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Nutritional programming of hypothalamic development: critical periods and windows of opportunity.

ABSTRACT: Obesity is increasing at an alarming rate throughout the world, particularly among children. Epidemiological and experimental data have suggested that suboptimal nutrition and growth during prenatal and/or postnatal life can have a significant role in the development of obesity and related diseases. Similarly, exposure to malnutrition during perinatal life can result in lifelong metabolic disorders. Although the precise biological mechanisms governing metabolic programming have not been fully elucidated, there is growing evidence that obesity and other metabolic diseases may result from a change in the underlying developmental program of the hypothalamic pathways that regulate energy balance. The hypothalamus undergoes tremendous growth beginning in the embryonic period and continuing through adolescence, and an alteration in perinatal nutrition can affect various developmental processes, including neurogenesis and axon growth, which can lead to abnormal hypothalamic development. Metabolic hormones, particularly leptin, are capable of transmitting signals to the developing hypothalamus in response to alterations in the nutritional environment and may underlie potential maladaptive responses to early metabolic perturbations. A better understanding of the optimal perinatal hormonal and nutritional environment during hypothalamic development may help ameliorate and reverse the metabolic malprogramming of the fetus and/or neonate.

SUBMITTER: Bouret SG

PROVIDER: S-EPMC4850605 | biostudies-other | 2012 Dec

REPOSITORIES: biostudies-other

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Project description:Many mechanisms purport to explain how nutritional signals during early development are manifested as disease in the adult offspring. While these describe processes leading from nutritional insult to development of the actual pathology, the initial underlying cause of the programming effect remains elusive. To establish the primary drivers of programming, this study aimed to capture embryonic gene and protein changes in the whole embryo at the time of nutritional insult rather than downstream phenotypic effects. By using a cross-over design of two well established models of maternal protein and iron restriction we aimed to identify putative common "gatekeepers" which may drive nutritional programming.Both protein and iron deficiency in utero reduced the nephron complement in adult male Wistar and Rowett Hooded Lister rats (P<0.05). This occurred in the absence of damage to the glomerular ultrastructure. Microarray, proteomic and pathway analyses identified diet-specific and strain-specific gatekeeper genes, proteins and processes which shared a common association with the regulation of the cell cycle, especially the G1/S and G2/M checkpoints, and cytoskeletal remodelling. A cell cycle-specific PCR array confirmed the down-regulation of cyclins with protein restriction and the up-regulation of apoptotic genes with iron deficiency.The timing and experimental design of this study have been carefully controlled to isolate the common molecular mechanisms which may initiate the sequelae of events involved in nutritional programming of embryonic development. We propose that despite differences in the individual genes and proteins affected in each strain and with each diet, the general response to nutrient deficiency in utero is perturbation of the cell cycle, at the level of interaction with the cytoskeleton and the mitotic checkpoints, thereby diminishing control over the integrity of DNA which is allowed to replicate. These findings offer novel insight into the primary causes and mechanisms leading to the pathologies which have been identified by previous programming studies.

Project description:Seasonal windows of opportunity are intervals within a year that provide improved prospects for growth, survival, or reproduction. However, few studies have sufficient temporal resolution to examine how multiple factors combine to constrain the seasonal timing and extent of developmental opportunities. Here, we document seasonal changes in milkweed (Asclepias fascicularis)-monarch (Danaus plexippus) interactions with high resolution throughout the last three breeding seasons prior to a precipitous single-year decline in the western monarch population. Our results show early- and late-season windows of opportunity for monarch recruitment that were constrained by different combinations of factors. Early-season windows of opportunity were characterized by high egg densities and low survival on a select subset of host plants, consistent with the hypothesis that early-spring migrant female monarchs select earlier-emerging plants to balance a seasonal trade-off between increasing host plant quantity and decreasing host plant quality. Late-season windows of opportunity were coincident with the initiation of host plant senescence, and caterpillar success was negatively correlated with heatwave exposure, consistent with the hypothesis that late-season windows were constrained by plant defense traits and thermal stress. Throughout this study, climatic and microclimatic variations played a foundational role in the timing and success of monarch developmental windows by affecting bottom-up, top-down, and abiotic limitations. More exposed microclimates were associated with higher developmental success during cooler conditions, and more shaded microclimates were associated with higher developmental success during warmer conditions, suggesting that habitat heterogeneity could buffer the effects of climatic variation. Together, these findings show an important dimension of seasonal change in milkweed-monarch interactions and illustrate how different biotic and abiotic factors can limit the developmental success of monarchs across the breeding season. These results also suggest the potential for seasonal sequences of favorable or unfavorable conditions across the breeding range to strongly affect monarch population dynamics.

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Nutritional programming of hypothalamic development: critical periods and windows of opportunity.

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