Metabolic programming in response to overnourishment in the immediate postnatal life in rats
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Altered nutrient exposure in the early developmental periods of life (in utero and/or immediate postnatal period) has been shown to contribute to the onset of metabolic disorders in adulthood. Rats raised in small litters (SL) is a well-established animal model for overnourishment in the immediate postnatal life. Reduction of litter size to three pups/dam (SL) resulted in increases in body weight gains and serum levels of insulin and leptin during the suckling period which persisted in the postweaning period resulting in adult-onset obesity. Using the SL rat model, the aim of the first study in chapter 3, was to investigate the mechanisms that underlie the development of insulin resistance in the skeletal muscle of young (21 day-old) and adult female SL rats (140 day-old). Our results show that overnutrition during the suckling period resulted in increased body weight gains, hyperphagia and adult-onset obesity as well as increased levels of serum glucose, insulin, and leptin in SL rats. No differences in the expression of total protein as well as tyrosine phosphorylation of insulin receptor beta; and glucose transporter 4 (GLUT4) were observed in skeletal muscle between the two groups at both ages. A significant decrease of total insulin receptor substrate 1(IRS-1) protein and an increase in serine phosphorylation of IRS-1 were observed in skeletal muscle from adult SL rats only. Hypermethylation of specific CpG dinucleotides in the proximal promoter region was observed for the Irs1 and Glut4 genes which were consistent with the reduction in Irs1 and Glut4 mRNA levels in skeletal muscle of adult SL female rats. Results from this study suggest that epigenetic modifications of the key genes involved in the insulin signaling pathway in skeletal muscle could result in the development of insulin resistance in SL female rats. Hyperphagic behavior and development of obesity due to alterations of hypothalamic neuropeptides are observed in SL rats. Therefore, the aim of the second study in chapter 4 was to investigate if two levels of caloric restriction (CR) in the early postweaning period can reverse the obese phenotype in SL rats. The control litter (CL) had 12 pups/dam and SL had 3 male pups/dam from postnatal day 3 until 21. In the postweaning period rats consumed lab chow as indicated: (i) CL and SL groups were on ad libitum regimen up to day 140, (ii) another SL group was pair-fed (SL/PF) to CL(mild ~14% reduction), (iii) SL/PF/AL group was pair-fed up to day 94 and then switched over to ad libitum feeding, (iv) SL/CR group received 24% reduction (moderate CR) in daily food intake compared to SL, and (v) SL/CR/AL group was on 24% CR up to day 94 and then switched over to ad libitum feeding. Pair-feeding reduced body weight gains and serum insulin and leptin levels in SL/PF rats compared to SL rats, but these parameters were restored to SL levels in the SL/PF/AL rats after switching to ad libitum feeding. Interestingly, the moderate CR normalized these parameters in SL/CR and SL/CR/AL rats compared to CL. The expression of neuropeptide Y, pro-opiomelanocortin and leptin receptor returned to control levels in the hypothalami from SL/CR and SL/CR/AL rats. These results indicate that appropriate manipulation of energy intake during the early postweaning period could lead to longer lasting effects on the regulation of body weight homeostasis via reversal of the early preweaning metabolic programming effects on the hypothalamic appetite regulation mechanism. In the context of the human obesity epidemic, dietary caloric restrictions implanted during childhood may reverse metabolic programming effects in individuals for whom overfeeding in infancy predisposes them to the development of obesity.