Covering the cycle of life and the balance between plasticity and reversibility with the focus on metabolic hormones leptin and ghrelin.
Abstract: Early life overweight is a significant risk factor for developmental programming of adult obesity due to changes in the availability of metabolic factors crucial for the maturation of brain appetite-regulatory circuitry. The appetite-stimulating hormone, ghrelin, has been recently identified as a major regulator of the establishment of hypothalamic feeding pathways. Ghrelin exists in circulation in two major forms, as acylated and des-acylated ghrelin. While most research has focused on acyl ghrelin, the role of neonatal des-acyl ghrelin in metabolic programming is currently unknown. Here we assessed the influences of early life overfeeding in male rats on the ghrelin system, including acyl and des-acyl ghrelin's ability to access the hypothalamus. Our data show that early life overfeeding influences the ghrelin system short-term, leading to an acute reduction in circulating des-acyl ghrelin and increased expression of the growth hormone secretagogue receptor (GHSR) in the arcuate nucleus of the hypothalamus (ARC). These changes are associated with increased neuronal activation in response to exogenous acyl, but not des-acyl, ghrelin in the ARC and the paraventricular nucleus of the hypothalamus (PVN). Interestingly, while we observed no differences in the accessibility of the ARC to acyl or des-acyl ghrelin, less exogenous acyl ghrelin reaches the PVN in the neonatally overfed. Importantly, the influences of neonatal overfeeding on the ghrelin system were not maintained into adulthood. Therefore, while early life overfeeding results in excess body weight and stimulates acute changes in the brain's sensitivity to metabolic signals, this developmental mal-programming is at least partially alleviated in adulthood.
Pub.: 28 Sep '16, Pinned: 25 Aug '17
Abstract: Early life diet influences metabolic programming, increasing the risk for long-lasting metabolic ill-health. Neonatally overfed rats have an early increase in leptin that is maintained long-term and is associated with a corresponding elevation in body weight. However, the immediate and long-term effects of neonatal overfeeding on hypothalamic anorexigenic pro-opiomelanocortin (POMC) and orexigenic agouti-related peptide (AgRP) / neuropeptide Y (NPY) circuitry, and if these are directly mediated by leptin, have not yet been examined. Here we examined the effects of neonatal overfeeding on leptin-mediated development of hypothalamic POMC and AgRP/NPY neurons and whether these effects can be normalised by neonatal leptin antagonism in male Wistar rats. Neonatal overfeeding led to an acute (neonatal) resistance of hypothalamic neurons to exogenous leptin, but this leptin resistance was resolved by adulthood. While there were no effects of neonatal overfeeding on POMC immunoreactivity in neonates or adults, the neonatal overfeeding-induced early increase in (arcuate nucleus) (ARC) AgRP/NPY fibres was reversed by adulthood so that neonatally overfed adults had reduced NPY immunoreactivity in the ARC compared with controls, with no further differences in AgRP immunoreactivity. Short-term neonatal leptin antagonism did not reverse the excess body weight or hyperleptinemia in the neonatally overfed, suggesting factors other than leptin may also contribute to the phenotype. Our findings show that changes in the availability of leptin during early life period influence the development of hypothalamic connectivity short-term but this is partly resolved by adulthood; novel evidence that there is an adaptation to the metabolic mal-programming effects of neonatal overfeeding.
Pub.: 30 Apr '17, Pinned: 25 Aug '17
Abstract: Background and aims: Caloric restriction (CR) is the most robust and reproducible intervention for slowing aging, and maintaining health and vitality in animals. Previous studies found that CR is associated with changes in specific biomarkers in monkeys that were also associated with reduced risk of mortality in healthy men. In this study we examine the association between other potential biomarkers related to CR and extended lifespan in healthy humans. Methods: Based on the Baltimore Longitudinal Study of Aging, “long-lived” participants who survived to at least 90 years of age (n=41, cases) were compared with “short-lived” participants who died between 72–76 yrs of age (n=31, controls) in the nested case control study. Circulating levels of ghrelin, insulin, leptin, interleukin 6, adiponectin and testosterone were measured from samples collected between the ages 58 to 70 yrs. Baseline differences between groups were examined with t-test or Wilcoxon test, and mixed effects general linear model was used for a logistic model to differentiate the two groups with multiple measurements on some subjects. Results: At the time of biomarkers evaluation (58–70 yrs), none of the single biomarker levels was significantly different between the two groups. However, after combining information from multiple biomarkers by adding the z-transformed values, the global score differentiated the long- and short-lived participants (p=0.05). Conclusions: In their sixties, long-lived and short-lived individuals do not differ in biomarkers that have been associated with CR in animals. However, difference between the groups was only obtained when multiple biomarker dysregulation was considered.
Pub.: 29 Apr '14, Pinned: 25 Aug '17
Abstract: Many studies have shown the importance of an adequate nutritional environment during development to optimally establish the neurohormonal circuits that regulate feeding behaviour. Under- or over-nutrition during early stages of life can lead to alterations in the physiology and brain networks that control food intake, resulting in a greater vulnerability to suffer maladjustments in energy metabolism in adulthood. These alterations produced by under- or over-nourishment during development differ between males and females, as does the modulatory action that estradiol exerts on the alterations produced by malnutrition. Estradiol regulates metabolism and brain metabolic circuits through the same transcription factor pathway, STAT3, that leptin and ghrelin use to program feeding circuits. Although more research is needed to disentangle the actual role of estradiol during development on the programming of feeding circuits, a synergistic role together with leptin and/or ghrelin might be hypothesized.
Pub.: 30 Jul '17, Pinned: 25 Aug '17
Join Sparrho today to stay on top of science
Discover, organise and share research that matters to you