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

Abstract

SUMMARYNorthern elephant seal pups naturally endure a 2-3month post-weaning fast that is associated with activation of systemic renin-angiotensin system (RAS), a decrease in plasma adiponectin (Acrp30), and insulin resistance (IR)-like conditions. Angiotensin II (Ang II) and tumor necrosis factor-alpha (TNF-α) are potential causal factors of IR, while Acrp30 may improve insulin signaling. However, the effects of fasting-induced activation of RAS on IR-like conditions in seals are not well described. To assess the effects of prolonged food deprivation on systemic and local RAS, and their potential contribution to TNF-α as they relate to an IR condition, the mRNA expressions of adipose and muscle RAS components and immuno-relevant molecules were measured along with plasma RAS components. Mean plasma renin activity and Ang II concentrations increased by 89 and 1658%, respectively, while plasma angiotensinogen (AGT) decreased by 49% over the fast, indicative of systemic RAS activation. Prolonged fasting was associated with decreases in adipose and muscle AGT mRNA expressions of 69 and 68%, respectively, corresponding with decreases in tissue protein content, suggesting suppression of local AGT production. Muscle TNF-α mRNA and protein increased by 239 and 314%, whereas those of adipose Acrp30 decreased by 32 and 98%, respectively. Collectively, this study suggests that prolonged fasting activates a systemic RAS, which contributes to an increase in muscle TNF-α and suppression of adipose Acrp30. This targeted and tissue-specific regulation of TNF-α and Acrp30 is likely coordinated to synergistically contribute to the development of an IR-like condition, independent of local RAS activity. These data enhance our understanding of the adaptive mechanisms evolved by elephant seals to tolerate potentially detrimental conditions.

Adiposity and fat metabolism during combined fasting and lactation in elephant seals

“…Fasting NES require continued lipolysis and indeed display insulin resistance Fowler et al, 2008). Adipocyte TNFα expression levels are stable throughout the fast and increase in the muscle of NES weanlings (Suzuki et al, 2013;. These expression patterns from early to late fasting in NES weanlings align with observed metabolic patterns such as elevated lipolysis and insulin resistance.…”

“…In humans, adiponectin is inversely related to fat mass, contrary to most of the other adipocytokines (Hotta et al, 2001), whereas apelin increases with fat mass (Boucher et al, 2005). Both adiponectin and apelin are typically associated with improved insulin sensitivity (Okamoto et al, 2008;Yue et al, 2010) and both decrease over the fasting duration in NES weanlings (Viscarra et al, 2011a(Viscarra et al, ,b, 2012Suzuki et al, 2013). NES weanlings display insulin resistance (Viscarra et al, 2011a), thus the decrease in these adipocytokines is consistent with decreased insulin sensitivity.…”

Plasma FGF21 concentrations, adipose fibroblast growth factor receptor-1 and β-klotho expression decrease with fasting in northern elephant seals

“…In rat and human adipocytes, TNFα can suppress KLB expression and impair FGF21 signaling as a consequence of insulin resistance (Díaz-Delfín et al 2012). Previously, we reported an increase in muscle TNFα (Suzuki et al, 2013) and IR-like condition in adipose (Viscarra et al, 2011) during late fasting in elephant seal pups suggesting that a local increase in TNFα and/or induction of an IR-like condition may contribute to the down-regulation of KLB. Consistent with the decrease in KLB, adipose FGFR1 expression was also suppressed with fasting duration.…”

“…RNA extraction, cDNA synthesis and qPCR were performed according to a previously reported procedure (Suzuki et al, 2013). Briefly, RNA was extracted from adipose with TRIzol (Life Technologies, Grand Island, NY).…”

A nutrigenomic approach to detect nutritional stress from gene expression in blood samples drawn from Steller sea lions

“…GAPDH has often been used as a normaliser in gene expression studies of seals and fur seals (Sharp et al, 2006;Fonfara et al, 2007Fonfara et al, , 2008, and has been shown to be stable in elephant seals experiencing prolonged fasts Suzuki et al, 2013). Nevertheless, the expression of reference genes can sometimes be influenced by stress or applied treatments, and GAPDH is part of the glycolytic pathway.…”