44-LB: Hypothalamic Glucocorticoid Action Regulates Lipid Metabolism

Aberrant lipid homeostasis is a feature of diabetes and obesity. This metabolic imbalance is associated with excessive levels and/or actions of glucocorticoids (GCs) and contributes to dyslipidemia including elevated hepatic triglyceride (TG)-rich very low-density lipoprotein (VLDL-TG) secretion. The mediobasal hypothalamus (MBH) is a nutrient and hormone sensing brain region that regulates whole-body lipid metabolism and VLDL-TG secretion. We aimed to assess GC action in the MBH in regulating VLDL-TG secretion in health and diet-induced hyperlipidemia.

Sprague Dawley rats received stereotaxic MBH cannulation and vascular catheterizations to enable direct MBH infusions, intravenous injections, and blood sampling. Plasma TG levels and the rate VLDL-TG secretion were measured in 10h-fasted rats following intravenous poloxamer injection with concomitant MBH infusions. In healthy rats, direct MBH GC infusion increased VLDL-TG secretion compared to controls. MBH GC action is mediated via its receptor (GR) since mifepristone (GR antagonist) co-infusion, chronic inhibition of GRs in the MBH with GR shRNA, or inhibition of heat shock protein 90 (required for in vivo GR function) negated the MBH GC-induced increases in VLDL-TG secretion rate. High-fat diet-fed rats had both elevated basal plasma GC levels and hepatic TG secretion compared to healthy rats. Remarkably, chronic MBH GR loss-of-function lowered VLDL-TG secretion in high-fat diet-induced hyperlipidemic rats, independent of changes in body weight.

Here, we provide novel in vivo evidence that MBH GC action modulates VLDL-TG secretion and suggest that blocking excessive GC action in the brain improves lipid homeostasis in diet-induced hyperlipidemic rats. These findings may provide insight on lowering lipid levels in diabetes and obesity.