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Jennifer Rojas, Ph.D.

Department: Molecular Physiology & Biophysics, 2013

Faculty Mentor: Kevin Niswender, M.D., Ph.D.

Dissertation Title: Obesity dyslipidemia: the effect of central nervous system neuropeptide Y on hepatic lipoprotein metabolism

Dissertation Abstract: Elevated very low-density lipoprotein (VLDL)-triglyceride (TG) secretion from liver contributes to atherogenic dyslipidemia that is associated with obesity, diabetes, and the metabolic syndrome. Numerous models of obesity are characterized by increased central nervous system (CNS) neuropeptide Y (NPY) tone which contributes to positive energy balance and obesity. In fact, an acute, single intracerebroventricular (ICV) administration of NPY in lean fasted rats elevates hepatic VLDL-TG secretion. Thus, our overarching hypothesis is that elevated CNS NPY action contributes to dyslipidemia by activating central circuits that modulate liver lipid metabolism. Our studies focused on identifying molecular determinants in the hypothalamus and the liver by which increased CNS NPY signaling modulates hepatic lipoprotein metabolism.
First, we sought to determine if the effects of NPY on feeding and/or obesity are dissociable from effects on hepatic VLDL-TG secretion. ICV NPY-treated chow-fed rats pair-fed to vehicle-treated controls develop hypertriglyceridemia in the absence of increased food intake and body fat accumulation. Acute ICV injection of selective Y1, Y2, Y4, and Y5 receptor agonists all induced hyperphagia in lean ad-libitum fed rats with the Y2 receptor agonist having the most pronounced effect. The NPY Y1 receptor agonist robustly stimulated hepatic VLDL-TG secretion, while a Y2 receptor agonist had a modest effect on VLDL-TGs, and no effect was observed for Y4 and Y5 receptor agonists in lean fasted rats. These findings raise the possibility that NPY regulates feeding and lipoprotein metabolism partially via separate NPY receptor systems and/or mechanisms.

Lastly, we sought to identify novel regulatory mechanisms in the liver engaged by CNS NPY signaling. We observed, in ICV NPY- and Y1 agonist-treated lean fasted rats, that oleic and linoleic acid were enriched in the liver phospholipid (PL) pool and secreted into plasma TGs. Furthermore, CNS NPY signaling via the Y1 receptor robustly activated key hepatic regulatory enzymes, ADP-ribosylation factor-1 and lipin-1, involved in remodeling liver PL into TG for VLDL maturation and secretion. Altogether, this body of work has overarching implications in further understanding how obesity-related CNS dysfunction contributes to the pathophysiology of atherogenic dyslipidemia associated with obesity, diabetes, and the metabolic syndrome.