Epigenomic and metabolic responses of hypothalamic POMC neurons to gestational nicotine exposure in adult offspring.
Epidemiological and animal studies have reported that prenatal nicotine exposure (PNE) leads to obesity and type-2 diabetes in offspring. Central leptin-melanocortin signaling via hypothalamic arcuate proopiomelanocortin (POMC) neurons is crucial for the regulation of energy and glucose balance. Furthermore, hypothalamic POMC neurons were recently found to mediate the anorectic effects of nicotine through activation of acetylcholine receptors. Here, we hypothesized that PNE impairs leptin-melanocortinergic regulation of energy balance in first-generation offspring by altering expression of long non-coding RNAs (lncRNAs) putatively regulating development and/or function of hypothalamic POMC neurons.



C57BL/6J females were exposed ad libitum to nicotine through drinking water and crossed with C57BL/6J males. Nicotine exposure was sustained during pregnancy and discontinued at parturition. Offspring development was monitored from birth into adulthood. From the age of 8 weeks, central leptin-melanocortin signaling, diabetes, and obesity susceptibility were assessed in male offspring fed a low-fat or high-fat diet for 16 weeks. Nicotine-exposed and non-exposed C57BL/6J females were also crossed with C57BL/6J males expressing the enhanced green fluorescent protein specifically in POMC neurons. Transgenic male offspring were subjected to laser microdissections and RNA sequencing (RNA-seq) analysis of POMC neurons for determination of nicotine-induced gene expression changes and regulatory lncRNA/protein-coding gene interactions.



Contrary to expectation based on previous studies, PNE did not impair but rather enhanced leptin-melanocortinergic regulation of energy and glucose balance via POMC neurons in offspring. RNA-seq of laser microdissected POMC neurons revealed only one consistent change, upregulation of Gm15851, a lncRNA of yet unidentified function, in nicotine-exposed offspring. RNA-seq further suggested 82 cis-regulatory lncRNA/protein-coding gene interactions, 19 of which involved coding genes regulating neural development and/or function, and revealed expression of several previously unidentified metabolic, neuroendocrine, and neurodevelopment pathways in POMC neurons.



PNE does not result in obesity and type 2 diabetes but instead enhances leptin-melanocortinergic feeding and body weight regulation via POMC neurons in adult offspring. PNE leads to selective upregulation of Gm15851, a lncRNA, in adult offspring POMC neurons. POMC neurons express several lncRNAs and pathways possibly regulating POMC neuronal development and/or function.
Department of Psychiatry and Behavioral Sciences and Center for Therapeutic Innovation, Miller School of Medicine, University of Miami, Miami, FL, 33136, USA. jossil68@gmail.com.
Jose P
JP
Silva
Department of Psychiatry and Behavioral Sciences and Center for Therapeutic Innovation, Miller School of Medicine, University of Miami, Miami, FL, 33136, USA.
Guerline
G
Lambert
John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, 33136, USA.
Derek
D
van Booven
Department of Psychiatry and Behavioral Sciences and Center for Therapeutic Innovation, Miller School of Medicine, University of Miami, Miami, FL, 33136, USA.
Claes
C
Wahlestedt
D000284:Administration, Oral; D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D003433:Crosses, Genetic; D059305:Diet, High-Fat / Q000379:methods; D004734:Energy Metabolism / Q000187:drug effects / Q000235:genetics; D005260:Female; D018507:Gene Expression Regulation, Developmental; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D020738:Leptin / Q000235:genetics* / Q000378:metabolism; D008297:Male; D018811:Maternal Exposure; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009538:Nicotine / Q000494:pharmacology*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000235:genetics* / Q000378:metabolism; D011333:Pro-Opiomelanocortin / Q000235:genetics* / Q000378:metabolism; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism; D017423:Sequence Analysis, RNA; D015398:Signal Transduction
D020738:Leptin; D062085:RNA, Long Noncoding; D049452:Green Fluorescent Proteins; D011333:Pro-Opiomelanocortin; D009538:Nicotine
Epigenomics; Gestational nicotine exposure; Gm15851; Leptin-melanocortin signaling; Obesity; POMC neurons; Transcriptomics; Type 2 diabetes; lncRNA