Hindbrain Glucocorticoid Action Regulates Hepatic Lipid Metabolism

• Author / Creator

  Vasilev, Boyan S

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

• Subjects / Keywords

  • Glucocorticoids
  • Obesity
  • Diabetes
  • Metabolism
  • Triglycerides
  • Brain
  • Hindbrain

• Graduation date

  Fall 2024

• Type of Item

  Thesis

• Degree

  Master of Science

• DOI

  https://doi.org/10.7939/r3-astr-8a15

• License

  This thesis is made available by the University of Alberta Library with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.