Glucocorticoid Action in the Mediobasal Hypothalamus Regulates Glucose Production In Vivo

• Author / Creator

  Beaulieu-Bayne, Emilie

• Background: Diabetes is characterized by dysregulated glucose homeostasis that leads to hyperglycemia, due in part to increased hepatic glucose production (GP) and insulin resistance. Excessive levels and/or action of glucocorticoids (GCs) are associated with obesity, insulin resistance, and hyperglycemia. Whereas the peripheral effect of GCs to elevate glycemia is well known, less is known about the brain effect of GCs to modulate metabolism. The brain senses nutrients and hormones to regulate glucose homeostasis. This study aims to delineate a mechanism of GC action in the mediobasal hypothalamus (MBH) that modulates GP in normal and pre-obese rodents. I hypothesize that GC action in the brain alters glucose metabolism.

  Methods: Male SD rats underwent stereotaxic MBH bilateral cannulation and intravenous (iv) and intraarterial catheterization to enable simultaneous direct infusions into the MBH, iv infusions, and blood sampling, respectively. Mildly hyperinsulinemic-euglycemic clamps with tracer dilution methodology combined with MBH GC infusion ± GC receptor (GR) inhibition enabled measurement of GP and utilization while assessing MBH GC interaction with its MBH receptors independent of changes in plasma insulin, glucagon, and glucose levels.

  Results: In healthy regular-chow (RC) fed rats, MBH GC infusion potently stimulates GP and lowers the requirement for exogenous glucose infusion without altering glucose utilization. This effect is mediated via GRs since co-infusion of GR antagonist mifepristone (MIF), or a Hsp90 inhibitor, as well as chronic MBH GR or Hsp90 inhibition with MBH GR shRNA or MBH Hsp90 shRNA negates the ability of MBH GCs to increase GP. MBH GCs similarly increased glucose excursions during iv glucose tolerance tests (ivGTT), which were reversed with concomitant MBH MIF infusion. Rats fed with high fat diet (HFD) for 3 days had altered glucose kinetics and increased basal plasma corticosterone, insulin, and blood glucose levels without changes in body weight. MBH MIF infusion or chronic MBH GR inhibition with MBH GR shRNA lowered GP compared to MBH vehicle and mismatch control HFD rats with MBH saline infusions, suggesting that blocking excessive MBH GC action in a model of pre-obesity with hypercorticosteronemia resulting from HFD feeding attenuates GP to improve glucose homeostasis.

  Conclusion: This study provides novel evidence that MBH GC action modulates GP in healthy and pre-obese rats. Importantly, targeted inhibition of MBH GC action may help improve glucose regulation in obesity-related metabolic disease.

• Subjects / Keywords

  • hypothalamus
  • diabetes
  • glucocorticoids
  • neuroendocrinology
  • metabolism
  • mediobasal hypothalamus
  • obesity
  • corticosterone

• Graduation date

  Fall 2019

• Type of Item

  Thesis

• Degree

  Master of Science

• DOI

  https://doi.org/10.7939/r3-eahb-a894

• License

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