Central nervous system neuropeptide Y signaling modulates VLDL triglyceride secretion.

Abstract

Objective: Elevated triglyceride (TG) is the major plasma lipid abnormality in obese and diabetic patients and contributes to cardiovascular morbidity in these disorders. We sought to identify novel mechanisms leading to hypertriglyceridemia. Resistance to negative feedback signals from adipose tissue in key CNS energy homeostatic circuits contributes to the development of obesity. Because triglyceride (TG) represents both the largest energy depot in the body and is elevated in both the plasma and adipose in obesity and diabetes, we hypothesized that the same neural circuits that regulate energy balance also regulate the secretion of TG into plasma.

Methods: In normal fasting rats, the TG secretion rate was estimated by serial blood sampling after intravascular tyloxapol pre-treatment. NPY signaling in the CNS was modulated by intracerebroventricular (ICV) injection of NPY, receptor antagonist, and receptor agonist.

Results: A single ICV injection of NPY increased TG secretion by 2.5-fold in the absence of food intake, and this was determined to be very-low density lipoprotein (VLDL) by fast protein liquid chromatography (FPLC). This effect was recapitulated by activating NPY signaling in downstream neurons with an NPY-Y5 receptor agonist. An NPY-Y1 receptor antagonist decreased the VLDL-TG secretion rate by 50% compared to vehicle. Increased TG secretion was due to increased secretion of VLDL particles, rather than secretion of larger particles, as apolipoprotein B100 was elevated in FPLC fractions corresponding to VLDL.

Conclusion: We find that a key neuropeptide system involved in energy homeostasis in the CNS exerts control over VLDL-TG secretion into the bloodstream.