Brain-derived neurotrophic factor in the hypothalamic paraventricular nucleus increases energy expenditure by elevating metabolic rate

2007 ◽  
Vol 293 (3) ◽  
pp. R992-R1002 ◽  
Author(s):  
ChuanFeng Wang ◽  
Eric Bomberg ◽  
Charles Billington ◽  
Allen Levine ◽  
Catherine M. Kotz
Keyword(s):  
Gene Expression ◽  
Body Weight ◽  
Food Intake ◽  
Energy Expenditure ◽  
Metabolic Rate ◽  
Paraventricular Nucleus ◽  
Neurotrophic Factor ◽  
Brain Derived Neurotrophic Factor ◽  
Hypothalamic Paraventricular Nucleus ◽  
Sites Of Action

Brain-derived neurotrophic factor (BDNF) decreases food intake and body weight, but few central sites of action have been identified. The hypothalamic paraventricular nucleus (PVN) is important in energy metabolism regulation, and expresses both BDNF and its receptor. We tested three hypotheses: 1) PVN BDNF reduces feeding and increases energy expenditure (EE), 2) PVN BDNF-enhanced thermogenesis results from increased spontaneous physical activity (SPA) and resting metabolic rate (RMR), and 3) PVN BDNF thermogenic effects are mediated, in part, by uncoupling protein 1 (UCP1) in brown adipose tissue (BAT). BDNF (0.5 μg) was injected into the PVN of Sprague-Dawley rats; and oxygen consumption, carbon dioxide production, food intake, and SPA were measured for 24 h in an indirect calorimeter. SPA was also measured in open-field activity chambers for 48 h after BDNF injection. Animals were killed 6 or 24 h after BDNF injection, and BAT UCP1 gene expression was measured with quantitative real-time PCR. BDNF significantly decreased food intake and body weight gain 24 h after injection. Heat production and RMR were significantly elevated for 7 h immediately after BDNF injection. BDNF had no effect on SPA, but increased UCP1 gene expression in BAT at 6 h, but not 24 h after injection. In conclusion, PVN BDNF reduces body weight by decreasing food intake and increasing EE consequent to increased RMR, which may be due, in part, to BAT UCP1 activity. These data suggest that the PVN is an important site of BDNF action to influence energy balance.

Brain-derived neurotrophic factor in the hypothalamic paraventricular nucleus reduces energy intake

2007 ◽  
Vol 293 (3) ◽  
pp. R1003-R1012 ◽  
Author(s):  
ChuanFeng Wang ◽  
Eric Bomberg ◽  
Charles Billington ◽  
Allen Levine ◽  
Catherine M. Kotz
Keyword(s):  
Body Weight ◽  
Weight Gain ◽  
Paraventricular Nucleus ◽  
Neurotrophic Factor ◽  
Body Weight Gain ◽  
Brain Derived Neurotrophic Factor ◽  
Brain Regions ◽  
Hypothalamic Paraventricular Nucleus ◽  
Bdnf Mrna ◽  
Hypothalamic Arcuate Nucleus

Recent studies show that brain-derived neurotrophic factor (BDNF) decreases feeding and body weight after peripheral and ventricular administration. BDNF mRNA and protein, and its receptor tyrosine kinase B (TrkB) are widely distributed in the hypothalamus and other brain regions. However, there are few reports on specific brain sites of actions for BDNF. We evaluated the effect of BDNF in the hypothalamic paraventricular nucleus (PVN) on feeding. BDNF injected unilaterally or bilaterally into the PVN of food-deprived and nondeprived rats significantly decreased feeding and body weight gain within the 0- to 24-h and 24- to 48-h postinjection intervals. Effective doses producing inhibition of feeding behavior did not establish a conditioned taste aversion. PVN BDNF significantly decreased PVN neuropeptide Y (NPY)-induced feeding at 1, 2, and 4 h following injection. BDNF administration in the PVN abolished food-restriction-induced NPY gene expression in the hypothalamic arcuate nucleus. In conclusion, BDNF in the PVN significantly decreases food intake and body weight gain, suggesting that the PVN is an important site of action for BDNF in its effects on energy metabolism. Furthermore, BDNF appears to interact with NPY in its anorectic actions, although a direct effect on NPY remains to be established.

scholarly journals Chronic administration of brain-derived neurotrophic factor in the hypothalamic paraventricular nucleus reverses obesity induced by high-fat diet

2010 ◽  
Vol 298 (5) ◽  
pp. R1320-R1332 ◽  
Author(s):  
ChuanFeng Wang ◽  
Rebecca J. Godar ◽  
Charles J. Billington ◽  
Catherine M. Kotz
Keyword(s):  
Body Weight ◽  
Body Fat ◽  
Paraventricular Nucleus ◽  
Neurotrophic Factor ◽  
High Fat Diet ◽  
Control Diet ◽  
Brain Derived Neurotrophic Factor ◽  
Hypothalamic Paraventricular Nucleus ◽  
High Fat ◽  
Metabolic Indices

An acute injection of brain-derived neurotrophic factor (BDNF) in the hypothalamic paraventricular nucleus (PVN) reduces body weight by decreasing feeding and increasing energy expenditure (EE), in animals on standard laboratory chow. Animals have divergent responses to a high-fat diet (HFD) exposure, with some developing obesity and others remaining lean. In the current study, we tested two hypotheses: 1) BDNF in the PVN reverses HFD-induced obesity, and 2) animals with higher body fat have a greater physiological response to BDNF than those with less body fat. Eighty-four 10-wk old rats were allowed HFD ad libitum for 9 wk and then prepared with bilateral PVN cannulas. Animals were then divided into tertiles based on their body fat rank: high, intermediate, and low (H, I, and L). Each group was further divided into 2 subgroups and then PVN injected with BDNF or control (artificial cerebrospinal fluid, aCSF) every other day for 3 wk. Energy intake (EI), body weight, and body composition were measured. At study's end, rats were killed to allow measurement of other metabolic indices. In parallel, another 12 rats were fed control diet (CD), PVN-cannulated and injected with aCSF. HFD exposure induced obesity, particularly in the H body fat group, with a significant increase in EI, body weight, fat mass, liver size, and serum glucose, triglycerides, insulin, and leptin. BDNF significantly reduced EI, body weight, body fat, lean mass, and serum metabolic indices. These BDNF effects were greatest in the H body fat group. These data indicate that BDNF reduced HFD-induced obesity and metabolic syndrome-like measures, and the animals with the most body fat had the most significant response to BDNF.

scholarly journals Inhibition of BDNF signaling in the paraventricular nucleus of the hypothalamus lowers acute stress-induced pressor responses

2018 ◽  
Vol 120 (2) ◽  
pp. 633-643 ◽  
Author(s):  
Chris L. Schaich ◽  
Theresa L. Wellman ◽  
Zachary Einwag ◽  
Richard A. Dutko ◽  
Benedek Erdos
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Body Weight ◽  
Food Intake ◽  
Paraventricular Nucleus ◽  
Neurotrophic Factor ◽  
Restraint Stress ◽  
Acute Stress ◽  
Cardiovascular Responses ◽  
High Affinity

Brain-derived neurotrophic factor (BDNF) expression increases in the paraventricular nucleus of the hypothalamus (PVN) during stress, and our recent studies indicate that BDNF induces sympathoexcitatory and hypertensive responses when injected acutely or overexpressed chronically in the PVN. However, it remained to be investigated whether BDNF is involved in the mediation of stress-induced cardiovascular responses. Here we tested the hypothesis that inhibition of the high-affinity BDNF receptor TrkB in the PVN diminishes acute stress-induced cardiovascular responses. Male Sprague-Dawley rats were equipped with radiotelemetric transmitters for blood pressure measurement. BDNF-TrkB signaling was selectively inhibited by viral vector-mediated bilateral PVN overexpression of a dominant-negative truncated TrkB receptor (TrkB.T1, n = 7), while control animals ( n = 7) received green fluorescent protein (GFP)-expressing vector injections. Rats were subjected to acute water and restraint stress 3–4 wk after vector injections. We found that body weight, food intake, baseline mean arterial pressure (MAP), and heart rate were unaffected by TrkB.T1 overexpression. However, peak MAP increases were significantly reduced in the TrkB.T1 group compared with GFP both during water stress (GFP: 39 ± 2 mmHg, TrkB.T1: 27 ± 4 mmHg; P < 0.05) and restraint stress (GFP: 41 ± 3 mmHg, TrkB.T1: 34 ± 2 mmHg; P < 0.05). Average MAP elevations during the poststress period were also significantly reduced after both water and restraint stress in the TrkB.T1 group compared with GFP. In contrast, heart rate elevations to both stressors remained unaffected by TrkB.T1 overexpression. Our results demonstrate that activation of BDNF high-affinity TrkB receptors within the PVN is a major contributor to acute stress-induced blood pressure elevations. NEW & NOTEWORTHY We have shown that inhibition of the high-affinity brain-derived neurotrophic factor receptor TrkB in the paraventricular nucleus of the hypothalamus significantly reduces blood pressure elevations to acute stress without having a significant impact on resting blood pressure, body weight, and food intake.

scholarly journals Disruption of brain-derived neurotrophic factor production from individual promoters generates distinct body composition phenotypes in mice

2018 ◽  
Vol 315 (6) ◽  
pp. E1168-E1184 ◽  
Author(s):  
Liam McAllan ◽  
Kristen R. Maynard ◽  
Alisha S. Kardian ◽  
Amanda S. Stayton ◽  
Shelby L. Fox ◽  
...  
Keyword(s):  
Body Composition ◽  
Food Intake ◽  
Energy Expenditure ◽  
Neurotrophic Factor ◽  
Fluorescent Protein ◽  
Donor Site ◽  
Brain Derived Neurotrophic Factor ◽  
Splice Donor Site ◽  
Wild Type ◽  
Distinct Body

Brain-derived neurotrophic factor (BDNF) is a key neuropeptide in the central regulation of energy balance. The Bdnf gene contains nine promoters, each producing specific mRNA transcripts that encode a common protein. We sought to assess the phenotypic outcomes of disrupting BDNF production from individual Bdnf promoters. Mice with an intact coding region but selective disruption of BDNF production from Bdnf promoters I, II, IV, or VI (Bdnf-e1−/−, -e2−/−, -e4−/−, and -e6−/−) were created by inserting an enhanced green fluorescent protein-STOP cassette upstream of the targeted promoter splice donor site. Body composition was measured by MRI weekly from age 4 to 22 wk. Energy expenditure was measured by indirect calorimetry at 18 wk. Food intake was measured in Bdnf-e1−/− and Bdnf-e2−/− mice, and pair feeding was conducted. Weight gain, lean mass, fat mass, and percent fat of Bdnf-e1−/− and Bdnf-e2−/− mice (both sexes) were significantly increased compared with wild-type littermates. For Bdnf-e4−/− and Bdnf-e6−/− mice, obesity was not observed with either chow or high-fat diet. Food intake was increased in Bdnf-e1−/− and Bdnf-e2−/− mice, and pair feeding prevented obesity. Mutant and wild-type littermates for each strain (both sexes) had similar total energy expenditure after adjustment for body composition. These findings suggest that the obesity phenotype observed in Bdnf-e1−/− and Bdnf-e2−/− mice is attributable to hyperphagia and not altered energy expenditure. Our findings show that disruption of BDNF from specific promoters leads to distinct body composition effects, with disruption from promoters I or II, but not IV or VI, inducing obesity.

Expression of NPY Y1 and Y5 receptors in the hypothalamic paraventricular nucleus of aged Fischer 344 rats

2004 ◽  
Vol 287 (1) ◽  
pp. R69-R75 ◽  
Author(s):  
Jessica D. Coppola ◽  
Barbara A. Horwitz ◽  
Jock Hamilton ◽  
Roger B. McDonald
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Paraventricular Nucleus ◽  
Hypothalamic Paraventricular Nucleus ◽  
Receptor Protein ◽  
Mrna Levels ◽  
Adult Rats ◽  
Fischer 344 ◽  
Significant Difference ◽  
Intracerebroventricular Injections

Many mammals, nearing the end of life, spontaneously decrease their food intake and body weight, a stage we refer to as senescence. The spontaneous decrease in food intake and body weight is associated with attenuated responses to intracerebroventricular injections of neuropeptide Y (NPY) compared with old presenescent or with young adult rats. In the present study, we tested the hypothesis that this blunted responsiveness involves the number and expression of hypothalamic paraventricular nucleus (PVN) Y1 and/or Y5 NPY receptors, both of which are thought to mediate NPY-induced food intake. We found no significant difference in mRNA levels, via quantitative PCR, for Y1 and Y5 receptors in the PVN of senescent vs. presenescent rats. In contrast, immunohistochemistry indicated that the number of PVN neurons staining for Y1 receptor protein was greater in presenescent compared with senescent rats. We conclude that a decreased expression and number of Y1 or Y5 receptors in the PVN cannot explain the attenuated responsiveness of the senescent rats to exogenous NPY.

scholarly journals Gastrin-Releasing Peptide Messenger Ribonucleic Acid Expression in the Hypothalamic Paraventricular Nucleus Is Altered by Melanocortin Receptor Stimulation and Food Deprivation

Endocrinology ◽  
2009 ◽  
Vol 150 (2) ◽  
pp. 672-678 ◽  
Author(s):  
Ellen E. Ladenheim ◽  
Robert R. Behles ◽  
Sheng Bi ◽  
Timothy H. Moran
Keyword(s):  
Gene Expression ◽  
Energy Balance ◽  
Food Intake ◽  
Mrna Expression ◽  
Food Deprivation ◽  
Paraventricular Nucleus ◽  
Hypothalamic Paraventricular Nucleus ◽  
Melanocortin System ◽  
Gastrin Releasing Peptide ◽  
Stimulation Of

Gastrin-releasing peptide (GRP) is a bombesin-like peptide widely distributed in the gastrointestinal tract and central nervous system. In the brain, GRP mRNA is located in the hypothalamic paraventricular nucleus (PVN), a region that receives neural input from the arcuate nucleus and plays a critical role in food intake and energy balance. Because GRP neurons are localized in the vicinity of projection sites in the PVN for peptides that participate in energy homeostasis, we investigated whether GRP mRNA expression in the PVN may be sensitive to challenges imposed by either 38 h food deprivation or stimulation of the melanocortin system by the melanocortin 3/4 receptor agonist, melanotan II (MTII). We found that food deprivation significantly decreased GRP mRNA expression, whereas lateral ventricular MTII administration increased GRP mRNA expression in ad libitum-fed rats 4 h after administration. Furthermore, administration of MTII at a dose that reduces 24 h food intake and body weight prevented the decrease in GRP mRNA expression observed in animals that were pair fed to the amount of food consumed by those injected with MTII. These results demonstrate that food deprivation and stimulation of the melanocortin system produce opposing changes in GRP gene expression in the PVN, suggesting that GRP-containing neurons in the PVN may be part of the hypothalamic signaling pathway controlling food intake and energy balance. Gastrin-releasing peptide gene expression in the hypothalamic paraventricular nucleus is responsive to signals related to energy balance.

scholarly journals Appetite-modifying actions of pro-neuromedin U-derived peptides

2009 ◽  
Vol 297 (2) ◽  
pp. E545-E551 ◽  
Author(s):  
David A. Bechtold ◽  
Tina R. Ivanov ◽  
Simon M. Luckman
Keyword(s):  
Body Weight ◽  
Energy Balance ◽  
Food Intake ◽  
Energy Expenditure ◽  
Metabolic Rate ◽  
Knockout Mice ◽  
Gene Knockout ◽  
Central Administration ◽  
Reduced Body ◽  
Gene Knockout Mouse

Neuromedin U (NMU) is known to have potent actions on appetite and energy expenditure. Deletion of the NMU gene in mice leads to an obese phenotype, characterized by hyperphagia and decreased energy expenditure. Conversely, transgenic mice that overexpress proNMU exhibit reduced body weight and fat storage. Here, we show that central administration of NMU or the related peptide neuromedin S (NMS) dose-dependently decreases food intake, increases metabolic rate, and leads to significant weight loss in mice. The effects of NMU and NMS on both feeding and metabolism are almost completely lost in mice lacking the putative CNS receptor for NMU and NMS, NMUr2. However, NMUr2 knockout mice do not exhibit overt differences in body weight or energy expenditure compared with wild-type mice, suggesting that the dramatic phenotype of the NMU gene knockout mouse is not due simply to the loss of NMU/NMUr2 signaling. Putative proteolytic cleavage sites indicate that an additional peptide is produced from the NMU precursor protein, which is extremely well conserved between human, mouse, and rat. Here, we demonstrate that this peptide, proNMU104-136, has a pronounced effect on energy balance in mice. Specifically, central administration of proNMU104-136 causes a significant but transient (∼4 h) increase in feeding, yet both food intake and body weight are decreased over the following 24 h. proNMU104-136 administration also significantly increased metabolic rate. These results suggest that proNMU104-136 is a novel modulator of energy balance and may contribute to the phenotype exhibited by NMU knockout mice.

Chemical sympathectomy alters regulation of body weight during prolonged ICV leptin infusion

2003 ◽  
Vol 284 (4) ◽  
pp. E778-E787 ◽  
Author(s):  
Robert L. Dobbins ◽  
Lidia S. Szczepaniak ◽  
Weiguo Zhang ◽  
J. Denis McGarry
Keyword(s):  
Physical Activity ◽  
Nervous System ◽  
Body Weight ◽  
Food Intake ◽  
Energy Expenditure ◽  
Sympathetic Nervous System ◽  
Metabolic Rate ◽  
Resting Metabolic Rate ◽  
Chemical Sympathectomy ◽  
Sympathetic Nervous

To assess the importance of the sympathetic nervous system in regulating body weight during prolonged leptin infusion, we evaluated food intake, body weight, and physical activity in conscious, unrestrained rats. Initial studies illustrated that prolonged intracerebroventricular (ICV) infusion of leptin enhanced substrate oxidation so that adipose tissue lipid stores were completely ablated, and muscle triglyceride and liver glycogen stores were depleted. After neonatal chemical sympathectomy, changes in weight and food intake were compared in groups of sympathectomized (SYM) and control (CON) adult animals during ICV infusion of leptin. CON animals lost 60 ± 9 g over 10 days vs. 25 ± 3 g in the SYM animals when food intake was matched between the two groups. Greater weight loss despite similar energy intake points to an important role of the sympathetic nervous system in stimulating energy expenditure during ICV leptin infusion by increasing the resting metabolic rate, since no differences in physical activity were observed between CON and SYM groups. In conclusion, activation of the SNS by leptin increases energy expenditure by augmenting the resting metabolic rate.

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