Ghrelin – the defender of fat. Implications for a target in obesity treatment

Z.R. Patterson, T. Rodrigues, A. Abizaid

Location: Hall F-J
Presentation Time: Sunday, Oct 14, 2012, 3:00 PM – 4:00 PM
See details on OASIS

Chronic activation of the stress response can lead to a number of metabolic disturbances such as obesity, metabolic syndrome, Type II diabetes and cardiovascular disease. The exact mechanisms underlying these metabolic changes are currently uncharacterized. Traditionally, many of these effects have been attributed to the increased levels of circulating glucocorticoids (cortisol in humans and corticosterone in rodents) as a function of hypothalamic pituitary adrenal (HPA) axis hyperactivity. However, recent evidence suggests that the gut derived hormone ghrelin may be a key contributor to the physiological changes generated in response to chronic stress. Ghrelin is a gut-brain peptide that promotes appetite and the accumulation of adipose tissue by encouraging the utilization of carbohydrates as a fuel source, while sparing fat tissue. Interestingly, plasma ghrelin concentrations increase in response to stressful stimuli, and remain elevated following cessation of the stressor. Given that stressful conditions increase plasma ghrelin concentrations while promoting an obesogenic phenotype, we hypothesized that ghrelin signaling plays a key role in the development of metabolic dysfunctions as a consequence of chronic social defeat stress. To this end we conducted a series of experiments wherein ghrelin signaling was interrupted pharmacologically in mice exposed to a chronic social defeat stress paradigm. Results show that the chronic social defeat stress paradigm causes a significant increase in caloric intake that persists throughout the recovery period, in the absence of the stressor. Furthermore, in the presence of ghrelin signaling, chronic social defeat stress promotes a metabolic profile that reflects a preference to breakdown carbohydrates and proteins as a fuel source while sparing fat stores, ultimately leading to increased adiposity. Contrary, when ghrelin signaling is interrupted, stressed animal’s show an attenuated response to changes in caloric intake while continuing to utilize fat as a fuel substrate thereby preventing the accumulation of visceral adipose tissue. Finally, chronic social defeat stress causes changes of hypothalamic gene expression in signaling pathways that regulate mitochondrial fatty acid oxidation, in a ghrelin signaling-dependent fashion. These data suggest that ghrelin signaling mediates the metabolic switch that occurs as a consequence of prolonged stress. In particular, it appears that ghrelin is capable of dictating the real estate from which an organism gathers its energy resources, resulting in phenotypic changes reminiscent of a hypermetabolic state.