Neuropeptide Y in hypothalamic paraventricular nucleus: a center coordinating energy metabolism

1994 ◽  
Vol 266 (6) ◽  
pp. R1765-R1770 ◽  
Author(s):  
C. J. Billington ◽  
J. E. Briggs ◽  
S. Harker ◽  
M. Grace ◽  
A. S. Levine
Keyword(s):  
Gene Expression ◽  
Energy Metabolism ◽  
Neuropeptide Y ◽  
Paraventricular Nucleus ◽  
Neural Circuit ◽  
Uncoupling Protein ◽  
Brown Fat ◽  
Mrna Levels ◽  
Ad Libitum ◽  
White Fat

Intracerebroventricular injection of neuropeptide Y (NPY) has two effects on energy metabolism in addition to increased feeding: decreased brown fat thermogenesis and increased white fat lipoprotein lipase (LPL) enzymatic activity. We hypothesized that the paraventricular nucleus (PVN) of the hypothalamus is the controlling neural site for these responses. We further hypothesized that NPY stimulation at PVN would reduce gene expression for the critical brown fat thermogenic protein, uncoupling protein (UCP), and increase gene expression for the key white fat storage enzyme, LPL. In the first experiment, three groups of rats received injections every 6 h for 24 h (5 injections total) into the PVN:1) NPY (1 micrograms/1 microliters injection) and ad libitum food; 2) NPY (1 micrograms/1 microliters injection) and food restricted to control intake; 3) saline injection (1 microliter) and ad libitum food. Both NPY-treated groups showed significant reductions (P < 0.05) in brown fat UCP mRNA levels and marked stimulation of LPL mRNA levels relative to controls. In the second experiment, four groups of seven rats had NPY injected into the PVN:0 (vehicle control); 0.1 microgram; 0.5 microgram; and 1 microgram. Injections were made every 6 h for 24 h. There was a dose-related reduction in UCP mRNA produced by the NPY treatment. NPY treatment increased LPL mRNA, but a smooth dosing effect was not evident. The observation that NPY in the PVN can coordinate more than one component of energy metabolism is significant when considered with many reports of responsiveness of NPY activity in the arcuate nucleus-PVN neural circuit to perturbations of energy balance such as fasting and feeding, diabetes, and genetic obesity.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Manipulation of dietary amino acids prevents and reverses obesity in mice through multiple mechanisms that modulate energy homeostasis

2020 ◽  
Author(s):  
Ada Admin ◽  
Chiara Ruocco ◽  
Maurizio Ragni ◽  
Fabio Rossi ◽  
Pierluigi Carullo ◽  
...  
Keyword(s):  
Amino Acids ◽  
Energy Metabolism ◽  
Energy Homeostasis ◽  
Molecular Mechanisms ◽  
Uncoupling Protein ◽  
Essential Amino Acids ◽  
Brown Fat ◽  
Acid Oxidation ◽  
White Fat

Reduced activation of energy metabolism increases adiposity in humans and other mammals. Thus, exploring dietary and molecular mechanisms able to improve energy metabolism is of paramount medical importance, as such mechanisms can be leveraged as a therapy for obesity and related disorders. Here, <a>we show that a designer protein-deprived diet enriched in free essential amino acids can i) promote the brown fat thermogenic program and fatty acid oxidation, ii) stimulate uncoupling protein 1 (UCP1)-independent respiration in subcutaneous white fat, iii) change the gut microbiota composition, and iv) prevent and reverse obesity and dysregulated glucose homeostasis in multiple mouse models, prolonging the healthy lifespan. </a>These effects are independent of unbalanced amino acid ratio, energy consumption, and intestinal calorie absorption. A brown fat-specific activation of the mechanistic target of rapamycin complex 1 seems involved in the diet-induced beneficial effects, as also strengthened by <i>in vitro</i> experiments. Hence, our results suggest that brown and white fat may be targets of specific amino acids to control UCP1-dependent and -independent thermogenesis, thereby contributing to the improvement of metabolic health.

Naltrexone induces arcuate nucleus neuropeptide Y gene expression in the rat

1996 ◽  
Vol 271 (1) ◽  
pp. R289-R294 ◽  
Author(s):  
C. M. Kotz ◽  
M. K. Grace ◽  
J. E. Briggs ◽  
C. J. Billington ◽  
A. S. Levine
Keyword(s):  
Energy Balance ◽  
Food Intake ◽  
Neuropeptide Y ◽  
Food Deprivation ◽  
Arcuate Nucleus ◽  
Uncoupling Protein ◽  
Endogenous Opioids ◽  
Brown Fat ◽  
Mrna Levels ◽  
Sprague Dawley

Neuropeptide Y (NPY) has potent effects on several components of energy metabolism, including increased feeding and decreased brown fat thermogenesis. Negative energy balance, such as food deprivation, increases NPY mRNA in hypothalamic arcuate nucleus (ARC). Naltrexone (NLTX), an opioid receptor antagonist, decreases NPY-induced feeding. We hypothesized that NLTX would alter ARC NPY mRNA and change NPY effects on brown fat. Osmotic minipumps prefilled with either saline or NLTX (70 micrograms/h) were implanted subcutaneously in 32 male Sprague-Dawley rats. One-half of the rats were food deprived and one-half were allowed food ad libitum for 48 h. Food intake was measured at 24 and 48 h. At 48 h, ARC NPY mRNA and brown fat uncoupling protein (UCP) mRNA levels were determined using cDNA probes. Forty-eight-hour food intake was significantly decreased by 24% after NLTX infusion. Food deprivation and NLTX treatment significantly and independently increased ARC NPY mRNA and decreased UCP mRNA levels in brown fat, suggesting a complex interaction between hypothalamic NPY and endogenous opioids in the regulation of energy balance.

Dietary fat interacts with QTLs controlling induction of Pgc-1α and Ucp1 during conversion of white to brown fat

2003 ◽  
Vol 14 (2) ◽  
pp. 139-147 ◽  
Author(s):  
Ann Allen Coulter ◽  
Christie M. Bearden ◽  
Xiaotuan Liu ◽  
Robert A. Koza ◽  
Leslie P. Kozak
Keyword(s):  
Energy Metabolism ◽  
Dietary Fat ◽  
High Fat Diet ◽  
Brown Fat ◽  
Brown Adipocyte ◽  
Chromosome 3 ◽  
Mrna Levels ◽  
High Fat ◽  
Chromosome 5 ◽  
White Fat

To identify novel regulatory factors controlling induction of the brown adipocyte-specific mitochondrial uncoupling protein ( Ucp1) mRNA in the retroperitoneal white fat depot, we previously mapped quantitative trait loci (QTLs) that control this trait to chromosomes 2, 3, 8, and 19. Since the peroxisome proliferator activator receptor-γ coactivator-1α (PGC-1α) regulates Ucp1 and other genes of energy metabolism, we have evaluated whether the QTLs controlling Ucp1 mRNA levels also modulate Pgc-1α mRNA levels by analysis of backcross progeny from the A/J and C57BL/6J strains of mice. The results indicate that a locus on chromosome 3 orchestrates expression of Pgc-1α and Ucp1 in retroperitoneal fat of mice fed a low-fat diet; however, the effect of this locus on Pgc-1α is lost, and a significant correlation between Ucp1 and Pgc-1α is severely reduced in mice fed a high-fat diet. An additional QTL located on chromosome 5 has also been identified for the selective regulation of Ucp1 mRNA levels. Similar to the effects of a high-fat diet on the chromosome 3 QTL, linkage of the chromosome 5 QTL is also lost in mice on a high-fat diet. Thus dietary fat has a profound influence on PGC-1α-regulated pathways controlling energy metabolism in white fat. The allelic variation observed in the regulation of Ucp1 and Pgc-1α expression in brown adipocytes of white fat but not interscapular brown fat suggests that fundamentally different regulatory mechanisms exist to control the thermogenic capacities of these tissues.

Effects of intracerebroventricular injection of neuropeptide Y on energy metabolism

1991 ◽  
Vol 260 (2) ◽  
pp. R321-R327 ◽  
Author(s):  
C. J. Billington ◽  
J. E. Briggs ◽  
M. Grace ◽  
A. S. Levine
Keyword(s):  
Neuropeptide Y ◽  
Lipoprotein Lipase ◽  
Lipase Activity ◽  
Serum Insulin ◽  
Brown Fat ◽  
Lipoprotein Lipase Activity ◽  
Sprague Dawley ◽  
Ad Libitum ◽  
The Right ◽  
White Fat

Our objective was to find out if central injection of neuropeptide Y (NPY) would alter brown fat thermogenesis and white fat lipoprotein lipase activity. The following three groups of Sprague-Dawley rats received five injections over 24 h into the right lateral ventricle: 1) NPY (5 micrograms/injection) and ad libitum food; 2) NPY (5 micrograms/injection) and food restricted to control intake; 3) saline injection and ad libitum food. The NPY ad libitum-fed group consumed more food than the saline controls or NPY food-restricted animals. Brown fat thermogenic activity, assessed by GDP binding, was decreased relative to saline controls in both NPY-treated groups. White fat lipoprotein lipase activity was greatly increased in both NPY treatment groups compared with saline controls. The NPY effects on brown and white fat were not explained by measures of serum insulin, glucagon, glucose, or other metabolites. In a follow-up experiment, we asked whether food was necessary for expression of the NPY effects. Brown fat mitochondrial GDP binding indicated NPY effect even when no food was ingested. We conclude that intracerebroventricular administration of NPY promotes white fat lipid storage and decreases brown fat thermogenesis in addition to its known effect of stimulating food intake.

scholarly journals Manipulation of dietary amino acids prevents and reverses obesity in mice through multiple mechanisms that modulate energy homeostasis

2020 ◽  
Author(s):  
Ada Admin ◽  
Chiara Ruocco ◽  
Maurizio Ragni ◽  
Fabio Rossi ◽  
Pierluigi Carullo ◽  
...  
Keyword(s):  
Amino Acids ◽  
Energy Metabolism ◽  
Energy Homeostasis ◽  
Molecular Mechanisms ◽  
Uncoupling Protein ◽  
Essential Amino Acids ◽  
Brown Fat ◽  
Acid Oxidation ◽  
White Fat

Reduced activation of energy metabolism increases adiposity in humans and other mammals. Thus, exploring dietary and molecular mechanisms able to improve energy metabolism is of paramount medical importance, as such mechanisms can be leveraged as a therapy for obesity and related disorders. Here, <a>we show that a designer protein-deprived diet enriched in free essential amino acids can i) promote the brown fat thermogenic program and fatty acid oxidation, ii) stimulate uncoupling protein 1 (UCP1)-independent respiration in subcutaneous white fat, iii) change the gut microbiota composition, and iv) prevent and reverse obesity and dysregulated glucose homeostasis in multiple mouse models, prolonging the healthy lifespan. </a>These effects are independent of unbalanced amino acid ratio, energy consumption, and intestinal calorie absorption. A brown fat-specific activation of the mechanistic target of rapamycin complex 1 seems involved in the diet-induced beneficial effects, as also strengthened by <i>in vitro</i> experiments. Hence, our results suggest that brown and white fat may be targets of specific amino acids to control UCP1-dependent and -independent thermogenesis, thereby contributing to the improvement of metabolic health.

Aging and fasting regulation of leptin and hypothalamic neuropeptide Y gene expression

1998 ◽  
Vol 275 (3) ◽  
pp. E405-E411 ◽  
Author(s):  
Hua Li ◽  
Michael Matheny ◽  
Nihal Tümer ◽  
Philip J. Scarpace
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Neuropeptide Y ◽  
Mrna Levels ◽  
Aged Rats ◽  
Serum Leptin ◽  
Epididymal White Adipose Tissue ◽  
Ad Libitum ◽  
Fasted Rats

To investigate the role of aging on the fasting-induced suppression of leptin gene expression and increase in hypothalamic neuropeptide Y (NPY) gene expression, we fasted or fed ad libitum male F-344xBN rats aged 3, 24, and 31 mo for 2 days. We examined leptin mRNA levels in retroperitoneal, inguinal, and epididymal white adipose tissue (WAT); serum leptin levels; and NPY mRNA levels in the hypothalamus. We found that leptin mRNA levels were increased from 3 to 24 mo and leveled off between 24 and 31 mo in both retroperitoneal WAT and inguinal WAT but were unchanged with age in epididymal WAT. Serum leptin levels increased with age, whereas hypothalamic NPY mRNA levels did not change with age. Fasting suppressed leptin gene expression in all three WATs and serum leptin. Moreover, this suppression of serum leptin and of leptin message in retroperitoneal WAT was less in aged rats. Conversely, fasting increased hypothalamic NPY message, again to a lesser extent in aged rats. In both fed (ad libitum) and fasted rats, there was a strong correlation between serum leptin and hypothalamic NPY mRNA levels in the young but not in either of the two aged groups. These data suggest that aged F-344xBN rats are leptin resistant and that the fasting regulation of serum leptin, leptin mRNA, and hypothalamic NPY mRNA is impaired in aged rats.

Neural site of leptin influence on neuropeptide Y signaling pathways altering feeding and uncoupling protein

1998 ◽  
Vol 275 (2) ◽  
pp. R478-R484 ◽  
Author(s):  
Catherine M. Kotz ◽  
Jacqueline E. Briggs ◽  
James D. Pomonis ◽  
Martha K. Grace ◽  
Allen S. Levine ◽  
...  
Keyword(s):  
Gene Expression ◽  
Energy Balance ◽  
Neuropeptide Y ◽  
Paraventricular Nucleus ◽  
Arcuate Nucleus ◽  
Uncoupling Protein ◽  
Positive Energy ◽  
Potential Mechanism ◽  
Regulatory Pathway ◽  
Positive Energy Balance

Inhibition of a signal that produces positive energy balance involving neuropeptide Y (NPY) projection from arcuate nucleus (Arc; site of NPY synthesis) to paraventricular nucleus (PVN; site of NPY release) is one potential mechanism of leptin action. NPY in the PVN increases feeding and decreases uncoupling protein (UCP) activity in brown fat, whereas leptin decreases NPY biosynthesis in the Arc, which presumably decreases PVN NPY. It is hypothesized that decreased NPY activity is necessary for the satiety and thermogenic effects of leptin. To test this, we first determined the effect of leptin on feeding in two paradigms: satiated rats and food-deprived rats. Leptin was effective in decreasing feeding in the satiated rats but ineffective in the food-deprived rats. Next, we determined that leptin decreases NPY and increases UCP gene expression. Finally, we injected leptin intracerebroventricularly before specific PVN NPY microinjection. We found that repletion of NPY in PVN by specific NPY microinjection reverses the feeding-inhibitory and thermogenic effects of centrally administered leptin, the first functional evidence indicating that leptin acts on the Arc-PVN feeding-regulatory pathway.

scholarly journals Neuropeptide Y gene expression in lines of mice subjected to long-term divergent selection on fat content

1999 ◽  
Vol 23 (1) ◽  
pp. 77-83 ◽  
Author(s):  
T Boswell ◽  
MA Nicholson ◽  
L Bunger
Keyword(s):  
Gene Expression ◽  
Neuropeptide Y ◽  
Fat Content ◽  
Sensitivity Threshold ◽  
Mrna Levels ◽  
Fat Percentage ◽  
Fed State ◽  
Ad Libitum ◽  
Plasma Leptin

Lines of mice have been developed in our laboratory by divergent long-term selection for body fat content. This has resulted in a fivefold (23% vs 4%) higher fat percentage in the Fat line at 14 weeks of age, with little difference between the Fat and Lean lines in fat-free body weight. As part of an approach to characterize the physiological mechanisms underlying these different phenotypes, neuropeptide Y (NPY) mRNA levels in the hypothalamus and cerebral cortex of ad libitum-fed and fasted mice of the Fat and Lean selected lines were measured. Significant differences in NPY gene expression were confined to the hypothalamus. Under ad libitum-fed conditions, hypothalamic NPY mRNA levels did not differ significantly between the Fat and Lean lines. After an overnight fast of 18-20 h, hypothalamic NPY mRNA levels were increased significantly (P<0.05) by 31% in Lean animals relative to fed mice from the same line. However, fasting did not significantly stimulate NPY gene expression in the Fat line. Most plasma leptin measurements in the Lean line fell below the sensitivity threshold of the assay (0.1 ng/ml), but levels in the Fat line were at least 30 to 50 times higher under fasted and fed conditions respectively. After fasting, plasma leptin levels in the Fat line decreased significantly (P<0. 05) by 48%. Thus, unlike the situation in other rodent models, obesity in the Fat line is not associated with increased hypothalamic NPY mRNA levels in the ad libitum-fed state. The decreased sensitivity of hypothalamic NPY gene expression to fasting in the Fat line is consistent with an inhibitory effect of higher circulating leptin levels.

scholarly journals Neuropeptide Y1 and Y5 Receptors Mediate the Effects of Neuropeptide Y on the Hypothalamic-Pituitary-Thyroid Axis

Endocrinology ◽  
2002 ◽  
Vol 143 (12) ◽  
pp. 4513-4519 ◽  
Author(s):  
Csaba Fekete ◽  
Sumit Sarkar ◽  
William M. Rand ◽  
John W. Harney ◽  
Charles H. Emerson ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Food Intake ◽  
Neuropeptide Y ◽  
Paraventricular Nucleus ◽  
Receptor Agonist ◽  
Pituitary Thyroid Axis ◽  
Thyroid Axis ◽  
Ad Libitum ◽  
Thyroid Hormone Levels ◽  
Hpt Axis

Abstract Neuropeptide Y (NPY) is one of the most important hypothalamic-derived neuropeptides mediating the effects of leptin on energy homeostasis. Central administration of NPY not only markedly stimulates food intake, but simultaneously inhibits the hypothalamic-pituitary-thyroid axis (HPT axis), replicating the central hypothyroid state associated with fasting. To identify the specific NPY receptor subtypes involved in the action of NPY on the HPT axis, we studied the effects of the highly selective Y1 ([Phe7,Pro34]pNPY) and Y5 ([chicken pancreatic polypeptide1–7, NPY19–23, Ala31, Aib32 (aminoisobutyric acid), Q34]human pancreatic polypeptide) receptor agonists on circulating thyroid hormone levels and proTRH mRNA in hypophysiotropic neurons of the hypothalamic paraventricular nucleus. The peptides were administered continuously by osmotic minipump into the cerebrospinal fluid (CSF) over 3 d in ad libitum-fed animals and animals pair-fed to artificial CSF (aCSF)-infused controls. Both Y1 and Y5 receptor agonists nearly doubled food intake compared with that of control animals receiving aCSF, similar to the effect observed for NPY. NPY, Y1, and Y5 receptor agonist administration suppressed circulating levels of thyroid hormones (T3 and T4) and resulted in inappropriately normal or low TSH levels. These alterations were also associated with significant suppression of proTRH mRNA in the paraventricular nucleus, particularly in the Y1 receptor agonist-infused group [aCSF, NPY, Y1, and Y5 (density units ± sem), 97.2 ± 8.6, 39.6 ± 8.4, 19.9 ± 1.9, and 44.6 ± 8.4]. No significant differences in thyroid hormone levels, TSH, or proTRH mRNA were observed between the agonist-infused FSanimals eating ad libitum and the agonist-infused animals pair-fed with vehicle-treated controls. These data confirm the importance of both Y1 and Y5 receptors in the NPY-mediated increase in food consumption and demonstrate that both Y1 and Y5 receptors can mediate the inhibitory effects of NPY on the HPT axis.

scholarly journals Differential Effects of Refeeding on Melanocortin-Responsive Neurons in the Hypothalamic Paraventricular Nucleus

Endocrinology ◽  
2008 ◽  
Vol 149 (9) ◽  
pp. 4329-4335 ◽  
Author(s):  
Edith Sánchez ◽  
Praful S. Singru ◽  
Runa Acharya ◽  
Monica Bodria ◽  
Csaba Fekete ◽  
...  
Keyword(s):  
Gene Expression ◽  
Paraventricular Nucleus ◽  
Hypothalamic Paraventricular Nucleus ◽  
Mrna Levels ◽  
Sprague Dawley ◽  
Early Action ◽  
Sprague Dawley Rats ◽  
Melanocortin Signaling ◽  
Agouti Related Protein ◽  
Serum Tsh

To explore the effect of refeeding on recovery of TRH gene expression in the hypothalamic paraventricular nucleus (PVN) and its correlation with the feeding-related neuropeptides in the arcuate nucleus (ARC), c-fos immunoreactivity (IR) in the PVN and ARC 2 h after refeeding and hypothalamic TRH, neuropeptide Y (NPY) and agouti-related protein (AGRP) mRNA levels 4, 12, and 24 h after refeeding were studied in Sprague-Dawley rats subjected to prolonged fasting. Despite rapid reactivation of proopiomelanocortin neurons by refeeding as demonstrated by c-fos IR in ARC α-MSH-IR neurons and ventral parvocellular subdivision PVN neurons, c-fos IR was present in only 9.7 ± 1.1% hypophysiotropic TRH neurons. Serum TSH levels remained suppressed 4 and 12 h after the start of refeeding, returning to fed levels after 24 h. Fasting reduced TRH mRNA compared with fed animals, and similar to TSH, remained suppressed at 4 and 12 h after refeeding, returning toward normal at 24 h. AGRP and NPY gene expression in the ARC were markedly elevated in fasting rats, AGRP mRNA returning to baseline levels 12 h after refeeding and NPY mRNA remaining persistently elevated even at 24 h. These data raise the possibility that refeeding-induced activation of melanocortin signaling exerts differential actions on its target neurons in the PVN, an early action directed at neurons that may be involved in satiety, and a later action on hypophysiotropic TRH neurons involved in energy expenditure, potentially mediated by sustained elevations in AGRP and NPY. This response may be an important homeostatic mechanism to allow replenishment of depleted energy stores associated with fasting.

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