Abstract
Intrauterine growth restriction (IUGR) is closely linked with metabolic diseases, appetite disorders and obesity at adulthood. Leptin, a major adipokine secreted by adipose tissue, circulates in direct proportion to body fat stores, enters the brain and regulates food intake and energy expenditure. Deficient leptin neuronal signalling favours weight gain by affecting central homeostatic circuitry. The aim of this study was to determine if leptin resistance was programmed by perinatal nutritional environment and to decipher potential cellular mechanisms underneath.We clearly demonstrated that 5 months old IUGR rats develop a decrease of leptin sentivity, characterized by no significant reduction of food intake following an intraperitoneal injection of leptin.Apart from the resistance to leptin injection, results obtained from IUGR rats submitted to rapid catch-up growth differed from those of IUGR rats with no catch-up since we observed, for the first group only, fat accumulation, increased appetite for food rich in fat and increased leptin synthesis. Centrally, the leptin resistant state of both groups was associated with a complex and not always similar changes in leptin receptor signalling steps. Leptin resistance in IUGR rats submitted to rapid catch-up was associated with alteration in AKT and mTOR pathways. Alternatively, in IUGR rats with no catch-up, leptin resistance was associated with low hypothalamic expression of LepRa and LepRb. This study reveals leptin resistance as an early marker of metabolic disorders that appears before any evidence of body weight increase in IUGR rats but whose mechanisms could depend of nutritional environment of the perinatal period.
Highlights
Body weight is normally maintained within a narrow range by an appropriate balance between energy intake and energy expenditure
In complement to that work we demonstrated that rapid catch-up growth of intrauterine growth restriction (IUGR) rats lead to a reduction of leptin sensitivity at postnatal day 5 and 12 in arcuate nucleus (ARC)
Since hyperleptinemia is a sign of leptin resistance [25], we hypothesized that an adverse foetal and/or postnatal nutritional environment will program the development of leptin resistance at adulthood
Summary
Body weight is normally maintained within a narrow range by an appropriate balance between energy intake and energy expenditure. On a widely used animal model of nutritional programming, that low birth weight, as a consequence of an intrauterine growth restriction (IUGR), leads to metabolic alterations and feeding behaviour abnormalities when followed by a rapid catch-up growth [1]. Desai et al observed a reduction of leptin activated STAT3 pathway at PND1 after nursing IUGR pups by ad libitum fed dams in order to induce a rapid catch-up growth [5]. These and other findings of the literature reveal the important role of nutrition during the perinatal period in adverse adult health outcomes and permanent changes in energy homeostasis [6,7,8]
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