Abstract
Substantial evidence indicated that maternal malnutrition could increase the susceptibility to obesity, insulin resistance, and type 2 diabetes in adulthood. It is increasingly apparent that the brain, especially the hypothalamus, plays a critical role in glucose homeostasis. However, little information is known about the mechanisms linking maternal protein restriction combined with post-weaning high-fat (HF) feeding with altered expression of brain neurotransmitters, and investigations into the epigenetic modifications of hypothalamus in offspring have not been fully elucidated. Our objective was to explore the effects of maternal protein restriction combined with post-weaning HF feeding on glucose metabolism and hypothalamic POMC methylation in male offspring mice. C57/BL6 mice were fed on either low-protein (LP) or normal chow (NC) diet throughout gestation and lactation. Then, the male offspring were randomly weaned to either NC or high-fat (HF) diet until 32 weeks of age. Gene expressions and DNA methylation of hypothalamic proopiomelanocortin (POMC) and melanocortin receptor 4 (MC4R) were determined in male offspring. The results showed that birth weights and body weights at weaning were both significantly lower in male offspring mice of the dams fed with a LP diet. Maternal protein restriction combined with post-weaning high-fat feeding, predisposes higher body weight, persistent glucose intolerance (from weaning to 32 weeks of age), hyperinsulinemia, and hyperleptinemia in male offspring mice. POMC and MC4R expressions were significantly increased in offspring mice fed with maternal LP and postnatal high-fat diet (P < 0.05). Furthermore, maternal protein restriction combined with post-weaning high-fat feeding induced hypomethylation of POMC promoter in the hypothalamus (P < 0.05) and POMC-specific methylation (%) was negatively correlated with the glucose response to a glucose load in male offspring mice (r = −0.42, P = 0.039). In conclusion, maternal LP diet combined with post-weaning high-fat feeding predisposed the male offspring to impaired glucose metabolism and hypothalamic POMC hypomethylation. These findings can advance our thinking about hypothalamic POMC gene methylation between maternal LP diet combined with post-weaning high-fat feeding and metabolic health in offspring.
Highlights
Maternal malnutrition has been associated with the onset of metabolic diseases in adulthood, including obesity, insulin resistance, and diabetes [1,2,3,4]
It is reported that most peripheral organs, including the liver, pancreas, skeletal muscle, and adipose tissue appeared to be imprinted by unbalanced nutrition, which can be associated with epigenetic modulation of key developmental gene expressions [9, 10]
It has been widely reported that prenatal LP and postnatal HF diets can induce the occurrence of long-term metabolic disorders in mammals, including obesity, glucose intolerance, and type 2 diabetes [24, 25]
Summary
Maternal malnutrition has been associated with the onset of metabolic diseases in adulthood, including obesity, insulin resistance, and diabetes [1,2,3,4]. Numerous animal experiments, including our previous studies, have indicated that maternal low-protein (LP) diet combined with a post-weaning high-fat (HF) diet can significantly increase susceptibility to obesity, impaired glucose tolerance, and insulin resistance in offspring [1, 2, 5]. It is reported that most peripheral organs, including the liver, pancreas, skeletal muscle, and adipose tissue appeared to be imprinted by unbalanced nutrition, which can be associated with epigenetic modulation of key developmental gene expressions [9, 10]. Hypermethylation of these CpG islands has a specific effect on repressing transcription, whereas hypomethylation of CpG islands is related to transcriptional activation. Our previous study showed that maternal LP diet can program glucose metabolism and hepatic microRNA expressions in early life offspring [11]
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