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Central Nervous System Neuropeptide Y Signaling Modulates VLDL Triglyceride Secretion

¹ Division of Diabetes, Endocrinology, and Metabolism, Department of Internal Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee
² Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee
³ Department of Pathology, Vanderbilt University School of Medicine, Nashville, Tennessee
⁴ Tennessee Valley Healthcare System, Nashville, Tennessee

Corresponding author: Kevin Niswender, 7435G Medical Research Building IV, Nashville, TN 37232-4705. E-mail: kevin.niswender{at}vanderbilt.edu

Abbreviations: ACC, acetyl CoA carboxylase; apoB100, apolipoprotein B100; apoB48, apolipoprotein ARF-1, ADP-ribosylation factor-1; AUC, area under the curve; B48; CNS, central nervous system; FAS, fatty acid synthase; FFA, free fatty acid; FPLC, fast performance liquid chromatography; MC4R, melanocortin 4 receptor; MTII, melanotan II; MTP, microsomal triglyceride transfer protein; NPY, neuropeptide Y; POMC, proopiomelanocortin; SCD1, stearoyl-CoA desaturase-1; TG, triglyceride; VLDL-TG, elevated TGs in the form of VLDL

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 central nervous system (CNS) energy homeostatic circuits contributes to the development of obesity. Because triglycerides both represent the largest energy depot in the body and are 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 TGs into plasma.

RESEARCH DESIGN AND METHODS—In normal fasting rats, the TG secretion rate was estimated by serial blood sampling after intravascular tyloxapol pretreatment. Neuropeptide Y (NPY) signaling in the CNS was modulated by intracerebroventricular injection of NPY, receptor antagonist, and receptor agonist.

RESULTS—A single intracerebroventricular injection of NPY increased TG secretion by 2.5-fold in the absence of food intake, and this was determined to be VLDL by fast performance 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 elevated TGs in the form of VLDL secretion rate by 50% compared with vehicle. Increased TG secretion was due to increased secretion of VLDL particles, rather than secretion of larger particles, because apolipoprotein B100 was elevated in FPLC fractions corresponding to VLDL.

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

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