Ghrelin Resistance: A Possible Mechanism Underlying Antidepressant-Induced Obesity?

To The Editor:

We read with great interest the article recently published by Tunçel et al. (2016) entitled “Increased ghrelin levels and unchanged adipocytokine levels in major depressive disorder.” In this study, the authors demonstrated excellent findings showing that antidepressant sertraline exerting therapeutic effects and its potential side-effects obesity are probably both related with the increased serum levels of ghrelin. We totally agree with this conclusion and would like to present a hypothesis regarding the pathogenesis of antidepressant-induced obesity, which is highly relevant to the present study.

Ghrelin, a peptide hormone secreted by ghrelinergic cells, functions as a neuropeptide in the central nervous system through activating its specific binding receptor, ghrelin/growth hormone secretagogue receptor (GHSR) (Kojima et al. 1999; Nakazato et al. 2001). Interestingly, ghrelin has been reported to have a beneficial effect for treating depression (Himmerich et al. 2005). In addition, ghrelin has potential to protect against depressive symptoms induced by chronic stress (Lutter et al. 2008). A preclinical study using depression-prone GHSR-null mice by Walker et al. (2015) showed that social defeat stress induces inhibitory effects for cell proliferation and survival in the ventral dentate gyrus of hippocampus, which results in more severe depressive-like behavior. These findings suggested that the pathogenesis underlying depression is probably associated with the abnormal alteration of ghrelin levels.

Besides the peculiar effects of regulating mood disorder, ghrelin is intended to regulate the energy metabolism (Nakazato et al. 2001; Wren et al. 2001). On the contrary, dysregulation of ghrelin signaling may elicit a harmful effect for the inherent balance of energy intake and/or expenditure and, as a result, lead to malnutrition or obesity (Krsek et al. 2003). And also excessive increase of ghrelin levels facilitating food intake and ultimately leading to obesity is not to be neglected (Tunçel et al. 2016).

Mounting studies documented that patients with depression undergoing routine antidepressant treatment are prone to suffer from obesities (Mansoor et al. 2013; Shapiro et al. 2016). Although its exact mechanisms are not fully elucidated, abnormal increase of levels of ghrelin in brain may be involved in it, because GHSR may be resistant to ghrelin owing to downregulation of receptor sensitivity (Briggs et al. 2010). In the present study, the authors get an excellent conclusion that increased peripheral ghrelin after antidepressant treatment is probably a causative factor for the antidepressant-induced obesity. As discussed previously, the physiological effects of ghrelin signaling are mainly dependent on the normal role of GHSR. Excessive levels of ghrelin cause a relative deficiency of GHSR that could not provide enough combining sites for ghrelin. Although measuring the expression of GHSR, a specific binding site for ghrelin, in the brain of human subjects is unlikely in this study, we suggested that ghrelin resistance induced by abnormality of brain ghrelin–GHSR axis, at least partially, would be involved in the pathophysiological mechanisms of obesity elicited by chronic treatment of antidepressant agents.

In conclusion, we hold an opinion that ghrelin resistance induced by a relative deficiency of GHSR may underlie the pathogenesis of antidepressant-induced obesity. Future studies are required to fully elucidate the role of ghrelin resistance in the mechanisms of antidepressant-induced obesity.