Differential metabolic profiles between wild-type and ghsr ko mice following chronic social defeat stress

Z.R. Patterson, R. Khazall, M. Sleeman, H. Anisman, A.B. Abizaid

Chronic stress can result in a number of pathological conditions including metabolic alterations, diabetes, depression and cardiovascular disease. These effects are commonly associated with increased levels of circulating cortisol. Recent evidence suggests that ghrelin may be a key contributor to the physiological responses generated as a consequence of stress. For example, plasma ghrelin concentrations increase in response to stressful stimuli, and remain elevated following chronic stress. Here, we hypothesized that ghrelin acting through its only known receptor plays a key role in the metabolic changes that result as a consequence of chronic social defeat stress. To this end, mice lacking the ghrelin receptor (GHSR-KO) and their wild-type littermates (GHSR-WT) were exposed to a 3-week chronic social defeat stress paradigm. Throughout the stress period experimental mice were exposed daily to a larger dominant animal until fighting occurred at which point they were separated by a gate. Following the treatment period, mice were allowed to recover for 14 days after which they were sacrificed by rapid decapitation. Brains, carcasses and trunk blood were immediately collected and stored for future analysis. Results show a divergent metabolic phenotype between wild-type and GHSR KO mice as a consequence of the stress paradigm. Following the stress period, wild-type stressed mice had significantly higher respiratory exchange ratios as compared to their non-stressed controls, a change that reflects their preference to breakdown carbohydrates and proteins as a fuel source while sparing fat stores. Wild-type stressed animals also showed a significant increase of NPY and AgRP mRNA in the mediobasal hypothalamus compared to their non-stressed controls, while GHSR KO stressed animals showed no changes compared to their non-stressed controls. In contrast, GHSR KO stressed animals, but not wild-type stressed animals, showed an increase in lipoprotein lipase and Y2 receptor expression, as well as a decrease in fatty acid synthase expression in their adipocytes as compared to their non-stressed controls. These changes in adipocyte gene expression reflect a state that promotes fat accumulation, presumably to compensate for their lack of adipocyte stores. These data provide evidence that supports ghrelin as a contributor to the metabolic switch that occurs as a consequence of prolonged stress, reminiscent of the changes that arise in a hypermetabolic state.