Nicotine regulates mRNA expression of feeding peptides in the arcuate nucleus in neonatal rat pups.
Maternal smoking results in low birth weight. Using a neonatal gastric intubation model corresponding to the third trimester in humans, nicotine, the major psychoactive ingredient in tobacco, causes growth retardation in rat pups. Here, we wanted to determine the underlying mechanisms of nicotine's anorexic effects. In adults, body weight and energy expenditure are regulated by the adiposity hormone leptin and the orexigenic peptides neuropeptide Y (NPY) and agouti-related peptide (AgRP) and anorexic peptides proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) expressed in the hypothalamic arcuate (Arc) nucleus. Activation of nicotinic acetylcholine receptors (nAChRs) could regulate leptin release and/or peptide expression in the Arc. Neonatal rat pups were treated twice daily with nicotine (0.25, 1.5, and 3 mg/kg) from postnatal day 1 to 8 (P1-8). This resulted in an upregulation of heteromeric nAChR binding sites in the ventromedial nucleus of the hypothalamus and Arc. Nicotine at all three doses significantly reduced body weight gain and increased mRNA expression of NPY, AgRP, and POMC effects, which were blocked by dihydro-beta-erythroidine (DHbetaE), an alpha4beta2* nAChR antagonist, but CART expression was unaffected. In contrast, serum leptin levels were significantly increased only by 3 and 1.5 mg/kg, and the increase was only partially blocked by DHbetaE. These data suggest that in neonates chronic nicotine regulates body weight gain independent from serum leptin levels by a central mechanism involving alpha4beta2* heteromeric nAChRs and stimulated increased expression of the anorexic peptide POMC. Whereas, increased NPY and AgRP expression could be a secondary response to reduction in weight gain.
Huang
L Z
LZ
Department of Neuroscience and Experimental Therapeutics, Texas A&M University System, Health Sciences Center, Texas 77843-1114, USA.
Winzer-Serhan
U H
UH
D000367:Age Factors; D054369:Agouti-Related Protein; D000818:Animals; D000831:Animals, Newborn; D001111:Arcuate Nucleus of Hypothalamus / Q000187:drug effects* / Q000378:metabolism; D001345:Autoradiography / Q000379:methods; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D017403:In Situ Hybridization / Q000379:methods; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D020738:Leptin / Q000097:blood; D009478:Neuropeptide Y / Q000235:genetics / Q000378:metabolism; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D011247:Pregnancy; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D054369:Agouti-Related Protein; D036341:Intercellular Signaling Peptides and Proteins; D020738:Leptin; D009478:Neuropeptide Y; D018722:Nicotinic Agonists; D012333:RNA, Messenger; D011333:Pro-Opiomelanocortin; D009538:Nicotine