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

Abstract

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.

Dexamethasone-associated metabolic effects in male mice are partially caused by depletion of endogenous corticosterone

“…This symptomatology is similar to that observed in Cushing's patients with hypercortisolemia (7). In rodents, dexamethasone and corticosterone both cause insulin resistance and muscle atrophy (8)(9)(10). Corticosterone induces adiposity, but the effect of dexamethasone on body composition is not as clear, as both loss and gain of total fat mass have been reported (11)(12)(13).…”

Ghrelin deficiency sex-dependently affects food intake, locomotor activity, and adipose and hepatic gene expression in a binge-eating mouse model

“…Consistently, Mifune and colleagues demonstrated that male Ghrl -/mice have lower wheel running activity than WT mice under timerestricted feeding (72). However, other authors reported little to no effects of ghrelin or GHSR deficiency in non-rearing locomotor activity in male or female mice (41,74). Combined with these previous findings, our results suggest that the impact of ghrelin signaling on physical activity is not only dependent on dietary intervention, but also on the sex of the mice.…”

“…However, Ghsr deficiency does not improve glucose tolerance in female mice, which, generally, already have better glucose tolerance than males. meaning there is less to be improved on (74). Consistently, we show that the AUC of Ghrl -/males in the IPGTT remains similar to that of the female mice, regardless of diet.…”

“…In CW mice, locomotor activity was only significantly increased in females. The modulation of physical activity by ghrelin signaling has been described by several authors (41,(72)(73)(74). In male mice, acute acyl-ghrelin administration was shown to enhance locomotor activity (73).…”

Vamorolone improves Becker muscular dystrophy and increases dystrophin protein in bmx model mice

“… 42 , 46 , 47 In contrast, low-dose physiological glucocorticoid supplementation causes increases in rodent weight and aspects of adiposity or obesity. 48 , 49 , 50 , 51 Differences in the content or responses of brown fat in rodents, which helps protect against metabolic dysfunction, may contribute to species differences. 51 , 52 , 53 In rodent studies, factors such as dose, brown or browning fat, room temperature, diet, sex, genotype, and obesity status have all been found to affect glucocorticoid impacts on weight, muscle, metabolism, or obesity.…”