Role of central glucagon-like peptide-1 in hypothalamo-pituitary-adrenocortical facilitation following chronic stress

Abstract

Central glucagon-like peptide-1 (GLP-1) regulates food intake, glucose homeostasis, and behavioral and neuroendocrine responses to acute stress. Given its pronounced role in acute stress regulation, the GLP-1 system is a prime candidate for mediating the prolonged drive of the hypothalamo-pituitary-adrenocortical axis by chronic stress. To test this hypothesis, we evaluated the necessity and sufficiency of GLP-1 for production of chronic stress-induced changes in HPA axis function. Exogenous GLP-1 or the GLP-1 receptor antagonist, dHG-exendin, were delivered into the 3rd ventricle of control animals or animals exposed to chronic variable stress (CVS) for 7 days. Animals in the CVS groups received GLP-1 or dHG-exendin immediately prior to each stress exposure. Prior to and at the end of the 7-day trial, chronically-stressed animals were subjected to a novel stressor to test for HPA axis facilitation. Neither GLP-1 nor dHG-exendin affected CVS-associated increases in adrenal weight or decreases in basal plasma glucose levels. In addition, neither exogenous GLP-1 nor dHG-exendin altered any index of HPA axis activity in unstressed rats. However, GLP-1 enhanced CVS-induced facilitation of corticosterone (but not ACTH) response to an acute stress, whereas dHG-exendin inhibited facilitation. In addition, GLP-1 decreased body weight in chronically-stressed animals. dHG-exendin increased food intake and body weight in unstressed animals, consistent with a tonic role for GLP-1 in body weight regulation. Overall, our data suggest that brain GLP-1 modulates HPA axis activity within the context of chronic stress, perhaps at the level of the adrenal gland.

Figure 1

Experimental design. Pre- and post-CVS acute restraint tests were carried out in the morning of on day 1 (prior to the first stress) and day 8 of CVS/handling, respectively.

Figure 2

Plasma ACTH levels following restraint challenge prior to and after CVS (D–F) (mean ±S.E.M., n=4–6). Plasma ACTH levels were increased by restraint stress prior to and following CVS. ACTH responses were not altered by CVS or drug treatment, and no interaction effects were evident.

Figure 3

Plasma corticosterone levels following restraint challenge prior to and after CVS (A–C) (mean ±S.E.M., n=4–6). Exaggerated corticosterone responses were observed in vehicle (A) and GLP-1 (B) treated animals following CVS relative to pre-CVS values, marked by accentuated peak corticosterone secretion at t=30. In contrast, dHG-exendin treated animals did not show accentuated stress response profiles at t=30 (C). *=p<0.05.

Figure 4

Integrated plasma corticosterone responses to restraint, expressed as the area under curve (AUC). CVS-GLP-1 treated animals had a significant difference in corticosterone response to restraint challenge between pre- and post-CVS, whereas no differences in the integrated response magnitude were observed between any other groups. *=p<0.05.

Figure 5

Plasma corticosterone levels following restraint challenge prior to (Pre) and after (Post) a one-week, bidaily vehicle, GLP-1 or dHG-exendin injection/handling regimen (A–C) (mean ±S.E.M., n=4–6). Corticosterone responses to restraint were not affected by the intervening series of daily handling and icv injections (vehicle group). In addition, neither GLP-1 nor dHG-exendin affected subsequent responses to restraint.

Figure 6

Basal (A) and peak stress induced (30 min) plasma glucose levels prior to and after CVS exposure. Overall, basal plasma glucose levels (A) were not affected by drug treatment, but were significantly decreased by CVS (p≤0.05). The GLP-1 group showed significant decrease in basal glucose following CVS (p≤0.05). There were no drug or CVS effects on peak glucose levels (t=30) (B). *=p<0.05.

Figure 7

Daily food intake (mean ±S.E.M., n=4–6). Figure 7A shows daily food intake of all 6 groups. Food intake in each drug treatment groups were compared in figures 7B–D to clearly depict the effects of chronic stress and drug treatment. CVS did not affect food intake within the control (B) or GLP-1 (C) treated animals, but decreased intake in dHG-exendin treated animals (D). *=p<0.05.

Figure 8

Body weight change, presented as % of original weight (mean ±S.E.M., n=4–6). Figure 8A shows body weight change of all 6 groups. Body weight change in each drug treatment groups were compared in figures 8B–D to clearly depict the effects of chronic stress and drug treatment. Stress did not affect the body weight in vehicle treated animals (B), but negatively affected body weight in both GLP-1 (C) and dHG-exendin (D) treated animals. *=p<0.05.