A pinboard by
Luba Sominsky

VC Postdoctoral Fellow, RMIT University


Establishing novel targets to treat the effects of stress on fertility

Infertility has become alarmingly common, with 70 to 80 million couples worldwide currently experiencing infertility, including 1 in 6 Australian couples. Stress is an unavoidable facet of life and is usually dealt with by an appropriate and regulated neuroendocrine response. While psychological stress affects us all at some point, individuals differ in the impact this has on their physiology, including fertility. Those experiencing extreme or long-term stress or those more vulnerable to its effects may be particularly vulnerable to fertility consequences. In those individuals, stress has been shown to have a substantial negative impact on every aspect of fertility, from libido to pregnancy, even in normally-fertile men and women. However, attempts to isolate single causal links between stress and infertility have not yet been successful due to their multi-faceted aetiologies. The metabolic hormone ghrelin regulates stress and plays a crucial role in fertility. It may therefore be pivotal in the integration of the stress and reproductive systems and functions.

In this study, we hypothesised that chronic stress would lead to deleterious effects on reproductive function that are mediated by ghrelin-induced activation of its receptor. We tested this hypothesis using a mouse-model of chronic stress, with and without a chronic treatment with ghrelin receptor antagonist. Chronic stress led to significant disruption of the stress response, and some of these effects were rescued by abolishing the effects of ghrelin on its receptor. The effects of chronic stress were accompanied by a substantial increase in circulating ghrelin. Importantly, chronic stress robustly reduced the numbers of the finite population of primordial follicles in the ovary, and this was mitigated by the ghrelin receptor antagonist. These data suggest that chronic stress-induced increase in ghrelin may act as a crucial neuroendocrine link between stress and reproductive dysfunction that can be pharmacologically targeted to mitigate the negative effects of stress on fertility.


Eating behavior and stress: a pathway to obesity.

Abstract: Stress causes or contributes to a huge variety of diseases and disorders. Recent evidence suggests obesity and other eating-related disorders may be among these. Immediately after a stressful event is experienced, there is a corticotropin-releasing-hormone (CRH)-mediated suppression of food intake. This diverts the body's resources away from the less pressing need to find and consume food, prioritizing fight, flight, or withdrawal behaviors so the stressful event can be dealt with. In the hours following this, however, there is a glucocorticoid-mediated stimulation of hunger and eating behavior. In the case of an acute stress that requires a physical response, such as a predator-prey interaction, this hypothalamic-pituitary-adrenal (HPA) axis modulation of food intake allows the stressful event to be dealt with and the energy used to be replaced afterward. In the case of ongoing psychological stress, however, chronically elevated glucocorticoids can lead to chronically stimulated eating behavior and excessive weight gain. In particular, stress can enhance the propensity to eat high calorie "palatable" food via its interaction with central reward pathways. Activation of this circuitry can also interact with the HPA axis to suppress its further activation, meaning not only can stress encourage eating behavior, but eating can suppress the HPA axis and the feeling of stress. In this review we will explore the theme of eating behavior and stress and how these can modulate one another. We will address the interactions between the HPA axis and eating, introducing a potential integrative role for the orexigenic hormone, ghrelin. We will also examine early life and epigenetic modulation of the HPA axis and how this can influence eating behavior. Finally, we will investigate the clinical implications of changes to HPA axis function and how this may be contributing to obesity in our society.

Pub.: 27 May '14, Pinned: 27 Jul '17

Neonatal overfeeding induces early decline of the ovarian reserve: Implications for the role of leptin

Abstract: Early life nutrition is crucial for reproduction. Overweight and obese girls are more likely to experience early menarche, increasing the risk of adult disease. We have previously demonstrated neonatal overfeeding in the rat leads to accelerated growth, early puberty and increased circulating levels of leptin, an adipocyte-derived hormone that regulates puberty. However, the long-term consequences of accelerated puberty and metabolic dysfunction on ovarian reserve are unknown. Here we show that neonatal overfeeding reduced the number of ovarian follicles in adult rats; specifically, the primordial follicle pool was reduced compared to controls. The reduction of ovarian reserve coincided with a diminished release of pituitary gonadotropins at ovulation and altered expression of ovarian markers important for follicular recruitment and survival. These changes were associated with increased levels of ovarian leptin and its receptor. Postnatal administration of leptin antagonist did not reverse the weight gain induced by early life overfeeding, but rescued the decline in the primordial follicle pool and abolished the differences in circulating leptin and gonadotropins. Our findings suggest that the acute effects of elevated circulating leptin may be responsible for the long-term reproductive outcomes after neonatal overfeeding, leading to premature ovarian ageing and changes in reproductive efficiency.

Pub.: 03 May '16, Pinned: 27 Jul '17

Early life disruption to the ghrelin system with over-eating in male rats is resolved in adulthood.

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: 27 Jul '17

Hypothalamic effects of neonatal diet: reversible and only partially leptin-dependent.

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: 27 Jul '17