The additive effect of allopregnanolone on ghrelin's orexigenic effect in rats

Löfgren, Mats; Holmberg, Ellinor; Bäckström, Torbjörn; Egecioglu, Emil; Dickson, Suzanne L.

doi:10.1016/j.npep.2019.101937

Cited by 7 publications

(7 citation statements)

References 79 publications

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“…Consistent with this, the orexigenic response to ghrelin in females was augmented after ovariectomy, whereas the same response was blocked in males if these were pre-treated with estradiol (Clegg et al 2007). In contrast, allopregnanolone, a metabolite of progesterone can augment the orexigenic and metabolic effects of ghrelin (Löfgren et al 2019).…”

supporting

confidence: 55%

Ghrelin receptor signaling is not required for glucocorticoid-induced obesity in female mice

Silver

Abbott-Tate

Hyland

et al. 2021

Journal of Endocrinology

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Chronic exposure to high circulating glucocorticoid or ghrelin concentrations increases food intake, weight gain and adiposity, suggesting that ghrelin could contribute to the metabolic effects of chronic glucocorticoids. In male mice, however, blocking ghrelin receptor (GHSR) signalling increased the weight gain and adiposity induced by chronic corticosterone (CORT), rather than attenuating them. In the current study, we investigated the role of GHSR signalling in the metabolic effects of chronic exposure to high circulating CORT in female mice. To do this, female WT and GHSR KO mice were treated with either CORT in a 1% ethanol (EtOH) solution or 1% EtOH alone in their drinking water for 32 days (N=5-8/group). Body weight, food, and water intake as well as vaginal cyclicity were assessed daily. As expected, CORT treatment induced significant increases in body weight, food intake, adiposity and also impaired glucose tolerance. In contrast to results observed in male mice, WT and GHSR KO female mice did not differ on any of these parameters. Neither plasma levels of ghrelin, LEAP-2, the endogenous GHSR antagonist produced by the liver, nor their ratio were altered by chronic glucocorticoid exposure. In addition, CORT treatment disrupted vaginal cyclicity, produced a reduction in sucrose consumption and increased locomotor activity regardless of genotype. Chronic CORT also decreased exploration in WT but not GHSR KO mice. Collectively, these data suggest that most metabolic, endocrine, reproductive and behavioral effects of chronic CORT exposure are independent of GHSR signalling in female mice.

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supporting

confidence: 55%

Ghrelin receptor signaling is not required for glucocorticoid-induced obesity in female mice

Silver

Abbott-Tate

Hyland

et al. 2021

Journal of Endocrinology

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“…Progesterone and its metabolite allopregnenalone stimulates food intake in male rodents (136). A recent study showed that allopregnanolone increased food intake when co-administered with ghrelin in male rats and significantly increased the orexigenic capabilities of ghrelin in a subset of rats in the study (137) possibly via its action as a positive modulator of the GABA A receptor (138). The interaction between ghrelin and progesterone in females remains to be determined.…”

Section: Discussionmentioning

confidence: 98%

Ghrelin and the Control of Energy Balance in Females

2022

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Ghrelin is considered one of the most potent orexigenic peptide hormones and one that promotes homeostatic and hedonic food intake. Research on ghrelin, however, has been conducted predominantly in males and particularly in male rodents. In female mammals the control of energy metabolism is complex and it involves the interaction between ovarian hormones like estrogen and progesterone, and metabolic hormones. In females, the role that ghrelin plays in promoting feeding and how this is impacted by ovarian hormones is not well understood. Basal ghrelin levels are higher in females than in males, and ghrelin sensitivity changes across the estrus cycle. Yet, responses to ghrelin are lower in female and seem dependent on circulating levels of ovarian hormones. In this review we discuss the role that ghrelin plays in regulating homeostatic and hedonic food intake in females, and how the effects of ghrelin interact with those of ovarian hormones to regulate feeding and energy balance.

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“…Studies of benzodiazepine‐induced food intake indicate that the most abundant α‐subunits of the GABA A receptor in the arcuate nucleus and paraventricular nucleus are α3 and α2 82 . Allo in concentrations as low as 2 n m significantly increased the spontaneous postsynaptic current in single dissociated cells in both the arcuate nucleus and paraventricular nucleus 83 . Animal studies have shown that Allo increased meal size in a dose‐dependent manner 84 and that calorie dense food was preferred compared to less palatable food 85 .…”

Section: Examples Of Disorders and Symptoms Related To Variations In ...mentioning

confidence: 99%

“…82 Allo in concentrations as low as 2 nm significantly increased the spontaneous postsynaptic current in single dissociated cells in both the arcuate nucleus and paraventricular nucleus. 83 Animal studies have shown that Allo increased meal size in a dose-dependent manner 84 and that calorie dense food was preferred compared to less palatable food. 85 Moreover, Allo compared to placebo increased body weight significantly in rats after five treatment days, and weight gain was highly correlated with increased food intake.…”

Section: Food Consumption and Weight Increasementioning

confidence: 99%

Positive GABA_A receptor modulating steroids and their antagonists: Implications for clinical treatments

Bäckström

Das

Bixo

2021

J Neuroendocrinology

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GABA is the main inhibitory neurotransmitter in the brain and GABAergic transmission has been shown to be of importance for regulation of mood, memory and food intake. The progesterone metabolite allopregnanolone (Allo) is a positive GABAA receptor modulating steroid with potent effects. In humans, disorders such as premenstrual dysphoric disorder (PMDD), hepatic encephalopathy and polycystic ovarian syndrome are associated with elevated Allo levels and increased negative mood, disturbed memory and increased food intake in some individuals. This is surprising because Allo shares many properties with benzodiazepines and is mainly considered to be anxiolytic and anti‐depressant. However, it is well established that, in certain individuals, GABAA receptor activating compounds could have paradoxical effects and thus be anxiogenic in low physiological plasma concentrations but anxiolytic at high levels. We have demonstrated that isoallopregnanolone (Isoallo), the 3β‐OH sibling of Allo, functions as a GABAA receptor modulating steroid antagonist (GAMSA) but without any effects of its own on GABAA receptors. The antagonistic effect is noted in most GABAA subtypes investigated in vitro to date. In vivo, Isoallo can inhibit Allo‐induced anaesthesia in rats, as well as sedation or saccadic eye velocity in humans. Isoallo treatment has been studied in women with PMDD. In a first phase II study, Isoallo (Sepranolone; Asarina Pharma) injections significantly ameliorated negative mood in women with PMDD compared with placebo. Several GAMSAs for oral administration have also been developed. The GAMSA, UC1011, can inhibit Allo induced memory disturbances in rats and an oral GAMSA, GR3027, has been shown to restore learning and motor coordination in rats with hepatic encephalopathy. In humans, vigilance, cognition and pathological electroencephalogram were improved in patients with hepatic encephalopathy on treatment with GR3027. In conclusion GAMSAs are a new possible treatment for disorders and symptoms caused by hyperactivity in the GABAA system.

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The additive effect of allopregnanolone on ghrelin's orexigenic effect in rats

Cited by 7 publications

References 79 publications

Ghrelin receptor signaling is not required for glucocorticoid-induced obesity in female mice

Ghrelin receptor signaling is not required for glucocorticoid-induced obesity in female mice

Ghrelin and the Control of Energy Balance in Females

Positive GABA_A receptor modulating steroids and their antagonists: Implications for clinical treatments

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The additive effect of allopregnanolone on ghrelin's orexigenic effect in rats

Cited by 7 publications

References 79 publications

Ghrelin receptor signaling is not required for glucocorticoid-induced obesity in female mice

Ghrelin receptor signaling is not required for glucocorticoid-induced obesity in female mice

Ghrelin and the Control of Energy Balance in Females

Positive GABAA receptor modulating steroids and their antagonists: Implications for clinical treatments

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Product

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Positive GABA_A receptor modulating steroids and their antagonists: Implications for clinical treatments