GLP-1(7-36)-amide and Exendin-4 Stimulate the HPA Axis in Rodents and Humans

Gil‐Lozano, Manuel; Pérez-Tilve, Diego; Álvarez-Crespo, Mayte; Martís, Aurelio; Fernández, Adolfo; Catalina, Pablo A. F.; González-Matías, Lucas C.; Mallo, Federico

doi:10.1210/en.2009-0915

Cited by 79 publications

(75 citation statements)

References 33 publications

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“…Therefore, bouts of hyperphagia due to the more palatable food among HF-fed animals may contribute to elevated circulating ACTH levels. However, GLP1-induced increases are transient and ACTH levels return to baseline within 20 min of injection (Gil-Lozano et al 2010).…”

Section: Discussionmentioning

confidence: 96%

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The lipocalin-type prostaglandin D2 synthase knockout mouse model of insulin resistance and obesity demonstrates early hypothalamic–pituitary–adrenal axis hyperactivity

Evans

Islam²,

Urade³

et al. 2012

Journal of Endocrinology

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Obesity and diabetes are closely associated with hyperactivation of the hypothalamicpituitary-adrenal (HPA) axis. In this study, the diet-induced obese C57BL/6 mouse was used to test the hypothesis that chronically elevated metabolic parameters associated with the development of obesity such as cholesterol and glucose can aggravate basal HPA axis activity. Because the lipocalin-type prostaglandin D 2 synthase (L-PGDS) knockout (KO) mouse is a model of accelerated insulin resistance, glucose intolerance, and obesity, it was further hypothesized that HPA activity would be greater in this model. Starting at 8 weeks of age, the L-PGDS KO and C57BL/6 mice were maintained on a low-fat or high-fat diet. After 20 or 37 weeks, fasting metabolic parameters and basal HPA axis hormones were measured and compared between genotypes. Correlation analyses were performed to identify associations between obesity-related chronic metabolic changes and changes in the basal activity of the HPA axis. Our results have identified strong positive correlations between total cholesterol, LDL-cholesterol, glucose, and HPA axis hormones that increase with age in the C57BL/6 mice. These data confirm that obesity-related elevations in cholesterol and glucose can heighten basal HPA activity. Additionally, the L-PGDS KO mice show early elevations in HPA activity with no age-related changes relative to the C57BL/6 mice.

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Section: Discussionmentioning

confidence: 96%

“…Glucagon-like peptide-1 (GLP1), released in response to food intake, can increase the activity of the HPA axis in rodents and humans (Gil-Lozano et al 2010). Therefore, bouts of hyperphagia due to the more palatable food among HF-fed animals may contribute to elevated circulating ACTH levels.…”

Section: Discussionmentioning

confidence: 99%

The lipocalin-type prostaglandin D2 synthase knockout mouse model of insulin resistance and obesity demonstrates early hypothalamic–pituitary–adrenal axis hyperactivity

Evans

Islam²,

Urade³

et al. 2012

Journal of Endocrinology

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“…This proposed ability of the GLP-1R to "sense" metabolic flux is intriguing and merits further study. We also cannot exclude the possibility that central GLP-1R activation stimulates basal Endo R a even as it raises fasting insulin levels due to known stimulatory effects of central GLP-1r activation on stress hormones (17,22,45). Interestingly, the phenotype observed in icv Ex-9-infused mice is identical to the response associated with prolonged fasting.…”

Section: Studies From Our Laboratory Using Glp1rmentioning

confidence: 87%

Acute activation of central GLP-1 receptors enhances hepatic insulin action and insulin secretion in high-fat-fed, insulin resistant mice

Burmeister¹,

Ferré²,

Ayala³

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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Glucagon-like peptide-1 (GLP-1) receptor knockout (Glp1r Ϫ/Ϫ ) mice exhibit impaired hepatic insulin action. High fat (HF)-fed Glp1r Ϫ/Ϫ mice exhibit improved, rather than the expected impaired, hepatic insulin action. This is due to decreased lipogenic gene expression and triglyceride accumulation. The present studies overcome these secondary adaptations by acutely modulating GLP-1R action in HF-fed wild-type mice. The central GLP-1R was targeted given its role as a regulator of hepatic insulin action. We hypothesized that acute inhibition of the central GLP-1R impairs hepatic insulin action beyond the effects of HF feeding. We further hypothesized that activation of the central GLP-1R improves hepatic insulin action in HF-fed mice. Insulin action was assessed in conscious, unrestrained mice using the hyperinsulinemic euglycemic clamp. Mice received intracerebroventricular (icv) infusions of artificial cerebrospinal fluid, GLP-1, or the GLP-1R antagonist exendin-9 (Ex-9) during the clamp. Intracerebroventricular Ex-9 impaired the suppression of hepatic glucose production by insulin, whereas icv GLP-1 improved it. Neither treatment affected tissue glucose uptake. Intracerebroventricular GLP-1 enhanced activation of hepatic Akt and suppressed hypothalamic AMPactivated protein kinase. Central GLP-1R activation resulted in lower hepatic triglyceride levels but did not affect muscle, white adipose tissue, or plasma triglyceride levels during hyperinsulinemia. In response to oral but not intravenous glucose challenges, activation of the central GLP-1R improved glucose tolerance. This was associated with higher insulin levels. Inhibition of the central GLP-1R had no effect on oral or intravenous glucose tolerance. These results show that inhibition of the central GLP-1R deteriorates hepatic insulin action in HF-fed mice but does not affect whole body glucose homeostasis. Contrasting this, activation of the central GLP-1R improves glucose homeostasis in HF-fed mice by increasing insulin levels and enhancing hepatic insulin action.glucagon-like peptide-1; liver; glucose metabolism GLUCAGON-LIKE PEPTIDE-1 (GLP-1) is secreted from intestinal L cells in response to nutrient intake. Binding of GLP-1 to a GLP-1 receptor (GLP-1R) expressed in pancreatic ␤-cells enhances insulin secretion (14). GLP-1 also delays gastric emptying, inhibits glucagon secretion, and suppresses food intake (14). Taken together, these actions demonstrate a key role for GLP-1 in the maintenance of metabolic homeostasis following a meal.We have shown that a functional loss of GLP-1R expression in Glp1r-knockout (Glp1r Ϫ/Ϫ ) mice impairs the suppression of hepatic glucose production (HGP) but enhances the stimulation of muscle glucose uptake (MGU) during a hyperinsulinemic euglycemic clamp in chow-fed mice (4). This proposes a novel role for the GLP-1R to reciprocally regulate hepatic and muscle insulin action independently of its ability to stimulate insulin secretion. When fed a high-fat (HF) diet to promote insulin resistance, Glp1rϪ/Ϫ mice exhibit ...

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“…administration of the GLP-1 (7-36) amide to conscious, freely moving or anesthetized rats increases the circulating levels of adrenal steroids (corticosterone and aldosterone) in a time-dependent manner (Gil-Lozano et al 2013. This marked elevation of corticosteroid levels triggered by GLP-1 is preceded by an increase in ACTH levels, and it is not surprising that the activation of the HPA axis is weaker when GLP-1 is injected intraperitoneally 230:2 (i.p., Gil-Lozano et al 2010). Similarly, its Ex-4 analogue effectively increases the circulating GC levels when administered centrally or peripherally.…”

Section: Glucagon-like Peptide 1 (Glp-1) and Hpa Axis Crosstalkmentioning

confidence: 99%

Stressing diabetes? The hidden links between insulinotropic peptides and the HPA axis

Diz-Chaves

Gil‐Lozano

Toba

et al. 2016

Journal of Endocrinology

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Diabetes mellitus exerts metabolic stress on cells and it provokes a chronic increase in the long-term activity of the hypothalamus-pituitary-adrenocortical (HPA) axis, perhaps thereby contributing to insulin resistance. GLP-1 receptor (GLP-1R) agonists are pleiotropic hormones that not only affect glycaemic and metabolic control, but they also produce many other effects including activation of the HPA axis. In fact, several of the most relevant effects of GLP-1 might involve, at least in part, the modulation of the HPA axis. Thus, the anorectic activity of GLP-1 could be mediated by increasing CRF at the hypothalamic level, while its lipolytic effects could imply a local increase in glucocorticoids and glucocorticoid receptor (GC-R) expression in adipose tissue. Indeed, the potent activation of the HPA axis by GLP-1R agonists occurs within the range of therapeutic doses and with a short latency. Interestingly, the interactions of GLP-1 with the HPA axis may underlie most of the effects of GLP-1 on food intake control, glycaemic metabolism, adipose tissue biology and the responses to stress. Moreover, such activity has been observed in animal models (mice and rats), as well as in normal humans and in type I or type II diabetic patients. Accordingly, better understanding of how GLP-1R agonists modulate the activity of the HPA axis in diabetic subjects, especially obese individuals, will be crucial to design new and more efficient therapies for these patients.

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GLP-1(7-36)-amide and Exendin-4 Stimulate the HPA Axis in Rodents and Humans

Cited by 79 publications

References 33 publications

The lipocalin-type prostaglandin D2 synthase knockout mouse model of insulin resistance and obesity demonstrates early hypothalamic–pituitary–adrenal axis hyperactivity

The lipocalin-type prostaglandin D2 synthase knockout mouse model of insulin resistance and obesity demonstrates early hypothalamic–pituitary–adrenal axis hyperactivity

Acute activation of central GLP-1 receptors enhances hepatic insulin action and insulin secretion in high-fat-fed, insulin resistant mice

Stressing diabetes? The hidden links between insulinotropic peptides and the HPA axis

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