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Central nervous system neuropeptide Y regulates mediators of hepatic phospholipid remodeling and very low-density lipoprotein triglyceride secretion via sympathetic innervation.

Rojas JM, Bruinstroop E, Printz RL, Alijagic-Boers A, Foppen E, Turney MK, George L, Beck-Sickinger AG, Kalsbeek A, Niswender KD - Mol Metab (2015)

Bottom Line: 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.Lastly, we show that the effects of CNS NPY on key liporegulatory proteins are attenuated by hepatic sympathetic denervation.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, United States.

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus

Changes in plasma and liver lipid content in response to CNS NPY and Y1 receptor agonist signaling. Plasma and liver samples from lean 4-h fasted rats (n = 5–6/group) were collected 60 min post-icv injection of either NPY (1 nmol; black bars) or the Y1 receptor agonist [F7, P34]-NPY (1 nmol; gray bars) or Veh (white bars) and were used to measure the following: plasma TG, FFA, and PL content in icv NPY- (A) or Y1 receptor agonist- (B) or Veh-treated rats. FFA composition of plasma TG was analyzed for changes in individual FFA levels of myristic acid (14:0), palmitic acid (16:0), palmitoleic acid (16:1), stearic acid (18:0), oleic acid (18:1), and linoleic acid (18:2) after icv treatment with NPY (C) or the Y1 receptor agonist (D). Levels of total TG, FFA, and PL fractions in liver (E) were measured from icv NPY- or Veh-treated rats. FFA composition of liver TG (F), FFA (G), or PL (H) were analyzed for changes in individual FFA levels of 14:0, 16:0, 16:1, 18:0, 18:1, and 18:2 after icv treatment with NPY. Data are presented as mean ± SEM and were analyzed by Student's t-test (unpaired, two-tailed); *indicates a significant difference (p < 0.05) between icv treatment vs. Veh.
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fig2: Changes in plasma and liver lipid content in response to CNS NPY and Y1 receptor agonist signaling. Plasma and liver samples from lean 4-h fasted rats (n = 5–6/group) were collected 60 min post-icv injection of either NPY (1 nmol; black bars) or the Y1 receptor agonist [F7, P34]-NPY (1 nmol; gray bars) or Veh (white bars) and were used to measure the following: plasma TG, FFA, and PL content in icv NPY- (A) or Y1 receptor agonist- (B) or Veh-treated rats. FFA composition of plasma TG was analyzed for changes in individual FFA levels of myristic acid (14:0), palmitic acid (16:0), palmitoleic acid (16:1), stearic acid (18:0), oleic acid (18:1), and linoleic acid (18:2) after icv treatment with NPY (C) or the Y1 receptor agonist (D). Levels of total TG, FFA, and PL fractions in liver (E) were measured from icv NPY- or Veh-treated rats. FFA composition of liver TG (F), FFA (G), or PL (H) were analyzed for changes in individual FFA levels of 14:0, 16:0, 16:1, 18:0, 18:1, and 18:2 after icv treatment with NPY. Data are presented as mean ± SEM and were analyzed by Student's t-test (unpaired, two-tailed); *indicates a significant difference (p < 0.05) between icv treatment vs. Veh.

Mentions: Previously, we demonstrated that icv administration of NPY or a selective NPY Y1 receptor agonist into the third ventricle of lean rats rapidly increases hepatic VLDL-TG secretion independently of feeding and energy balance [13], [14]. To test the hypothesis that liver PL stores may be tightly associated with plasma TG levels in response to an acute modulation of CNS NPY signaling via the NPY Y1 receptor, lean 4-h fasted rats were given an icv injection of either NPY (1 nmol), a selective Y1 receptor agonist ([F7, P34]-NPY; 1 nmol), or Veh (saline), and at 60 min post-injection, trunk blood and liver samples were collected. Of note, NPY and the Y1 receptor agonist were tested in a separate cohort of animals, and each cohort was compared to its corresponding Veh control group. Both NPY and the Y1 receptor agonist treatment increased plasma TG levels by 2.0- and 1.6-fold, respectively (Figure 2A,B). When FFA composition of plasma TG was analyzed for changes in individual FFA concentration after icv treatment with NPY (Figure 2C) or its Y1 receptor agonist (Figure 2D), most individual FFA concentrations increased, further confirming an increase in plasma TG. In addition, plasma PL increased with NPY and the Y1 receptor agonist treatment (Figure 2A,B), while there was no change in plasma FFA (Figure 2A,B). While we did not detect increases in plasma FFA levels, we did not specifically assess FFA flux. Moreover, consistent with our previous findings [13], this increase in plasma TG in response to icv NPY treatment did not alter blood glucose, plasma insulin or glucagon concentrations (Table 1). Although icv Y1 receptor agonist treatment did not alter plasma glucagon and blood glucose levels, plasma insulin levels were moderately increased (Table 1), suggesting that even in the face of a modest increase in insulin levels, increased central Y1 receptor tone can increase hepatic VLDL-TG secretion.


Central nervous system neuropeptide Y regulates mediators of hepatic phospholipid remodeling and very low-density lipoprotein triglyceride secretion via sympathetic innervation.

Rojas JM, Bruinstroop E, Printz RL, Alijagic-Boers A, Foppen E, Turney MK, George L, Beck-Sickinger AG, Kalsbeek A, Niswender KD - Mol Metab (2015)

Changes in plasma and liver lipid content in response to CNS NPY and Y1 receptor agonist signaling. Plasma and liver samples from lean 4-h fasted rats (n = 5–6/group) were collected 60 min post-icv injection of either NPY (1 nmol; black bars) or the Y1 receptor agonist [F7, P34]-NPY (1 nmol; gray bars) or Veh (white bars) and were used to measure the following: plasma TG, FFA, and PL content in icv NPY- (A) or Y1 receptor agonist- (B) or Veh-treated rats. FFA composition of plasma TG was analyzed for changes in individual FFA levels of myristic acid (14:0), palmitic acid (16:0), palmitoleic acid (16:1), stearic acid (18:0), oleic acid (18:1), and linoleic acid (18:2) after icv treatment with NPY (C) or the Y1 receptor agonist (D). Levels of total TG, FFA, and PL fractions in liver (E) were measured from icv NPY- or Veh-treated rats. FFA composition of liver TG (F), FFA (G), or PL (H) were analyzed for changes in individual FFA levels of 14:0, 16:0, 16:1, 18:0, 18:1, and 18:2 after icv treatment with NPY. Data are presented as mean ± SEM and were analyzed by Student's t-test (unpaired, two-tailed); *indicates a significant difference (p < 0.05) between icv treatment vs. Veh.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

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fig2: Changes in plasma and liver lipid content in response to CNS NPY and Y1 receptor agonist signaling. Plasma and liver samples from lean 4-h fasted rats (n = 5–6/group) were collected 60 min post-icv injection of either NPY (1 nmol; black bars) or the Y1 receptor agonist [F7, P34]-NPY (1 nmol; gray bars) or Veh (white bars) and were used to measure the following: plasma TG, FFA, and PL content in icv NPY- (A) or Y1 receptor agonist- (B) or Veh-treated rats. FFA composition of plasma TG was analyzed for changes in individual FFA levels of myristic acid (14:0), palmitic acid (16:0), palmitoleic acid (16:1), stearic acid (18:0), oleic acid (18:1), and linoleic acid (18:2) after icv treatment with NPY (C) or the Y1 receptor agonist (D). Levels of total TG, FFA, and PL fractions in liver (E) were measured from icv NPY- or Veh-treated rats. FFA composition of liver TG (F), FFA (G), or PL (H) were analyzed for changes in individual FFA levels of 14:0, 16:0, 16:1, 18:0, 18:1, and 18:2 after icv treatment with NPY. Data are presented as mean ± SEM and were analyzed by Student's t-test (unpaired, two-tailed); *indicates a significant difference (p < 0.05) between icv treatment vs. Veh.
Mentions: Previously, we demonstrated that icv administration of NPY or a selective NPY Y1 receptor agonist into the third ventricle of lean rats rapidly increases hepatic VLDL-TG secretion independently of feeding and energy balance [13], [14]. To test the hypothesis that liver PL stores may be tightly associated with plasma TG levels in response to an acute modulation of CNS NPY signaling via the NPY Y1 receptor, lean 4-h fasted rats were given an icv injection of either NPY (1 nmol), a selective Y1 receptor agonist ([F7, P34]-NPY; 1 nmol), or Veh (saline), and at 60 min post-injection, trunk blood and liver samples were collected. Of note, NPY and the Y1 receptor agonist were tested in a separate cohort of animals, and each cohort was compared to its corresponding Veh control group. Both NPY and the Y1 receptor agonist treatment increased plasma TG levels by 2.0- and 1.6-fold, respectively (Figure 2A,B). When FFA composition of plasma TG was analyzed for changes in individual FFA concentration after icv treatment with NPY (Figure 2C) or its Y1 receptor agonist (Figure 2D), most individual FFA concentrations increased, further confirming an increase in plasma TG. In addition, plasma PL increased with NPY and the Y1 receptor agonist treatment (Figure 2A,B), while there was no change in plasma FFA (Figure 2A,B). While we did not detect increases in plasma FFA levels, we did not specifically assess FFA flux. Moreover, consistent with our previous findings [13], this increase in plasma TG in response to icv NPY treatment did not alter blood glucose, plasma insulin or glucagon concentrations (Table 1). Although icv Y1 receptor agonist treatment did not alter plasma glucagon and blood glucose levels, plasma insulin levels were moderately increased (Table 1), suggesting that even in the face of a modest increase in insulin levels, increased central Y1 receptor tone can increase hepatic VLDL-TG secretion.

Bottom Line: 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.Lastly, we show that the effects of CNS NPY on key liporegulatory proteins are attenuated by hepatic sympathetic denervation.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, United States.

ABSTRACT

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.

No MeSH data available.


Related in: MedlinePlus