ABSTRACT
Hypothalamic neuropeptide Y (NPY) and superoxide dismutase (SOD) have been reported to participate in the regulation of appetite-suppressing effect of phenylpropanolamine (PPA), a sympathomimetic agent. This study explored whether Y1 receptor (Y1R) and/or Y5 receptor (Y5R) was involved in this regulation. Wistar rats were treated with PPA for 24 h. Changes in food intake and hypothalamic NPY, Y1R, Y5R, and SOD contents were assessed and compared. Results showed that food intake and NPY contents were decreased following PPA treatment, while Y1R and SOD contents were increased and Y5R contents remained unchanged. Moreover, although Y1R or Y5R knockdown by themselves could modify the food intake, Y1R but not Y5R knockdown could modify PPA-induced anorexia as well as NPY and SOD contents. In addition, selective inhibition of Y1R but not Y5R could modulate PPA-induced anorexia. It is suggested that Y1R but not Y5R participates in the anorectic response of PPA via the modulation of NPY and SOD. Results provide molecular mechanism of NPY-mediated PPA anorexia and may aid the understanding of the toxicology of PPA.
Subject(s)
Anorexia/chemically induced , Appetite Depressants/toxicity , Neuropeptide Y/physiology , Oxidative Stress/drug effects , Phenylpropanolamine/toxicity , Receptors, G-Protein-Coupled/physiology , Receptors, Neuropeptide/physiology , Superoxide Dismutase/physiology , Sympathomimetics/toxicity , Animals , Anorexia/physiopathology , Appetite/drug effects , Gene Knockdown Techniques , Hypothalamus/chemistry , Hypothalamus/drug effects , Hypothalamus/physiopathology , Injections, Intraventricular , Male , Oligonucleotides, Antisense/pharmacology , Rats , Rats, Wistar , Receptors, G-Protein-Coupled/antagonists & inhibitors , Receptors, G-Protein-Coupled/genetics , Receptors, Neuropeptide/antagonists & inhibitors , Receptors, Neuropeptide/genetics , Receptors, Neuropeptide Y/antagonists & inhibitors , Receptors, Neuropeptide Y/genetics , Receptors, Neuropeptide Y/physiologyABSTRACT
It has been reported that antioxidative enzymes, neuropeptide Y (NPY), and c-AMP response element-binding protein (CREB) are involved in regulating phenylpropanolamine (PPA)-mediated appetite suppression. Here, we investigated whether Y1 receptor (Y1R) might be involved in this regulation. Rats were daily treated with PPA for 4 days. Changes in the contents of NPY, Y1R, glutathione peroxidase (GP), and CREB were assessed and compared. Results showed that Y1R, GP, and CREB increased, with a maximal increase about 100, 200, and 150 %, respectively, on Day 2. By contrast, NPY decreased with a biggest reduction about 48 % on Day 2 and the pattern of expression during PPA treatment was opposite to those of Y1R, GP, and CREB. Central knockdown (using antisense) or inhibition (using antagonist) of Y1R expression modulated the anorectic response of PPA and the reciprocal regulation between NPY and GP (or CREB), revealing an essential role of Y1R in regulating NPY, GP, and CREB. These results suggest that Y1R participates in the reciprocal regulation of NPY, GP, and CREB in the hypothalamus during PPA treatment in conscious rats. The present results may aid the therapeutic research of PPA and related antiobesity drugs.
Subject(s)
Appetite Depressants/pharmacology , Appetite Regulation/drug effects , Cyclic AMP Response Element-Binding Protein/metabolism , Gene Knockdown Techniques , Glutathione Peroxidase/metabolism , Hypothalamus/drug effects , Oligonucleotides, Antisense/administration & dosage , Phenylpropanolamine/pharmacology , Receptors, G-Protein-Coupled/metabolism , Receptors, Neuropeptide/metabolism , Animals , Arginine/analogs & derivatives , Arginine/pharmacology , Dose-Response Relationship, Drug , Down-Regulation , Eating/drug effects , Hypothalamus/enzymology , Injections, Intraventricular , Male , Neuropeptide Y/metabolism , Rats , Rats, Wistar , Receptors, G-Protein-Coupled/antagonists & inhibitors , Receptors, G-Protein-Coupled/genetics , Receptors, Neuropeptide/antagonists & inhibitors , Receptors, Neuropeptide/genetics , Signal Transduction/drug effects , Time FactorsABSTRACT
Recently, we reported that an initial decrease followed by recovery of food intake was observed during four days of amphetamine (AMPH) treatment and suggested that these changes in response were mediated by changes in neuropeptide Y (NPY) and proopiomelanocortin (POMC). Here we investigated if Y1 receptor (Y1R) and/or Y5 receptor (Y5R) might be involved in this regulation. Rats were treated daily with AMPH for four days. Changes in the expression levels of Y1R, Y5R, melanocortin receptor 3 (MC3R), and NPY were assessed and compared. Results showed that Y1R and MC3R increased, with a maximal increase of about 210% on Day 2 but with a restoration to the normal level on Day 4. In contrast, NPY decreased with a biggest reduction of about 45% on Day 2 and the pattern of expression during AMPH treatment was opposite to those of Y1R and MC3R, while the expression of Y5R was not changed. Central inhibitions of NPY formation or Y1R activity modulated the anorectic response of AMPH and the reciprocal regulation of NPY and MC3R, revealing a crucial role of Y1R in this action. It is suggested that Y1R participates in the reciprocal regulation of NPY- and MC3R-containing neurons in the hypothalamus during the anorectic effect of AMPH. These results may further the understanding of Y1R in the control of eating.
Subject(s)
Amphetamine/pharmacology , Appetite Depressants/pharmacology , Appetite Regulation/drug effects , Drug Tolerance , Hypothalamus/drug effects , Neurons/drug effects , Receptors, Neuropeptide Y/metabolism , Amphetamine/administration & dosage , Amphetamine/antagonists & inhibitors , Animals , Appetite Depressants/administration & dosage , Appetite Depressants/chemistry , Behavior, Animal/drug effects , Dopamine Antagonists/pharmacology , Dose-Response Relationship, Drug , Eating/drug effects , Gene Expression Regulation/drug effects , Haloperidol/pharmacology , Hypothalamus/metabolism , Male , Nerve Tissue Proteins/antagonists & inhibitors , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Neurons/metabolism , Neuropeptide Y/antagonists & inhibitors , Neuropeptide Y/genetics , Neuropeptide Y/metabolism , Oligonucleotides, Antisense , Rats , Rats, Wistar , Receptor, Melanocortin, Type 3 , Receptors, Melanocortin/metabolism , Receptors, Neuropeptide Y/antagonists & inhibitorsABSTRACT
This study determined if transcription factor NF-κB is involved in the effect of amphetamine (AMPH)-mediated feeding response. Moreover, possible roles of hypothalamic neuropeptide Y (NPY) and proopiomelanocortin (POMC) were also investigated. AMPH was administered daily to rats for four days. Changes in NF-κB, NPY and POMC expression were assessed and compared. The NPY gene was down-regulated with maximal response on Day 2 during AMPH treatment, which was consistent with the response to feeding behavior. In contrast, NF-κB and POMC genes were up-regulated, and their expression was increased by about 200% and 450%, respectively, with maximal response on Day 2. Moreover, NF-κB DNA binding ability and expression were increased similar to that of POMC. To examine further if NF-κB was involved, intracerebroventricular infusion of NF-κB antisense oligonucleotide was performed 1 h before the daily AMPH dosing in freely moving rats. Results showed that NF-κB knockdown could modify AMPH anorexia as well as NPY and POMC expression. The present findings prove that cerebral NF-κB participates in AMPH-mediated appetite suppression, possibly by modulating NPY and POMC expression. These results may aid in therapeutic research on AMPH and AMPH-like anti-obesity drugs.
Subject(s)
Amphetamine/pharmacology , Central Nervous System Stimulants/pharmacology , Feeding Behavior/drug effects , Hypothalamus/drug effects , NF-kappa B/genetics , Animals , Appetite/drug effects , Appetite/physiology , Down-Regulation/drug effects , Feeding Behavior/physiology , Hypothalamus/metabolism , Male , NF-kappa B/metabolism , Neuropeptide Y/genetics , Neuropeptide Y/metabolism , Oligodeoxyribonucleotides, Antisense , Pro-Opiomelanocortin/genetics , Pro-Opiomelanocortin/metabolism , Rats , Rats, Wistar , Up-Regulation/drug effectsABSTRACT
AIMS: Studies have reported that redox signaling in the hypothalamus participates in nutrient sensing. The current study aimed to determine if the activation of reactive oxygen species-related enzymes (ROS-RE) in the hypothalamus participates in regulating neuropeptide Y (NPY)-mediated eating. Moreover, possible roles of proopiomelanocortin (POMC) and atypical protein kinase C (aPKC) were also investigated. Rats were treated daily with phenylpropanolamine (PPA) for 4 days. Changes in the expression levels of ROS-RE, POMC, NPY, and aPKC were assessed and compared. RESULTS: Results showed that ROS-RE, POMC, and aPKC increased, with a maximal response on Day 2 (anorectic effect) and with a restoration to the normal level on Day 4 (tolerant effect). By contrast, NPY expression decreased, and the expression pattern of NPY proved opposite those of ROS-RE and POMC. Central inhibition of ROS production by ICV infusion of ROS scavenger attenuated PPA anorexia, revealing a crucial role of ROS in regulating eating. Cerebral aPKC knockdown by ICV infusion of antisense aPKC modulated the expression of ROS-RE, POMC, and NPY. CONCLUSION: Results suggest that ROS-RE/POMC- and NPY-containing neurons function reciprocally in regulating both the anorectic and tolerant effects of PPA, while aPKC is upstream of these regulators. INNOVATION: These results may further the understanding of ROS-RE and aPKC in the control of PPA anorexia.
