The role of two main forms of ghrelin in Hypothalamic Pituitary Adrenal axes.
Neonatal overfeeding induces minor changes in ghrelin- regulated apetite circuitry in males that do not last in adulthood. In females we explored ghrelin role with application to stress.
Abstract: Ghrelin is a stomach hormone normally associated with feeding behavior and energy homeostasis. Recent studies highlight that ghrelin targets the brain to regulate a diverse number of functions, including learning, memory, motivation, stress responses, anxiety, and mood. In this review, we discuss recent animal and human studies showing that ghrelin regulates the hypothalamic-pituitary-adrenal axis and affects anxiety and mood disorders, such as depression and fear. We address the neural sites of action through which ghrelin regulates the hypothalamic-pituitary-adrenal axis and associated stress-induced behaviors, including the centrally projecting Edinger-Westphal nucleus, the hippocampus, amygdala, locus coeruleus, and the ventral tegmental area. Stressors modulate many behaviors associated with motivation, fear, anxiety, depression, and appetite; therefore, we assess the potential role for ghrelin as a stress feedback signal that regulates these associated behaviors. Finally, we briefly discuss important areas for future research that will help us move closer to potential ghrelin-based therapies to treat stress responses and related disorders.
Pub.: 24 Dec '14, Pinned: 25 Aug '17
Abstract: Parkinson's disease (PD) is a neurodegenerative disorder, characterized by a loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNc). Caloric restriction (CR) has been shown to exert ghrelin-dependent neuroprotective effects in the 1-methyl-4-phenyl-1,2,3,6-tetrathydropyridine (MPTP)-based animal model for PD. We here investigated whether CR is neuroprotective in the lactacystin (LAC) mouse model for PD, in which proteasome disruption leads to the destruction of the DA neurons of the SNc, and whether this effect is mediated via the ghrelin receptor. Adult male ghrelin receptor wildtype (WT) and knockout (KO) mice were maintained on an ad libitum (AL) diet or on a 30% CR regimen. After 3 weeks, LAC was injected unilaterally into the SNc, and the degree of DA neuron degeneration was evaluated 1 week later. In AL mice, LAC injection significanty reduced the number of DA neurons and striatal DA concentrations. CR protected against DA neuron degeneration following LAC injection. However, no differences were observed between ghrelin receptor WT and KO mice. These results indicate that CR can protect the nigral DA neurons from toxicity related to proteasome disruption; however, the ghrelin receptor is not involved in this effect.
Pub.: 10 Mar '17, Pinned: 25 Aug '17
Abstract: Ghrelin plays a key role in appetite, energy homeostasis and glucose regulation. Recent evidence suggests ghrelin suppresses inflammation in obesity, however whether this is modulated by the acylated and/or des-acylated peptide is unclear. We used mice deficient in acylated ghrelin (GOAT KO), wildtype littermates (WT) and C57BL/6 mice to examine the endogenous and exogenous effects of acyl and des-acyl ghrelin on inflammatory profiles under non-obese and obese conditions. We demonstrate that in the spleen, both ghrelin and Ghrelin O-Acyl Transferase (GOAT) are localized primarily in the red pulp. Importantly, in the thymus, ghrelin was predominantly localized to the medulla, while GOAT was found in the cortex, implying significant but differing roles in T cell development. Acute exogenous treatment with acyl/des-acyl ghrelin suppressed macrophage numbers in spleen and thymus in obese mice, whereas only acyl ghrelin increased CD3+ T cells in the thymus in both chow and HF fed mice. Consistent with this result, macrophages were increased in the spleen of KO mice on a HFD. While there was no difference in CD3+ T cells in the plasma, spleen or thymus of WT vs KO mice, KO chow and HF fed mice displayed decreased leukocytes. Our results suggest that the acylation status affects the anti-inflammatory properties of ghrelin under chow and HFD conditions.
Pub.: 04 Apr '17, Pinned: 25 Aug '17
Abstract: Ghrelin is a stomach-derived hormone that affects food intake and regulates blood glucose. The best-characterized actions of ghrelin are mediated by its binding to and activation of the growth hormone secretagogue receptor (GHSR; ghrelin receptor). Adequate examination of the identity, function, and relevance of specific subsets of GHSR-expressing neurons has been hampered by the absence of a suitable Cre recombinase (Cre)-expressing mouse line with which to manipulate gene expression in a targeted fashion within GHSR-expressing neurons. The present study aims to characterize the functional significance and neurocircuitry of GHSR-expressing neurons in the mediobasal hypothalamus (MBH), as they relate to ghrelin-induced food intake and fasting-associated rebound hyperphagia, using a novel mouse line in which Cre expression is controlled by the Ghsr promoter.A Ghsr-IRES-Cre mouse line that expresses Cre directed by the Ghsr promoter was generated. The line was validated by comparing Cre activity in reporter mice to the known brain distribution pattern of GHSR. Next, the requirement of MBH GHSR-expressing neuronal activity in mediating food intake in response to administered ghrelin and in response to fasting was assessed after stereotaxic delivery of inhibitory designer receptor exclusively activated by designer drugs (DREADD) virus to the MBH. In a separate cohort of Ghsr-IRES-Cre mice, stereotaxic delivery of stimulatory DREADD virus to the MBH was performed to assess the sufficiency of MBH GHSR-expressing neuronal activity on food intake. Finally, the distribution of MBH GHSR-expressing neuronal axonal projections was assessed in the DREADD virus-injected animals.The pattern of Cre activity in the Ghsr-IRES-Cre mouse line mostly faithfully reproduced the known GHSR expression pattern. DREADD-assisted inhibition of MBH GHSR neuronal activity robustly suppressed the normal orexigenic response to ghrelin and fasting-associated rebound food intake. DREADD-assisted stimulation of MBH GHSR neuronal activity was sufficient to induce food intake. Axonal projections of GHSR-expressing MBH neurons were observed in a subset of hypothalamic and extra-hypothalamic regions.These results suggest that 1) activation of GHSR-expressing neurons in the MBH is required for the normal feeding responses following both peripheral administration of ghrelin and fasting, 2) activation of MBH GHSR-expressing neurons is sufficient to induce feeding, and 3) axonal projections to a subset of hypothalamic and/or extra-hypothalamic regions likely mediate these responses. The Ghsr-IRES-Cre line should serve as a valuable tool to further our understanding of the functional significance of ghrelin-responsive/GHSR-expressing neurons and the neuronal circuitry within which they act.
Pub.: 29 Jul '17, Pinned: 25 Aug '17
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: 25 Aug '17
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: 25 Aug '17