Antony Kaspi1,2, Ishant Khurana1,2, Mark Ziemann1,2, Timothy Connor3, Briana Spolding3, Paul Zimmet1, Ken Walder3, Assam El-Osta1,2,4,5. 1. Central Clinical School, Faculty of Medicine, Monash University, Victoria, 3004, Australia. 2. Baker IDI Heart and Diabetes Institute, The Alfred Medical Research and Education Precinct, Melbourne, Victoria, 3004, Australia. 3. Metabolic Research Unit, Faculty of Health, Medicine, Nursing and Behavioral Sciences, Deakin University, Waurn Ponds, Victoria, 3216, Australia. 4. Department of Pathology, University of Melbourne, Parkville, Victoria, 3004, Australia. 5. Hong Kong Institute of Diabetes and Obesity, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR.
Abstract
SCOPE: Early life nutrition has long-lasting influence in adults through key mediators that modulate epigenetic states, although the determinants involved that underlie this response remain controversial. Because of the similarities between metabolic, physiological, and endocrine changes and those occurring in human type 2 diabetes, we studied the interaction of diet during pregnancy regulating RNA adenosine methylation (N6-methyladenosine [m6A]) and the transcriptome in Psammomys obesus. METHODS AND RESULTS: Breeding pairs were randomly allocated standard diet (total digestible energy 18 MJ kg-1 ) or low-fat diet (15 MJ kg-1 ). Offspring were weaned onto the low-fat diet at 4 weeks of age and given ad libitum access, resulting in two experimental groups: 1) male offspring of animals fed a low-fat diet and weaned onto the low-fat diet and 2) male offspring of animals fed a standard diet and weaned onto the low-fat diet. Hypothalamic RNA was used to assess m6A by immunoprecipitation. Parental low-fat diet alters the metabolic phenotype in offspring. An association between parental diet and hypothalamic m6A was observed in regulating the expression of FTO and METTL3 in the offspring. CONCLUSIONS: We propose the regulatory capacity is now broadened for the first time to include m6A in developmental programming and obesity phenotype.
SCOPE: Early life nutrition has long-lasting influence in adults through key mediators that modulate epigenetic states, although the determinants involved that underlie this response remain controversial. Because of the similarities between metabolic, physiological, and endocrine changes and those occurring in human type 2 diabetes, we studied the interaction of diet during pregnancy regulating RNA adenosine methylation (N6-methyladenosine [m6A]) and the transcriptome in Psammomys obesus. METHODS AND RESULTS: Breeding pairs were randomly allocated standard diet (total digestible energy 18 MJ kg-1 ) or low-fat diet (15 MJ kg-1 ). Offspring were weaned onto the low-fat diet at 4 weeks of age and given ad libitum access, resulting in two experimental groups: 1) male offspring of animals fed a low-fat diet and weaned onto the low-fat diet and 2) male offspring of animals fed a standard diet and weaned onto the low-fat diet. Hypothalamic RNA was used to assess m6A by immunoprecipitation. Parental low-fat diet alters the metabolic phenotype in offspring. An association between parental diet and hypothalamic m6A was observed in regulating the expression of FTO and METTL3 in the offspring. CONCLUSIONS: We propose the regulatory capacity is now broadened for the first time to include m6A in developmental programming and obesity phenotype.