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Abstract
A poor prenatal environment brings about perturbations in leptin surge and hypothalamic circuitry that program impaired ability to regulate energy homeostasis in adulthood. Here, using a rat model of moderate maternal caloric restriction during gestation, we aimed to investigate whether leptin supplementation with physiological doses throughout lactation is able to ameliorate the adverse developmental malprogramming effects exerted in offspring hypothalamus structure and function. Three groups of male and female rats were studied: the offspring of ad libitum fed dams (controls), the offspring of 20% calorie restricted dams during the first part of pregnancy (CR), and CR rats supplemented with physiological doses of leptin throughout lactation (CR-Leptin). Animals were sacrificed on postnatal day 25. Morphometric and immunohistochemical studies on arcuate (ARC) and paraventicular (PVN) nucleus were performed and hypothalamic expression levels of selected genes were determined. In CR males, leptin treatment restored, at least in part, the number of immunoreactive neuropeptide Y (NPY+) cells in ARC, the total number of cells in PVN, hypothalamic NPY, cocaine- and amphetamine-regulated transcript (CART) and suppressor of cytokine signalling-3 (SOCS-3) mRNA levels, and plasma leptin levels, which were decreased in CR animals. CR-Leptin males showed higher hypothalamic long-form leptin receptor (ObRb) mRNA levels, compared to control and CR animals. In CR females, leptin treatment reverted the increased number of cells in ARC and cell density in ARC and PVN, and reduced hypothalamic SOCS-3 mRNA expression to levels similar to controls. Leptin treatment also reverted the increased relative area of NPY+ fibers in the PVN occurring in CR animals. In conclusion, leptin supplementation throughout lactation is able to revert, at least partly, most of the developmental effects on hypothalamic structure and function caused by moderate maternal caloric restriction during gestation, and hence making this metabolic malprogramming reversible to some extent.
Highlights
Obesity is multifactorial in origin, but is mostly attributed to the interaction between environmental conditions and genetic predisposition [1]
Moderate caloric restriction during the first half of gestation in rats has been described to program the offspring for greater food intake as well as for insulin and leptin resistance, which results in higher body weight and body fat content in males but not in females [6,15]
Body weight gain and energy intake in dams Body weight gain and cumulative energy intake of dams during different periods of gestation and lactation are summarized in Table 2. 20% food restriction conducted at the beginning of gestation resulted in lower weight gain of calorie restricted dams (CR-dams) and, these animals showed lower body weight at the end of the restriction period with respect to their controls (p < 0.05; Student’s t test)
Summary
Obesity is multifactorial in origin, but is mostly attributed to the interaction between environmental conditions and genetic predisposition [1]. Moderate caloric restriction during the first half of gestation in rats has been described to program the offspring for greater food intake as well as for insulin and leptin resistance, which results in higher body weight and body fat content in males but not in females [6,15]. Despite these observations, elucidation of the mechanisms responsible for these ‘developmental origins of health and disease’ is a topic of great concern and still remains unclear
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