Interruption of ghrelin signaling in the PVN increases high-fat diet intake and body weight in stressed and non-stressed C57BL6J male mice

Abstract

Chronic social stress has been associated with increased caloric intake and adiposity. These effects have been linked to stress induced changes in the secretion of ghrelin, a hormone that targets a number of brain regions to increase food intake and energy expenditure and promote increased body fat content. One of the brain sites targeted by ghrelin is the hypothalamic paraventricular nucleus (PVN), a region critical for both the regulation of the stress response and the regulation of energy balance. Given these data, we examined the contribution of ghrelin receptors in the PVN to the metabolic and behavioral changes that are seen during chronic social stress in mice. To do this, mice were implanted with cannulae attached to osmotic minipumps and delivering either vehicle or the ghrelin receptor (growth hormone secretagogue receptor) antagonist [D-Lys-3]-GHRP-6 (20 nmol/day/mouse). Following a week of recovery, half of the animals in each group were exposed to chronic social defeat stress for a period of 3 weeks whereas the other half were left undisturbed. During this time, all animals were given ad libitum access to standard laboratory chow and presented a high-fat diet for 4 h during the day. Results showed that the ghrelin receptor antagonism did not decrease stressed induced caloric intake, but paradoxically increased the intake of the high fat diet. This would suggest that ghrelin acts on the PVN to promote the intake of carbohydrate rich diets while decreasing fat intake and blockade of ghrelin receptors in the PVN leads to more consumption of foods that are high in fat.

Influence of Aging and Gender Differences on Feeding Behavior and Ghrelin-Related Factors during Social Isolation in Mice

“…Ghrelin, a hormone produced in the peripheral organs and central nervous system, is known to be involved in the regulation of appetite, gastrointestinal motility, and growth hormone release. Recently, the abnormal kinetics of ghrelin due to stress loading have been reported [ 1 – 3 , 9 , 10 ]. Intracerebroventricular administration of CRF or exposure to psychological stress suppresses food intake in association with decreases in peripheral ghrelin levels during fasting [ 1 , 3 ].…”

Evaluation of Pharmacological Modification of Growth Hormone Secretagogue Receptor in a Mouse Model of Non-Obese Type 2 Diabetes Mellitus

“…Our data demonstrated that whereas ghrelin receptor antagonist tended to inhibit food intake during the first two hours after injection ( Figure 5.3A and B), it obviously increased cumulative food intake in MKR mice and tended to increase it in FVB mice through long-term treatment ( Figure 5.4A and B). In consistent with that, a recent study showed that [D-Lys3]-GHRP-6 did not decrease stress-induced caloric intake, but paradoxically increased the intake of HFD (343). Moreover, the infusion of [D-Lys3]-GHRP-6 in a rat model did not have a significant impact on food intake and appetite (342).…”

Stress and obesity: The ghrelin connection

“…The effects of ghrelin on the PVN under chronic stress conditions are also complex. Blocking GHSR in the PVN during chronic social defeat enhances the intake of a high calorie diet in stressed mice . One possible explaination for these data is that ghrelin acts on the PVN to enhance inhibitory tone onto CRH neurones as part of a negative‐feedback loop that tones down the HPA axis, and not producing ghrelin leaves CRH neurones at a lower threshold of activation.…”