Neonatal Overfeeding Induced by Small Litter Rearing Causes Altered Glucocorticoid Metabolism in Rats

Miao Hou,Yanhua Liu,Mei Guo,Jonas Burén,Lijun Zhu,Bin Sun,Xiaonan Li,Ingrid A Dahlman

doi:10.1371/journal.pone.0025726

Miao Hou, Yanhua Liu + Show 6 more

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https://doi.org/10.1371/journal.pone.0025726

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Abstract

Elevated glucocorticoid (GC) activity may be involved in the development of the metabolic syndrome. Tissue GC exposure is determined by the tissue-specific GC-activating enzyme 11β-hydroxysteriod dehydrogenase type 1 (11β-HSD1) and the GC-inactivating enzyme 5α-reductase type 1 (5αR1), as well as 5β-reductase (5βR). Our aim was to study the effects of neonatal overfeeding induced by small litter rearing on the expression of GC-regulating enzymes in adipose tissue and/or liver and on obesity-related metabolic disturbances during development. Male Sprague-Dawley rat pup litters were adjusted to litter sizes of three (small litters, SL) or ten (normal litters, NL) on postnatal day 3 and then given standard chow from postnatal week 3 onward (W3). Small litter rearing induced obesity, hyperinsulinemia, and higher circulating corticosterone in adults. 11β-HSD1 expression and enzyme activity in retroperitoneal, but not in epididymal, adipose tissue increased with postnatal time and peaked at W5/W6 in both groups before declining. From W8, 11β-HSD1 expression and enzyme activity levels in retroperitoneal fat persisted at significantly higher levels in SL compared to NL rats. Hepatic 11β-HSD1 enzyme activity in SL rats was elevated from W3 to W16 compared to NL rats. Hepatic 5αR1 and 5βR expression was higher in SL compared to NL rats after weaning until W6, whereupon expression decreased in the SL rats and remained similar to that in NL rats. In conclusion, small litter rearing in rats induced peripheral tissue-specific alterations in 11β-HSD1 expression and activity and 5αR1 and 5βR expression during puberty, which could contribute to elevated tissue-specific GC exposure and aggravate the development of metabolic dysregulation in adults.

Highlights

The global epidemic of obesity and related metabolic disorders continues to progress at an alarming rate in both adults and children [1,2]
At postnatal day 14 (P14), body weight was higher in SL compared to NL rats (Fig. 1A); this persisted until W16 (Fig. 1B)
Our most important finding was that peripheral 11b-HSD1 and 5a-reductase type 1 (5aR1) and 5bR expression had different developmental patterns in SL rats compared to NL rats. 11bHSD1 expression and activity in visceral adipose tissue was persistently higher from W8 afterward in SL rats compared to NL rats

Summary

Introduction

The global epidemic of obesity and related metabolic disorders continues to progress at an alarming rate in both adults and children [1,2]. Clinical and experimental studies have shown an association between the environments during the perinatal period and the development of features of metabolic syndrome, such as hypertension, type 2 diabetes, insulin resistance, and hyperlipidemia later in life [3]. Under- or overnutrition during the prenatal period increases the risk of obesity and hyperinsulinemia [4]. Rapid weight gain during infancy is consistently associated with increased subsequent risk for obesity [5]. The mechanisms behind the putative pathophysiological link between preand postnatal nutrition and obesity have not yet been established, glucocorticoids (GC) have been proposed as possible mediators of the permanent programming of obesity, insulin resistance, and other metabolic dysregulations [6]

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