Abstract
BackgroundInflammation is generally suppressed during hibernation, but select tissues (e.g. lung) have been shown to activate both antioxidant and pro-inflammatory pathways, particularly during arousal from torpor when breathing rates increase and oxidative metabolism fueling the rewarming process produces more reactive oxygen species. Brown and white adipose tissues are now understood to be major hubs for the regulation of immune and inflammatory responses, yet how these potentially damaging processes are regulated by fat tissues during hibernation has hardly been studied. The advanced glycation end-product receptor (RAGE) can induce pro-inflammatory responses when bound by AGEs (which are glycated and oxidized proteins, lipids, or nucleic acids) or damage associated molecular pattern molecules (DAMPs, which are released from dying cells).MethodsSince gene expression and protein synthesis are largely suppressed during torpor, increases in AGE-RAGE pathway proteins relative to a euthermic control could suggest some role for these pro-inflammatory mediators during hibernation. This study determined how the pro-inflammatory AGE-RAGE signaling pathway is regulated at six major time points of the torpor-arousal cycle in brown and white adipose from a model hibernator, Ictidomys tridecemlineatus. Immunoblotting, RT-qPCR, and a competitive ELISA were used to assess the relative gene expression and protein levels of key regulators of the AGE-RAGE pathway during a hibernation bout.ResultsThe results of this study revealed that RAGE is upregulated as animals arouse from torpor in both types of fat, but AGE and DAMP levels either remain unchanged or decrease. Downstream of the AGE-RAGE cascade, nfat5 was more highly expressed during arousal in brown adipose.DiscussionAn increase in RAGE protein levels and elevated mRNA levels of the downstream transcription factor nfat5 during arousal suggest the pro-inflammatory response is upregulated in adipose tissue of the hibernating ground squirrel. It is unlikely that this cascade is activated by AGEs or DAMPs. This research sheds light on how a fat-but-fit organism with highly regulated metabolism may control the pro-inflammatory AGE-RAGE pathway, a signaling cascade that is often dysregulated in other obese organisms.
Highlights
The advanced-glycation end product (AGE) and AGE receptor (AGE-RAGE) pathway is emerging as an important signal transduction pathway that influences an immune and oxidative stress response via the activation of mitogen-activated protein kinase (MAPK) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways (Sparvero et al, 2009)
White adipose tissue (WAT) showed no changes in relative S100 calcium-binding protein B (S100B) protein levels across the torpor-arousal cycle but high mobility group box 1 protein (HMGB1) levels significantly decreased during Early torpid (ET) and Late torpid (LT) compared to EC to 37% and 31% of the euthermic level, respectively (p < 0.05)
This study focused on the response of the proinflammatory AGE-RAGE signaling pathway in brown adipose tissue (BAT) and white adipose tissue (WAT) from hibernating 13-lined ground squirrels due to the importance the AGE-RAGE pathway in regulating inflammation and oxidative signaling
Summary
The advanced-glycation end product (AGE) and AGE receptor (AGE-RAGE) pathway is emerging as an important signal transduction pathway that influences an immune and oxidative stress response via the activation of mitogen-activated protein kinase (MAPK) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways (Sparvero et al, 2009). During the winter months, hibernating ground squirrels use a range of molecular adaptations to maintain tissue homeostasis until arousal in the spring These animals regulate tissue viability through antioxidant (Morin et al, 2008; Ni & Storey, 2010; Rouble, Tessier & Storey, 2014) and anti-apoptotic (Rouble et al, 2013; Logan et al, 2016; Logan, Luu & Storey, 2016) pathways to prevent the conditions (e.g., hypoxia, cell death) that could give rise to localized inflammation and subsequent tissue damage (Bouma et al, 2013; Bogren et al, 2014). This study determined how the pro-inflammatory AGE-RAGE signaling pathway is regulated at six major time points of the torpor-arousal cycle in brown and white adipose from a model hibernator, Ictidomys tridecemlineatus. This research sheds light on how a fat-but-fit organism with highly regulated metabolism may control the proinflammatory AGE-RAGE pathway, a signaling cascade that is often dysregulated in other obese organisms
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