Role of central glucagon-like peptide-1 in hypothalamo-pituitary-adrenocortical facilitation following chronic stress
Introduction
The hypothalamo-pituitary-adrenocortical (HPA) axis coordinates the release of glucocorticoids in response to stress. The HPA axis responds to real or anticipated homeostatic disruption by stimulating release of ACTH secretagogs (such as corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP)) from hypophysiotrophic neurons in the medial parvocellular region of paraventricular nucleus of hypothalamus (PVN) (Antoni, 1986, Whitnall, 1993). This neurohemal signal promotes release of adrenocorticotropic hormone (ACTH) by pituitary corticotrophs, which consequently causes a release of adrenal corticosteroids.
Ascending brainstem systems play a major role in excitation of HPA axis stress responses (c.f., (Herman et al., 2003, Sawchenko et al., 2000)). Recent studies from our group suggest that glucagon-like peptide-1 (GLP-1), a neuropeptide that is selectively expressed in the nucleus of solitary tract (NTS) and the ventrolateral medulla (Drucker, 1990, Kinzig et al., 2003, Merchenthaler et al., 1999), plays a major role in HPA activation (Kinzig et al., 2003). The PVN is heavily innervated by GLP-1 fibers that form direct synaptic contacts with CRH immunoreactive cell bodies (Larsen et al., 1997, Rinaman, 1999, Sarkar et al., 2003, Shughrue et al., 1996), confirming that GLP-1 is in position to directly modulate activity of CRH neurons. Intracerebroventricular infusions of GLP-1 increase plasma ACTH and/or corticosterone (Kinzig et al., 2003, Larsen et al., 1997), indicating that GLP-1 receptor binding is sufficient to trigger HPA activation. Furthermore, pretreatment of GLP-1 antagonist attenuated ACTH and corticosterone responses induced by systemic lithium chloride (LiCl) injection and elevated platform exposure (Kinzig et al., 2003), indicating that GLP-1 signaling is also necessary for acute HPA axis stress responses. GLP-1 containing neurons in the NTS are activated by visceral stress (LiCl injection) (Rinaman, 1999), consistent with a role in central stress integration. Overall, these data support the hypothesis that GLP-1 regulates HPA axis responses to a variety of stressors by stimulating CRH release from PVN neurons.
To date, the GLP-1 system has been studied exclusively in the realm of acute stress. While activation of the HPA axis is typically an adaptive response to an acute stress, chronic activation of the HPA axis can be deleterious and has been linked to a number of different pathologies, including metabolic disease and depression (McEwen and Stellar, 1993). Recent data strongly suggest that different brain circuitries are involved in acute and chronic stress responses. For example, regions such as the paraventricular thalamus regulate HPA axis responses to chronic, but not acute stressors (Bhatnagar and Dallman, 1998a). In addition, chronic stress produces a well-documented enhancement of HPA axis responses to new stressors, a process that may involve regions such as the paraventricular thalamus(Bhatnagar and Dallman, 1998a) and perhaps central amygdaloid nucleus (Dallman et al., 2003). Consequently, it is critical to determine whether the endogenous GLP-1 system is responsible for deleterious changes in HPA axis function seen following chronic stress. Therefore, the current study was designed to test the role of GLP-1 in the establishment and maintenance of chronic stress-induced HPA hyperactivity, as produced by a well-characterized chronic stress model (chronic variable stress (CVS)).
Section snippets
Animals
Male Sprague–Dawley rats (275–300 g) were acquired from Harlan Labs (Indianapolis, IN). All animals were individually housed in a temperature- and humidity-controlled facility at the University of Cincinnati, on a 6am to 6pm light-dark cycle with free access to standard chow and water. All experimental procedures were approved by the University of Cincinnati Institutional Animal Care and Use Committee.
Surgery
All rats were anesthetized by an intra-peritoneal injection with a cocktail of ketamine
Organ weights
Two-way ANOVA revealed that CVS significantly increased adrenal weight, as previously documented by our group (Ulrich-Lai et al., 2006). However, there was no effect of drug on the degree of chronic stress-induced adrenal hypertrophy. There was no effect of CVS or drug treatment on thymus weight.
Plasma ACTH
Resting AM ACTH levels, as determined from the initial blood sample on day 8, was not affected by either CVS or drug. In both the pre- and post-CVS restraint stress tests, plasma ACTH was elevated at
Discussion
Our results indicate that GLP-1 is involved in chronic stress-induced facilitation of corticosterone responses to a novel stressor. Chronic GLP-1 significantly decreased both body weight and resting glucose levels in animals exposed to chronic stress, suggesting that elevated GLP-1 activity may amplify the effects of chronic stress on the organism. However, central GLP-1 administration itself does not precipitate chronic stress-like effects on long-term consequences of HPA hyperactivity, such
Conclusion
Overall, our data indicate that central GLP-1 neurons act within the context of chronic stress to modify novel stress-induced facilitation of corticosterone release and body weight. Endogenous GLP-1 is involved in stress-induced facilitation of the HPA axis, but is not responsible for generating tonic changes in HPA secretion and consequent effects on stress-sensitive organ systems, such as the adrenal. Therefore, it is likely that the GLP-1 system is involved in central pathways responsible
Acknowledgments
The authors acknowledge the expert technical assistance of Ben Packard, Kenneth Jones and Amanda Robertson. This work was supported by MH069680.
References (39)
- et al.
Neuroanatomical basis for facilitation of hypothalamic-pituitary-adrenal responses to a novel stressor after chronic stress
Neuroscience
(1998) - et al.
Neuroanatomical basis for facilitation of hypothalamic-pituitary-adrenal responses to a novel stressor after chronic stress
Neuroscience
(1998) - et al.
Chronic mild stress affects sucrose intake and sleep in rats
Behav. Brain Res.
(2004) - et al.
Central mechanisms of stress integration: hierarchical circuitry controlling hypothalamo-pituitary-adrenocortical responsiveness
Front. Neuroendocrinol.
(2003) - et al.
Effects of intracerebroventricularly injected glucagon-like peptide-1 on cardiovascular parameters; role of central cholinergic system and vasopressin
Regul. Pept.
(2004) - et al.
Environmental stress modifies glycemic control and diabetes onset in type 2 diabetes prone Otsuka Long Evans Tokushima Fatty (OLETF) rats
Physiol. Behav.
(2000) - et al.
Glucagon like peptide-1 (7–36) amide (GLP-1) nerve terminals densely innervate corticotropin-releasing hormone neurons in the hypothalamic paraventricular nucleus
Brain Res.
(2003) - et al.
Circuits and mechanisms governing hypothalamic responses to stress: a tale of two paradigms
Prog. Brain Res.
(2000) Regulation of the hypothalamic corticotropin-releasing hormone neurosecretory system
Prog. Neurobiol.
(1993)- et al.
Feedback and facilitation in the adrenocortical system: unmasking facilitation by partial inhibition of the glucocorticoid response to prior stress
Endocrinology
(1992)
Hypothalamic control of adrenocorticotropin secretion: advances since the discovery of 41-residue corticotropin-releasing factor
Endocr. Rev.
Strain and gender specific effects in the forced swim test: effects of previous stress exposure
Stress
Effect of cortisol on energy expenditure and amino acid metabolism in humans
Am. J. Physiol.
Bed nucleus of the stria terminalis subregions differentially regulate hypothalamic-pituitary-adrenal axis activity: implications for the integration of limbic inputs
J. Neurosci.
Chronic stress and obesity: a new view of “comfort food”
Proc. Natl. Acad. Sci. U. S. A.
Effect of chronic central administration of glucagon-like peptide-1 (7–36) amide on food consumption and body weight in normal and obese rats
Obes. Res.
Glucagon and the glucagon-like peptides
Pancreas
Splanchnic neural activity modulates ultradian and circadian rhythms in adrenocortical secretion in awake rats
Neuroendocrinology
Distribution of glucagon-like peptide-I (GLP-I), glucagon, and glicentin in the rat brain: an immunocytochemical study
J. Comp. Neurol.
Cited by (40)
Anti-stress effects of the glucagon-like peptide-1 receptor agonist liraglutide in zebrafish
2021, Progress in Neuro-Psychopharmacology and Biological PsychiatryThe therapeutic potential of GLP-1 analogues for stress-related eating and role of GLP-1 in stress, emotion and mood: a review
2021, Progress in Neuro-Psychopharmacology and Biological PsychiatryCitation Excerpt :Pre-clinical studies (Table 2) consistently show a significant increase in corticosterone and ACTH release as a result of acute GLP-1 and GLP-1 agonist central and peripheral administration compared to baseline (Larsen et al., 1997; Katsurada et al., 2014) and compared to saline in rats (Malendowicz et al., 2003b; Kinzig et al., 2003; Gil-Lozano et al., 2013; Jessen et al., 2017), mice (Krass et al., 2012; Krass et al., 2015) and chickens (Tachibana et al., 2006). Chronically, GLP-1 increased (Krass et al., 2015; Malendowicz et al., 2003b; Gil-Lozano et al., 2013) or had no impact (Fan et al., 2010; Tauchi et al., 2008) on corticosterone and/or ACTH release in rats compared to saline or in the case of Fan et al. (2010) as an intramuscular GLP-1 plasmid injection compared to vacant plasmid. MacLusky et al. (2000) found GLP-1R knockout mice had equal basal morning circulating corticosterone at rest but an increased corticosterone response compared to wild type mice in response to an acute stressor.
Corticolimbic stress regulatory circuits, hypothalamo–pituitary–adrenocortical adaptation, and resilience
2020, Stress Resilience: Molecular and Behavioral AspectsCorticolimbic stress regulatory circuits, hypothalamo-pituitary-adrenocortical adaptation, and resilience
2019, Stress Resilience: Molecular and Behavioral Aspects