Intrauterine metabolic programming alteration increased susceptibility to non-alcoholic adult fatty liver disease in prenatal caffeine-exposed rat offspring.
An increase in susceptibility to metabolic syndromes (MetS) in rat offspring that experienced prenatal caffeine exposure (PCE) has been previously demonstrated. The present study aimed to clarify this increased susceptibility and elucidate the mechanism of foetal origin that causes or contributes to adult non-alcoholic fatty liver disease (NAFLD) as a result of PCE. Based on the results from both foetal and adult studies of rats that experienced PCE (120 mg/kgd), the foetal weight and serum triglyceride levels decreased significantly and hepatocellular ultrastructure was altered. Foetal livers exhibited inhibited insulin-like growth factor-1 (IGF-1), enhanced lipogenesis and reduced lipid output. In adult female offspring of PCE+lab chow, lipid synthesis, oxidation and output were enhanced, whereas lipogenesis was inhibited in their male conterparters. Furthermore, in adult offspring of PCE+ high-fat diet, catch-up growth appeared obvious with enhanced hepatic IGF-1, especially in females. Both males and females showed increased lipid synthesis and reduced output, which were accompanied by elevated serum triglyceride. Severe NAFLD appeared with higher Kleiner scores. Gluconeogenesis was continuously enhanced in females. Therefore, increased susceptibility to diet-induced NAFLD in PCE offspring was confirmed, and it appears to be mediated by intrauterine glucose and alterations in lipid metabolic programming. This altered programming enhanced foetal hepatic lipogenesis and reduced lipid output in utero, which continued into the postnatal phase and reappeared in adulthood with the introduction of a high-fat diet, thereby aggravating hepatic lipid accumulation and causing NAFLD.
Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071, China; Department of Orthopaedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
Linlong
L
Wang
Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071, China.
Lang
L
Shen
Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071, China.
Jie
J
Ping
Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071, China.
Li
L
Zhang
Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071, China.
Zhongfen
Z
Liu
Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071, China.
Yong
Y
Wu
Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071, China.
Yansong
Y
Liu
Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071, China.
Hegui
H
Huang
Department of Orthopaedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
Liaobin
L
Chen
Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071, China; Research Center of Food and Drug Evaluation, Wuhan University, Wuhan 430071, China. Electronic address: wanghui19@whu.edu.cn.
Hui
H
Wang
D000465:Algorithms; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D002110:Caffeine / Q000633:toxicity*; D000697:Central Nervous System Stimulants / Q000633:toxicity*; D005234:Fatty Liver / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D005260:Female; D047109:Fetal Development / Q000187:drug effects*; D005317:Fetal Growth Retardation / Q000139:chemically induced / Q000473:pathology; D005333:Fetus / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000502:physiology; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000473:pathology; D008297:Male; D065626:Non-alcoholic Fatty Liver Disease; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000503:physiopathology*; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D014280:Triglycerides / Q000097:blood
D001786:Blood Glucose; D000697:Central Nervous System Stimulants; D014280:Triglycerides; D002110:Caffeine; D012313:RNA; D007334:Insulin-Like Growth Factor I; D005947:Glucose
GC; Glucocorticoid; Glucose and lipid metabolism; IUGR; Insulin-like growth factor-1; NAFLD; Non-alcoholic fatty liver disease; PCE; Prenatal caffeine exposure; glucocorticoid; intrauterine growth retardation; non-alcoholic fatty liver disease; prenatal caffeine exposure