Hindbrain Glucocorticoid Action Regulates Hepatic Lipid Metabolism
Creators: Vasilev, Boyan S
Publisher: name: University of Alberta Library
Year: 2024

<p>Background: Dyslipidemia is a common characteristic in both diabetes and obesity,<br>
due in part to elevated triglyceride (TG)-rich very-low density lipoprotein (VLDL-TG)<br>
secretion from the liver. Excessive levels and/or action of glucocorticoids (GCs) is also<br>
observed in these metabolic diseases and can contribute to dyslipidemia via both<br>
peripheral and central mechanisms. While mechanisms of peripheral GC action to<br>
regulate lipid metabolism and VLDL-TG secretion are well known, less is understood<br>
about its central mechanisms to regulate metabolism. The brain can sense hormones<br>
and nutrients to coordinate whole-body homeostasis, including lipid metabolism. In<br>
particular, the nucleus of the solitary tract (NTS) is a hindbrain region known to regulate<br>
metabolism. However, whether GCs act in the NTS to regulate VLDL-TG secretion<br>
remains unknown. There has also been evidence that central GC action may regulate<br>
peripheral metabolism by activating the sympathetic nervous system (SNS).<br>
Furthermore, it was recently discovered that the action of GCs are mediated by both<br>
their canonical cytosolic GC receptors (cGRs) and also via novel membrane-associated<br>
GRs (mGRs). In this study, we aimed to explore if GCs acting in the NTS could regulate<br>
hepatic VLDL-TG release through sympathetic outflow, and whether mGRs in the NTS<br>
may be involved as well to better understand the mechanisms by which elevated GCs<br>
may contribute to dyslipidemia. I hypothesize that: 1) NTS GC infusion increases VLDL-<br>
TG secretion via the SNS; 2) infusing a mGR agonist into the NTS increases VLDL-TG<br>
secretion.<br>
Methods: Male Sprague-Dawley rats underwent stereotaxic NTS cannulation and<br>
vascular catheterizations to enable direct NTS infusions, intravenous injections, and<br>
arterial blood sampling. Following a 10-hour fast, rats were subjected to a direct, and<br>
continuous NTS infusion of a specific brain treatment or vehicle paired with an<br>
intravenous poloxamer injection to evaluate VLDL-TG secretion. Plasma was collected<br>
throughout the experiment, before euthanizing the rats and collecting tissues for further<br>
analysis.<br>
Results: NTS GC infusion increased VLDL-TG secretion compared to NTS vehicle, and<br>
this effect was negated with NTS GR or heat shock protein 90 (Hsp90) inhibition. Next,<br>
peripheral pharmacological denervation of the SNS blocked the lipostimulatory effects<br>
of NTS GCs. The increase in VLDL-TG secretion was not associated with changes in<br>
hepatic lipid metabolism-related gene or protein expression. However, elevated plasma<br>
free fatty acids (FFAs) were observed in NTS GC rats, alongside increased pHSL:HSL<br>
levels in white adipose tissue (WAT), and notably, these increases were negated with<br>
SNS inhibition.<br>
NTS infusion of a membrane-impermeant GC to target mGRs also stimulated<br>
VLDL-TG secretion. Interestingly, Hsp90 inhibition or NTS GR knockdown were not able<br>
to reverse the hyperlipidemic effects of NTS mGR agonism. However, antagonizing<br>
protein kinase C or mitogen-activated protein kinase specifically in the NTS blocked the<br>
lipostimulatory actions of NTS mGR activation. The changes in VLDL-TG secretion were<br>
associated with reduced hepatic expression of sterol regulatory element-binding protein<br>
1c and peroxisome proliferator-activated receptor alpha. We also discovered an<br>
upregulation in WAT adipose TG lipase levels, as well as increased plasma FFAs.<br>
Conclusion: We report that hindbrain GC action stimulates hepatic TG secretion via the<br>
SNS. Our data also indicates that novel mGRs in the NTS participate in the<br>
lipostimulatory actions of GCs. The findings in this thesis expand the knowledge of how<br>
excessive GC levels and/or actions can result in hypertriglyceridemia.</p>