Recent studies suggest that the biological importance of end

Recent studies suggest that the biological importance of endogenous ghrelin becomes accentuated during exposure to more metabolically-constrained and stressful environments. Indeed, mice lacking either ghrelin or GHSR demonstrate impaired ability to adapt metabolically and/or behaviorally to caloric restriction and psychological challenges. As such, a functional ghrelin system ensures protection from life-threatening falls in blood glucose in adult mice subjected to severe caloric restriction and in juvenile mice subjected to acute fasting [15], [16], [19], [20], [21], [22], minimizes depressive-like behaviors in mice subjected to chronic psychosocial stress, mediates the antidepressant-like and anxiolytic-like behavioral effects of caloric restriction [23], [24], and restricts body weight loss and stalls mortality associated with chronic anorexia/cachexia conditions [25]. Elevation of plasma ghrelin is a consistent feature in those challenging conditions [3], [23], [26], [27], [28], [29], suggesting that the ghrelin system is actively upregulated in those conditions as a protective measure. This upregulation of plasma ghrelin stands in SC-10 to the reduction in plasma ghrelin and resistance to ghrelin signaling to stimulate food intake in overly-abundant nutritional states such as obesity [30]. Therefore, an emerging notion is that the ghrelin system may serve as an essential response to metabolic and stressful challenges, minimizing perturbations to metabolic and psychological homeostasis to promote survival [12]. In this study, we aimed to study the biological significance of the ghrelin system in mice subjected to exercise as a metabolic challenge. Although the many health benefits of exercise – including weight maintenance, appetite control, improved insulin sensitivity, improved mental health, and secondary prevention of chronic diseases such as obesity, type II diabetes mellitus, cancer, and hypertension – are generally well-accepted, the molecular mechanisms that mediate and integrate these beneficial effects are poorly understood [31], [32], [33], [34], [35]. The potential role of the ghrelin system in mediating exercise capacity and the effects of exercise on food intake, body weight, and blood glucose are of particular interest given the central role of ghrelin in these processes [1], [12]. The effect of exercise on plasma ghrelin levels has been investigated in multiple human and rodent studies although the results have been inconsistent, demonstrating either a decrease, increase, or no change [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48]. Notwithstanding these discrepant observations on the changes in plasma ghrelin with exercise, the impact of the ghrelin system on performance of exercise, food intake after exercise, and, more broadly, the healthy metabolic outcomes of exercise is not well-established. Here, we use two mouse models of treadmill running to characterize the changes in plasma ghrelin with exercise as well as the function of the ghrelin system to influence exercise performance, food intake, and blood glucose acutely following exercise.
Material and methods
Results
Discussion There are several notable issues raised by our study. The first relates to the impact of exercise on plasma ghrelin levels. Plasma ghrelin increases in rodent models and humans when challenged with stressful conditions such as caloric restriction and psychosocial stress [15], [16], [20], [22], [23], [24]. Based on results from this study, we can include exercise as another challenge that increases plasma ghrelin, likely resulting at least in part from increased ghrelin secretion. Given the well-known effect of exercise to stimulate the sympathoadrenal system [63], [64], the effect of adrenergic agonists to stimulate ghrelin release [22], [65], [66], [67], and the requirement of β1-adrenergic receptors expressed on ghrelin cells for the elevation of plasma ghrelin during caloric restriction [22], we predict that the increase in plasma ghrelin during exercise is a direct consequence of increased adrenergic output onto ghrelin cells. The fall in insulin levels with exercise also may contribute to the increased ghrelin, as insulin is a potent negative regulator of ghrelin secretion [68].