The orexigenic hormone ghrelin defends against depressive symptoms of chronic stress

Abstract

We found that increasing ghrelin levels, through subcutaneous injections or calorie restriction, produced anxiolytic-and antidepressant-like responses in the elevated plus maze and forced swim test. Moreover, chronic social defeat stress, a rodent model of depression, persistently increased ghrelin levels, whereas growth hormone secretagogue receptor (Ghsr) null mice showed increased deleterious effects of chronic defeat. Together, these findings demonstrate a previously unknown function for ghrelin in defending against depressive-like symptoms of chronic stress.Chronic stress induces changes in mood, feeding and metabolism by a poorly understood neurobiological mechanism. Recent studies have suggested that key metabolic signals may interact with CNS circuits to regulate reward and mood 1 . To further explore these links, we investigated the potential role of ghrelin, an important feeding peptide, in the development of depressive symptoms. Ghrelin is a hormone synthesized predominantly by specialized gastrointestinal endocrine cells and is released during periods of negative energy balance 2 . In response to energy insufficiency, ghrelin induces a potent feeding response via activation of the growth hormone secretagogue receptor (GHSR, ghrelin receptor) 2,3 .To determine whether ghrelin can affect mood symptoms, we physiologically increased ghrelin levels by restricting the food intake of mice with a diet containing 60% of normal calories for Fig. 1). This resulted in a fourfold increase in circulating levels of acylated ghrelin (calorie restricted wild-type mice: 7.93 ± 1.59 pg mL −1 , n = 6; wildtype mice fed ad libitum: 1.98 ± 0.37 pg mL −1 , n = 5; P < 0.01). Calorie-restricted wild-type mice showed robust anxiolytic-and antidepressant-like behavior in the elevated plus maze (EPM) and forced swim test (FST), respectively, as compared with wild-type mice fed ad libitum (controls; Fig. 1a,c). In contrast, genetic blockade of ghrelin signaling in Ghsr −/− mice negated these calorie restriction-associated anxiolytic-and antidepressant-like effects. Further analyses demonstrated that the observed differences between the two genotypes cannot be attributed to differences in sensorimotor coordination, general locomotor activity or body weight ( Supplementary Figs. 1-3 online).We used a pharmacologic approach to extend our food-restriction results. We subcutaneously injected C57BL6/J mice with a dose of ghrelin that induces potent feeding (Fig. 1f) and tested them in the EPM and FST 45 min later. Mice receiving ghrelin demonstrated significantly less anxiety-and depression-like symptoms in these tests compared with saline-injected controls (Fig. 1b,d).Next, we determined whether ghrelin signaling regulates depressive symptoms in a mouse model of chronic stress. We used the chronic social defeat stress (CSDS) procedure, which subjects mice to ten daily bouts of social defeat by aggressive CD1 male mice 1,4 (Fig. 2). Mice subjected to CSDS showed lasting behavioral deficits, including social avoidance ( Suppl...

Effects of Toxoplasma gondii infection on anxiety, depression and ghrelin level in male rats

“…These findings of anxiogenic-like effects of raised ghrelin level differ from the results of several other studies. Calorie-restricted wild-type mice showed anxiolytic-and antidepressant-like behavior in the elevated plus maze and forced swim test, respectively, as compared to wild-type mice (Lutter et al 2008). Also, high-anxiety WKY rats had lower circulating ghrelin than SPD rats in both the fasted and fed state (Kristensson et al 2007).…”

“…It has been shown that ghrelin has anxiolytic and antidepressant effects. Calorie-restricted wild-type mice showed robust anxiolytic and antidepressant-like behavior in the elevated plus maze and forced swim test (Lutter et al 2008).…”

Leu72Met408 Polymorphism of the Ghrelin Gene Is Associated With Early Phase of Gastric Emptying in the Patients With Functional Dyspepsia in Japan

“…In addition, an increase in ghrelin occurs not only in response to states of energy insufficiency 7 but also against stress. 8 Therefore, human subjects suffering from acute psychosocial stress also display increased plasma ghrelin. 9 Asakawa et al 10 have reported that both central and peripheral administration of ghrelin is a potent inducer of anxiogenic behavior in mice.…”

Sex-specific differences in the dynamics of cocaine- and amphetamine-regulated transcript and nesfatin-1 expressions in the midbrain of depressed suicide victims vs. controls

“…Recently significant interest has arisen in possible interactions between central mood substrates and circuitries involved in metabolism (Gomez-Pinilla, 2008;Krishnan and Nestler, 2008;Kuperman et al, 2010;McBriar, 2006;Shao et al, 2008). More specifically, several neuropeptides with a clear role in metabolism, such as leptin, ghrelin, orexin, neuropeptide Yand urocortin 3, produce clear anti-depressant-like responses (Eaton et al, 2007;Heilig, 2004;Kuperman et al, 2010;Lu, 2007;Lutter et al, 2008;Yamada et al, 2011), whereas e.g. melanin-concentrating hormone and cholecystokinin evoke a pro-depressant-like phenotype in several rodent models (Becker et al, 2008;Georgescu et al, 2005).…”