Protopanaxadiol alleviates obesity in high-fat diet-fed mice via activation of energy-sensing neuron in the paraventricular nucleus of hypothalamus

The opioid peptides enkephalin (ENK) and dynorphin (DYN), when injected into the hypothalamus, are known to stimulate feeding behavior and preferentially increase the ingestion of a high-fat diet. Studies of another peptide, galanin (GAL), with similar effects on feeding demonstrate that a high-fat diet, in turn, can stimulate the expression of this peptide in the hypothalamus. The present study tested different diets and variable periods of high- vs. low-fat diet consumption to determine whether the opioid peptides respond in a similar manner as GAL. In six experiments, the effects of dietary fat on ENK and DYN were examined in three hypothalamic areas: the paraventricular nucleus (PVN), perifornical hypothalamus (PFH), and arcuate nucleus (ARC). The results demonstrated that the ingestion of a high-fat diet increases gene expression and peptide levels of both ENK and DYN in the hypothalamus. The strongest and most consistent effect is seen in the PVN. In this nucleus, ENK and DYN are increased by 50–100% after 1 wk, 1 day, 60 min, and even 15 min of high-fat diet consumption. While showing some effect in the PFH, these peptides in the ARC are considerably less responsive, exhibiting no change in response to the briefer periods of diet intake. This effect of dietary fat on PVN opioids can be observed with diets equal in caloric density and palatability and without a change in caloric intake, body weight, fat pad weight, or levels of insulin or leptin. The data reveal a strong and consistent association between these peptides and a rise in circulating levels of triglycerides, supporting a role for these lipids in the fat-induced stimulation of opioid peptides in the PVN, similar to GAL.

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Sim1 Haploinsufficiency Impairs Melanocortin-Mediated Anorexia and Activation of Paraventricular Nucleus Neurons

Molecular Endocrinology ◽

10.1210/me.2005-0483 ◽

2006 ◽

Vol 20 (10) ◽

pp. 2483-2492 ◽

Cited By ~ 73

Author(s):

Bassil M. Kublaoui ◽

J. Lloyd Holder ◽

Terry Gemelli ◽

Andrew R. Zinn

Keyword(s):

Energy Expenditure ◽

Paraventricular Nucleus ◽

High Fat Diet ◽

Linear Growth ◽

Wild Type ◽

High Fat ◽

Melanocortin 4 Receptor ◽

Melanocortin Signaling ◽

Fos Expression ◽

Six Genes

Abstract Single-minded 1 (SIM1) is one of only six genes implicated in human monogenic obesity. Haploinsufficiency of this hypothalamic transcription factor is associated with hyperphagic obesity and increased linear growth in both humans and mice. Additionally, Sim1 heterozygous mice show enhanced hyperphagia and obesity in response to a high-fat diet. Thus the phenotype of Sim1 haploinsufficiency is similar to that of agouti yellow (Ay), and melanocortin 4 receptor (Mc4r) knockout mice, both of which are defective in hypothalamic melanocortin signaling. Sim1 and Mc4r are both expressed in the paraventricular nucleus (PVN). Here we report that Sim1 heterozygous mice, which have normal energy expenditure, are hyperphagic despite having elevated hypothalamic proopiomelanocortin (Pomc) expression. In response to the melanocortin agonist melanotan-2 (MTII) they exhibit a blunted suppression of feeding yet increase their energy expenditure normally. They also fail to activate PVN neurons in response to the drug at a dose that induces robust c-Fos expression in a subset of Sim1 PVN neurons in wild-type mice. The resistance to melanocortin signaling in Sim1 heterozygotes is not due to a reduced number of Sim1 neurons in the PVN. Hypothalamic Sim1 gene expression is induced by leptin and MTII treatment. Our results demonstrate that Sim1 heterozygotes are resistant to hypothalamic melanocortin signaling and suggest that Sim1-expressing PVN neurons regulate feeding, but not energy expenditure, in response to melanocortin signaling.

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Adeno-associated virus-mediated knockdown of melanocortin-4 receptor in the paraventricular nucleus of the hypothalamus promotes high-fat diet-induced hyperphagia and obesity

Journal of Endocrinology ◽

10.1677/joe-08-0009 ◽

2008 ◽

Vol 197 (3) ◽

pp. 471-482 ◽

Cited By ~ 48

Author(s):

Jacob C Garza ◽

Chung Sub Kim ◽

Jing Liu ◽

Wei Zhang ◽

Xin-Yun Lu

Keyword(s):

Body Weight ◽

Food Intake ◽

Paraventricular Nucleus ◽

High Fat Diet ◽

Body Weight Gain ◽

High Fat ◽

Adult Rats ◽

Adult Rat ◽

Melanocortin 4 Receptor ◽

Key Enzyme

Pharmacological and genetic studies have suggested that melanocortin-4 receptor (MC4R) signaling in the paraventricular nucleus of hypothalamus (PVN) regulates appetite and energy balance. However, the specific role of MC4R signaling in PVN neurons in these processes remains to be further elucidated in normally developed animals. In the present study, we employed RNA interference to determine whether MC4R knockdown in the PVN modulates food intake and body weight in adult rats. Adeno-associated viral (AAV) vectors encoding short hairpin RNAs targeting MC4R (AAV-shRNA-MC4R) were generated to induce MC4R knockdown in the PVN. By in situ hybridization, we detected a high-level expression of Dicer, a key enzyme required for shRNA-mediated gene silencing, along the entire rostrocaudal extent of the PVN. Bilateral injection of AAV-shRNA-MC4R vectors into the PVN of the adult rat resulted in significant and specific reduction of MC4R mRNA expression. Animals with MC4R knockdown exhibited an increase in food intake and excessive body weight gain when exposed to a high-fat diet. Our results provide evidence that AAV-mediated silencing of MC4R on PVN neurons promotes hyperphagia and obesity in response to the dietary challenge in the adult animal.

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

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00844.2009 ◽

2010 ◽

Vol 298 (5) ◽

pp. R1320-R1332 ◽

Cited By ~ 37

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.

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Brain Transcriptional Responses to High-Fat Diet in Acads-Deficient Mice Reveal Energy Sensing Pathways

PLoS ONE ◽

10.1371/journal.pone.0041709 ◽

2012 ◽

Vol 7 (8) ◽

pp. e41709 ◽

Cited By ~ 7

Author(s):

Claudia Kruger ◽

K. Ganesh Kumar ◽

Randall L. Mynatt ◽

Julia Volaufova ◽

Brenda K. Richards

Keyword(s):

High Fat Diet ◽

High Fat ◽

Transcriptional Responses ◽

Energy Sensing ◽

Deficient Mice

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Correction: Paraventricular Nucleus Sim1 Neuron Ablation Mediated Obesity Is Resistant to High Fat Diet

PLoS ONE ◽

10.1371/annotation/9239a129-5677-43b0-8fe1-0c1e75e988df ◽

2014 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Dong Xi ◽

Jeff Roizen ◽

Meizan Lai ◽

Nilay Gandhi ◽

Bassil Kublaoui

Keyword(s):

Paraventricular Nucleus ◽

High Fat Diet ◽

High Fat

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High-fat feeding alters the cardiovascular role of the hypothalamic paraventricular nucleus

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00558.2009 ◽

2010 ◽

Vol 298 (3) ◽

pp. R799-R807 ◽

Cited By ~ 11

Author(s):

Feng Chen ◽

Joo Lee Cham ◽

Emilio Badoer

Keyword(s):

Blood Pressure ◽

Heart Rate ◽

Paraventricular Nucleus ◽

Sympathetic Nerve ◽

High Fat Diet ◽

Sympathetic Nerve Activity ◽

Hypothalamic Paraventricular Nucleus ◽

High Fat ◽

Nerve Activity

Increased sympathetic nerve activity is associated with obesity-related hypertension, but the underlying central neural mechanisms are not clear. We examined the role of the hypothalamic paraventricular nucleus (PVN) in the regulation of sympathetic nerve activity in rats fed a normal chow diet (controls) and rats fed a high-fat diet (36% fat) over 12 wk. The effects on blood pressure, heart rate, and lumbar sympathetic nerve activity (LSNA) induced by microinjection of the GABAA receptor agonist muscimol or the antagonist bicuculline were monitored in anesthetized rats. Body weight of rats fed the high-fat diet was not significantly different from controls, but a significant 80% increase in epididymal fat mass, significantly elevated fasting blood glucose, and significantly impaired glucose tolerance were observed in rats fed the high-fat diet. Resting blood pressure and heart rate were not significantly different between rats fed the high-fat diet and controls. Muscimol microinjected into the PVN elicited a greater reduction of blood pressure and LSNA in rats fed the high-fat diet than controls: −14 ± 6 vs. −7 ± 2 mmHg and −35 ± 6 vs. −10 ± 9% ( P < 0.05). Microinjection of bicuculline into the PVN increased blood pressure and LSNA, but the responses were similar in rats fed the high-fat diet and controls. In conclusion, the role of the paraventricular nucleus in cardiovascular regulation can be altered by a diet high in fat, even when hypertension and obesity are absent.

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