Central nervous system neuropeptide Y regulates mediators of hepatic phospholipid remodeling and very low-density lipoprotein triglyceride secretion via sympathetic innervation.
OBJECTIVE
Elevated very low-density lipoprotein (VLDL)-triglyceride (TG) secretion from the liver contributes to an atherogenic dyslipidemia that is associated with obesity, diabetes and the metabolic syndrome. Numerous models of obesity and diabetes are characterized by increased central nervous system (CNS) neuropeptide Y (NPY); in fact, a single intracerebroventricular (icv) administration of NPY in lean fasted rats elevates hepatic VLDL-TG secretion and does so, in large part, via signaling through the CNS NPY Y1 receptor. Thus, our overarching hypothesis is that elevated CNS NPY action contributes to dyslipidemia by activating central circuits that modulate liver lipid metabolism.


METHODS
Chow-fed Zucker fatty (ZF) rats were pair-fed by matching their caloric intake to that of lean controls and effects on body weight, plasma TG, and liver content of TG and phospholipid (PL) were compared to ad-libitum (ad-lib) fed ZF rats. Additionally, lean 4-h fasted rats with intact or disrupted hepatic sympathetic innervation were treated with icv NPY or NPY Y1 receptor agonist to identify novel hepatic mechanisms by which NPY promotes VLDL particle maturation and secretion.


RESULTS
Manipulation of plasma TG levels in obese ZF rats, through pair-feeding had no effect on liver TG content; however, hepatic PL content was substantially reduced and was tightly correlated with plasma TG levels. Treatment with icv NPY or a selective NPY Y1 receptor agonist in lean fasted rats robustly activated key hepatic regulatory proteins, stearoyl-CoA desaturase-1 (SCD-1), ADP-ribosylation factor-1 (ARF-1), and lipin-1, known to be involved in remodeling liver PL into TG for VLDL maturation and secretion. Lastly, we show that the effects of CNS NPY on key liporegulatory proteins are attenuated by hepatic sympathetic denervation.


CONCLUSIONS
These data support a model in which CNS NPY modulates mediators of hepatic PL remodeling and VLDL maturation to stimulate VLDL-TG secretion that is dependent on the Y1 receptor and sympathetic signaling to the liver.
Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, United States.
Jennifer M
JM
Rojas
Department of Endocrinology and Metabolism, Laboratory of Endocrinology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Eveline
E
Bruinstroop
Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, United States.
Richard L
RL
Printz
Department of Hypothalamic Integration Mechanisms, Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Science, Amsterdam, The Netherlands.
Aldijana
A
Alijagic-Boers
Department of Endocrinology and Metabolism, Laboratory of Endocrinology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Ewout
E
Foppen
Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, United States.
Maxine K
MK
Turney
Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, United States.
Leena
L
George
Institute of Biochemistry, Faculty of Bioscience, Pharmacy and Psychology, Leipzig University, Leipzig, Germany.
Annette G
AG
Beck-Sickinger
Department of Endocrinology and Metabolism, Laboratory of Endocrinology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands ; Department of Hypothalamic Integration Mechanisms, Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Science, Amsterdam, The Netherlands.
Andries
A
Kalsbeek
Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, United States ; Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, United States ; Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, United States.
Kevin D
KD
Niswender
AGPAT, 1-acyl-glycerol-3-phosphate acyltransferase; ARF-1, ADP-ribosylation factor-1; ApoB, apolipoprotein B; CNS, central nervous system; Cyto, cytoplasmic; DAG, diacylglycerol; DGAT, diacylglycerol acyltransferase; ER, endoplasmic reticulum; FFA(s), free fatty acid(s); GAPDH, glyceraldehyde 3-phosphate dehydrogenase; HDAC-1, histone deacetylase-1; Lipin-1; NE, norepinephrine; NPY Y1 receptor; NPY, neuropeptide Y; Nuc, nuclear; PA, phosphatidic acid; PAP-1, phosphatidic acid phosphatase-1; PF, pair-fed; PL, phospholipid; PLD, phospholipase D; POMC, proopiomelanocortin; Phospholipid; RPL13A, ribosomal protein L13a; RT-PCR, real-time PCR; SCD-1, stearoyl-CoA desaturase-1; SNS, sympathetic nervous system; Sham, sham-denervation; Sx, sympathetic denervation; Sympathetic denervation; TG, triglyceride; Triglyceride; VLDL; VLDL, very low-density lipoprotein; Veh, vehicle; ZF, Zucker fatty; ad-lib, ad-libitum; icv, intracerebroventricular