title: Nicotinamide supplementation induces detrimental metabolic and epigenetic changes in developing rats.
abstract: Ecological evidence suggests that niacin (nicotinamide and nicotinic acid) fortification may be involved in the increased prevalence of obesity and type 2 diabetes, both of which are associated with insulin resistance and epigenetic changes. The purpose of the present study was to investigate nicotinamide-induced metabolic changes and their relationship with possible epigenetic changes. Male rats (5 weeks old) were fed with a basal diet (control group) or diets supplemented with 1 or 4 g/kg of nicotinamide for 8 weeks. Low-dose nicotinamide exposure increased weight gain, but high-dose one did not. The nicotinamide-treated rats had higher hepatic and renal levels of 8-hydroxy-2'-deoxyguanosine, a marker of DNA damage, and impaired glucose tolerance and insulin sensitivity when compared with the control rats. Nicotinamide supplementation increased the plasma levels of nicotinamide, N1-methylnicotinamide and choline and decreased the levels of betaine, which is associated with a decrease in global hepatic DNA methylation and uracil content in DNA. Nicotinamide had gene-specific effects on the methylation of CpG sites within the promoters and the expression of hepatic genes tested that are responsible for methyl transfer reactions (nicotinamide N-methyltransferase and DNA methyltransferase 1), for homocysteine metabolism (betaine-homocysteine S-methyltransferase, methionine synthase and cystathionine β-synthase) and for oxidative defence (catalase and tumour protein p53). It is concluded that nicotinamide-induced oxidative tissue injury, insulin resistance and disturbed methyl metabolism can lead to epigenetic changes. The present study suggests that long-term high nicotinamide intake (e.g. induced by niacin fortification) may be a risk factor for methylation- and insulin resistance-related metabolic abnormalities.
authors.affiliation: Institute of Basic Medical Sciences, Medical College, Dalian University, Dalian 116622, People's Republic of China.
authors.forename: Da
authors.initials: D
authors.lastname: Li
authors.forename: Yan-Jie
authors.initials: YJ
authors.lastname: Tian
authors.forename: Jing
authors.initials: J
authors.lastname: Guo
authors.forename: Wu-Ping
authors.initials: WP
authors.lastname: Sun
authors.forename: Yong-Zhi
authors.initials: YZ
authors.lastname: Lun
authors.forename: Ming
authors.initials: M
authors.lastname: Guo
authors.forename: Ning
authors.initials: N
authors.lastname: Luo
authors.forename: Yu
authors.initials: Y
authors.lastname: Cao
authors.forename: Ji-Min
authors.initials: JM
authors.lastname: Cao
authors.forename: Xiao-Jie
authors.initials: XJ
authors.lastname: Gong
authors.forename: Shi-Sheng
authors.initials: SS
authors.lastname: Zhou
mesh_terms: D000818:Animals; D001622:Betaine / Q000097:blood; D002794:Choline / Q000097:blood; D018899:CpG Islands / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D019175:DNA Methylation / Q000187:drug effects*; D019587:Dietary Supplements / Q000009:adverse effects*; D044127:Epigenesis, Genetic / Q000187:drug effects*; D018149:Glucose Intolerance / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D006710:Homocysteine / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008659:Metabolic Diseases / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D009525:Niacin / Q000009:adverse effects*; D009536:Niacinamide / Q000009:adverse effects* / Q000031:analogs & derivatives / Q000097:blood; D018384:Oxidative Stress / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014498:Uracil / Q000378:metabolism; D014803:Vitamin B Complex / Q000009:adverse effects*; D015430:Weight Gain / Q000187:drug effects
chemical_list: D006710:Homocysteine; D014803:Vitamin B Complex; D009536:Niacinamide; D009525:Niacin; D001622:Betaine; D014498:Uracil; D004247:DNA; D002794:Choline; C024058:N(1)-methylnicotinamide