Basomedial hypothalamic injections of neuropeptide Y conjugated to saporin selectively disrupt hypothalamic controls of food intake.
Neuropeptide Y (NPY) conjugated to saporin (NPY-SAP), a ribosomal inactivating toxin, is a newly developed compound designed to selectively target and lesion NPY receptor-expressing cells. We injected NPY-SAP into the basomedial hypothalamus (BMH), just dorsal to the arcuate nucleus (ARC), to investigate its neurotoxicity and to determine whether ARC NPY neurons are required for glucoprivic feeding. We found that NPY-SAP profoundly reduced NPY Y1 receptor and alpha MSH immunoreactivity, as well as NPY, Agouti gene-related protein (AGRP), and cocaine and amphetamine-related transcript mRNA expression in the BMH. NPY-SAP lesions were localized to the injection site with no evidence of retrograde transport by hindbrain NPY neurons with BMH terminals. These lesions impaired responses to intracerebroventricular (icv) leptin (5 microg/5 microl x d) and ghrelin (2 microg/5 microl), which are thought to alter feeding primarily by actions on ARC NPY/AGRP and proopiomelanocortin/cocaine and amphetamine-related transcript neurons. However, the hypothesis that NPY/AGRP neurons are required downstream mediators of glucoprivic feeding was not supported. Although NPY/AGRP neurons were destroyed by NPY-SAP, the lesion did not impair either the feeding or the hyperglycemic response to 2-deoxy-D-glucose-induced blockade of glycolysis use. Similarly, responses to glucagon-like peptide-1 (GLP-1, 5 microg/3 microl icv), NPY (5 microg/3 microl icv), cholecystokinin octapeptide (4 microg/kg ip), and beta-mercaptoacetate (68 mg/kg ip) were not altered by the NPY-SAP lesion. Thus, NPY-SAP destroyed NPY receptor-expressing neurons in the ARC and selectively disrupted controls of feeding dependent on those neurons but did not disrupt peptidergic or metabolic controls dependent upon circuitry outside the BMH.
Bugarith
Kishor
K
Programs in Neuroscience, Washington State University, Pullman, Washington 99164-6520, USA.
Dinh
Thu T
TT
Li
Ai-Jun
AJ
Speth
Robert C
RC
Ritter
Sue
S
D054369:Agouti-Related Protein; D000662:Amphetamines / Q000378:metabolism; D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000187:drug effects; D001667:Binding, Competitive; D001835:Body Weight; D002395:Catecholamines / Q000378:metabolism; D002766:Cholecystokinin / Q000378:metabolism; D003042:Cocaine / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D054439:Ghrelin; D005934:Glucagon / Q000378:metabolism; D052216:Glucagon-Like Peptide 1; D007031:Hypothalamus / Q000187:drug effects*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D020128:Inhibitory Concentration 50; D036341:Intercellular Signaling Peptides and Proteins; D020738:Leptin / Q000378:metabolism; D008024:Ligands; D008297:Male; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism; D009478:Neuropeptide Y / Q000378:metabolism / Q000494:pharmacology*; D010446:Peptide Fragments / Q000378:metabolism; D036361:Peptide Hormones / Q000378:metabolism; D010455:Peptides / Q000737:chemistry; D010940:Plant Proteins / Q000494:pharmacology*; D011333:Pro-Opiomelanocortin / Q000378:metabolism; D011485:Protein Binding; D011498:Protein Precursors / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012249:Rhombencephalon / Q000378:metabolism; D013864:Thioglycolates / Q000378:metabolism; D013997:Time Factors; D014118:Toxins, Biological / Q000737:chemistry; D000521:alpha-MSH / Q000378:metabolism
D054369:Agouti-Related Protein; D000662:Amphetamines; D002395:Catecholamines; D018765:Dopamine Uptake Inhibitors; D054439:Ghrelin; D036341:Intercellular Signaling Peptides and Proteins; D020738:Leptin; D008024:Ligands; D009478:Neuropeptide Y; D010446:Peptide Fragments; D036361:Peptide Hormones; D010455:Peptides; D010940:Plant Proteins; D011498:Protein Precursors; D011506:Proteins; D012333:RNA, Messenger; D013864:Thioglycolates; D014118:Toxins, Biological; D000521:alpha-MSH; D011333:Pro-Opiomelanocortin; C017487:2-mercaptoacetate; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D002766:Cholecystokinin; D003042:Cocaine