in a fasting, but normothermic, mammal such as the northern elephant seal (Rea and Costa, 1992; Crocker et al, 1998).…”

Activation of systemic, but not local, renin-angiotensin system is associated with up-regulation of TNF-α during prolonged fasting in northern elephant seal pups

“…While the increased expression in muscle TNF-α was not sufficient to translate into increased circulating levels, the increase in muscle levels may be sufficient to contribute to local impairment of insulin signaling, especially because muscle is the primary sink of peripheral glucose utilization. Thus, the lack of an increase in adipose TNF-α may be adaptive to allow this relatively large mass of tissue to utilize glucose as needed to facilitate lipid metabolism to support the protracted fasting duration (Viscarra et al, 2012). Hence, the result is differential responsiveness of tissue TNF-α to increased plasma Ang II that is dependent on the metabolic contributions of the two tissues, adipose versus muscle.…”