Agouti-Related Protein Stimulates the Hypothalamic-Pituitary-Adrenal (HPA) Axis and Enhances the HPA Response to Interleukin-1 in the Primate

α-MSH antagonizes many of the immune and neuroendocrine effects induced by inflammatory cytokines. Studies have shown that α-MSH attenuates the stimulatory effect of IL-1 on the hypothalamic-pituitary-adrenal (HPA) axis and plays a physiological role in limiting the HPA response to IL-1. Recently an α-MSH antagonist, agouti-related protein (AGRP), has been identified in the hypothalamus, which stimulates food intake by antagonizing the effects of α-MSH at specific melanocortin receptors. It is unknown whether AGRP can also modulate neuroendocrine responses to inflammatory cytokines. We have therefore examined the effects of AGRP on the HPA axis and on prolactin (PRL) at baseline and in response to stimulation by IL-1β in nine ovariectomized rhesus monkeys. In the first study, the effects of intracerebroventricular (icv) infusion of 20 μg (n = 6) and 50 μg (n = 4) of human AGRP (83–132)-NH2 were compared with icv saline infusion. There was a significant stimulatory effect of 20 μg AGRP on cortisol release over time (P < 0.001). The area under the hormone response curve (AUC) for cortisol increased by 29% after 20 μg AGRP vs. saline; the AUC for ACTH increased by 166% (P = 0.028); the AUC for PRL increased by 108% (P = 0.046). There was a significant stimulatory effect of 50 μg AGRP on ACTH (P < 0.001), cortisol (P < 0.001), and PRL (P < 0.001) release over time. The AUC for ACTH after 50 μg AGRP increased by 98%; the AUC for cortisol increased by 37%; the AUC for PRL increased by 161%. The effects of AGRP on ACTH, cortisol, and PRL release were prevented by α-MSH infusion. In the second study, animals received icv either 50 ng of human IL-1β or 20 μg of AGRP followed by 50 ng IL-1β. AGRP significantly enhanced the ACTH (P < 0.05) response to IL-1β. The peak ACTH response to IL-1β alone was 124 ± 55 pg/ml vs. 430 ± 198 pg/ml after IL-1β plus AGRP; the peak cortisol response was 70 ± 8.2 μg/dl vs. 77 ± 6.2 μg/dl, but this was not significantly different. In conclusion, AGRP stimulated ACTH, cortisol, and PRL release in the monkey and enhanced the ACTH response to IL-1β. These studies suggest that, in addition to its known orexigenic effects, AGRP may play a role in neuroendocrine regulation and specifically that AGRP may interact with α-MSH to modulate neuroendocrine responses to inflammation.

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Neither Agouti-Related Protein nor Neuropeptide Y Is Critically Required for the Regulation of Energy Homeostasis in Mice

Molecular and Cellular Biology ◽

10.1128/mcb.22.14.5027-5035.2002 ◽

2002 ◽

Vol 22 (14) ◽

pp. 5027-5035 ◽

Cited By ~ 296

Author(s):

Su Qian ◽

Howard Chen ◽

Drew Weingarth ◽

Myrna E. Trumbauer ◽

Dawn E. Novi ◽

...

Keyword(s):

Body Weight ◽

Neuropeptide Y ◽

Energy Homeostasis ◽

Arcuate Nucleus ◽

Body Weight Gain ◽

Physiological Role ◽

Related Protein ◽

Double Knockout ◽

Orexigenic Peptide ◽

Agouti Related Protein

ABSTRACT Agouti-related protein (AgRP), a neuropeptide abundantly expressed in the arcuate nucleus of the hypothalamus, potently stimulates feeding and body weight gain in rodents. AgRP is believed to exert its effects through the blockade of signaling by α-melanocyte-stimulating hormone at central nervous system (CNS) melanocortin-3 receptor (Mc3r) and Mc4r. We generated AgRP-deficient (Agrp−/− ) mice to examine the physiological role of AgRP. Agrp−/− mice are viable and exhibit normal locomotor activity, growth rates, body composition, and food intake. Additionally, Agrp−/− mice display normal responses to starvation, diet-induced obesity, and the administration of exogenous leptin or neuropeptide Y (NPY). In situ hybridization failed to detect altered CNS expression levels for proopiomelanocortin, Mc3r, Mc4r, or NPY mRNAs in Agrp−/− mice. As AgRP and the orexigenic peptide NPY are coexpressed in neurons of the arcuate nucleus, we generated AgRP and NPY double-knockout (Agrp−/− ;Npy−/− ) mice to determine whether NPY or AgRP plays a compensatory role in Agrp−/− or NPY-deficient (Npy−/− ) mice, respectively. Similarly to mice deficient in either AgRP or NPY, Agrp−/− ;Npy−/− mice suffer no obvious feeding or body weight deficits and maintain a normal response to starvation. Our results demonstrate that neither AgRP nor NPY is a critically required orexigenic factor, suggesting that other pathways capable of regulating energy homeostasis can compensate for the loss of both AgRP and NPY.

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Differential regulation of agouti-related protein and neuropeptide Y in hypothalamic neurons following a stressful event

Journal of Molecular Endocrinology ◽

10.1677/jme.1.01819 ◽

2005 ◽

Vol 35 (1) ◽

pp. 159-164 ◽

Cited By ~ 45

Author(s):

Martien J H Kas ◽

Adrie W Bruijnzeel ◽

Jurgen R Haanstra ◽

Victor M Wiegant ◽

Roger A H Adan

Keyword(s):

Neuropeptide Y ◽

Hpa Axis ◽

Arcuate Nucleus ◽

Eating Behaviour ◽

Melanocortin Receptor ◽

Stressful Event ◽

Mrna Levels ◽

Related Protein ◽

Increased Sensitivity ◽

Agouti Related Protein

Stress affects eating behaviour in rodents and humans, suggesting that the regulation of energy balance and the stress response are coupled physiological processes. Neuropeptide Y (NPY) and agouti-related protein (AgRP) are potent food-stimulating neuropeptides that are highly co-localised in arcuate nucleus neurons of the hypothalamus. Recent studies have shown that NPY and AgRP mRNA levels in these neurons respond similarly to fasting and leptin, indicating functional redundancy of the neuropeptide systems in these orexigenic neurons. However, we have found that NPY and AgRP mRNA expression in arcuate nucleus neurons are dissociated immediately following a stressful event. Two hours following a brief session of inescapable foot shocks, AgRP mRNA levels are down-regulated (P < 0.0001). In contrast, NPY mRNA levels are up-regulated (P < 0.0001). To provide physiological relevance for this acute down-regulation of AgRP, an inverse agonist of melanocortin receptors, we have shown that acute intracerebroventricular injection of a melanocortin receptor agonist, α-melanocyte-stimulating hormone (α-MSH), caused a significantly stronger activation of the hypothalamus–pituitary–adrenal-cortical (HPA) axis following a stressful event than in controls. Thus, AgRP and NPY mRNA levels in similar arcuate nucleus neurons are differentially regulated following a stressful event. This may contribute to increased sensitivity for α-MSH to activate the HPA axis following a repeated stressful experience.

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Paraventricular Nucleus Administration of Calcitonin Gene-Related Peptide Inhibits Food Intake and Stimulates the Hypothalamo-Pituitary-Adrenal Axis

Endocrinology ◽

10.1210/en.2002-220902 ◽

2003 ◽

Vol 144 (4) ◽

pp. 1420-1425 ◽

Cited By ~ 42

Author(s):

Waljit S. Dhillo ◽

Caroline J. Small ◽

Preeti H. Jethwa ◽

Sabina H. Russell ◽

James V. Gardiner ◽

...

Keyword(s):

Food Intake ◽

Hpa Axis ◽

Male Rats ◽

Mrna Levels ◽

Related Protein ◽

Melanocyte Stimulating Hormone ◽

Calcitonin Gene ◽

Agouti Related Protein ◽

Prior Administration

Abstract Calcitonin gene-related protein (CGRP) inhibits food intake and stimulates the hypothalamo-pituitary-adrenal (HPA) axis after intracerebroventricular injection in rats. However, the hypothalamic site and mechanism of action are unknown. We investigated the effects of intraparaventricular nucleus administration (iPVN) of CGRP on food intake and the HPA axis in rats and the effect of CGRP on the release of hypothalamic neuropeptides in vitro. In addition, we investigated the effects of food deprivation on hypothalamic CGRP expression. CGRP dose-dependently reduced food intake in the first hour after iPVN injection in fasted male rats (saline, 5.1 ± 0.8 g; 0.3 nmol CGRP, 1.1 ± 0.5 g; P < 0.001 vs. saline). iPVN injection of CGRP8–37 (a CGRP1 receptor antagonist) alone had no effect on food intake. However, the reduction in food intake by iPVN CGRP was attenuated by prior administration of CGRP8–37 [CGRP8–37 (10 nmol)/CGRP (0.3 nmol), 3.0 ± 0.8 g; P < 0.05 vs. 0.3 nmol CGRP]. CGRP (100 nm) stimulated the release of α-melanocyte stimulating hormone, cocaine- and amphetamine-related transcript, corticotropin-releasing hormone, and arginine vasopressin from hypothalamic explants to 127 ± 19%, 148 ± 10%, 158 ± 17%, and 198 ± 21% of basal levels, respectively (P < 0.05 vs. basal), but did not alter the release of either neuropeptide Y or agouti-related protein. Hypothalamic CGRP mRNA levels in 24-h fasted rats were increased to 130 ± 8% of control levels [CGRP mRNA (arbitrary units), 4.75 ± 0.4; controls, 3.65 ± 0.34; P < 0.05]. Our data suggest that CGRP administered to the PVN inhibits food intake and stimulates the HPA axis.

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The role of photoperiod on the expression of hypothalamic genes regulating appetite in Chevrier’s field mouse (Apodemus chevrieri)

Animal Biology ◽

10.1163/15707563-00002460 ◽

2015 ◽

Vol 65 (1) ◽

pp. 45-56 ◽

Cited By ~ 2

Author(s):

Lin Zhang ◽

Fang Yang ◽

Jinhong Cai ◽

Chunmei Huang ◽

Zhengkun Wang ◽

...

Keyword(s):

Food Intake ◽

Neuropeptide Y ◽

Mrna Expression ◽

Physiological Role ◽

Field Mouse ◽

Related Protein ◽

Serum Leptin ◽

Significant Difference ◽

Agouti Related Protein

The hypothalamus and leptin play a key role in the regulation of food intake. The present study investigated the effects of 4 weeks of short- or long-photoperiod on serum leptin levels and food intake in relation to mRNA expression levels of neuropeptide Y, agouti-related protein, pro-opiomelanocortin, and cocaine- and amphetamine-regulated transcript in the hypothalamus of Chevrier’s field mouse (Apodemus chevrieri). There was a significant difference in body fat mass, food intake and neuropeptide Y mRNA expression between the two groups, but serum leptin level, agouti-related protein, pro-opiomelanocortin, and cocaine- and amphetamine-regulated transcript mRNA expression in the hypothalamus were not difference between the two groups. The elevation of neuropeptide Y mRNA regulated neuropeptides in the hypothalamus suggests a physiological role of neuroendocrine factors in food intake during the different photoperiod. We conclude that leptin may be involved in energy balance and body mass regulation.

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Activation of the hypothalamic–pituitary–adrenal axis by exogenous and endogenous GDF15

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2106868118 ◽

2021 ◽

Vol 118 (27) ◽

pp. e2106868118

Author(s):

Irene Cimino ◽

Hanna Kim ◽

Y. C. Loraine Tung ◽

Kent Pedersen ◽

Debra Rimmington ◽

...

Keyword(s):

Hpa Axis ◽

Cytokine Response ◽

Reduce Food Intake ◽

Wild Type ◽

Marked Rise ◽

Blocking Antibody ◽

Hypothalamic Pituitary Adrenal ◽

Acute Increase ◽

Corticosterone Response ◽

Hpa Response

An acute increase in the circulating concentration of glucocorticoid hormones is essential for the survival of severe somatic stresses. Circulating concentrations of GDF15, a hormone that acts in the brain to reduce food intake, are frequently elevated in stressful states. We now report that GDF15 potently activates the hypothalamic–pituitary–adrenal (HPA) axis in mice and rats. A blocking antibody to the GDNF-family receptor α-like receptor completely prevented the corticosterone response to GDF15 administration. In wild-type mice exposed to a range of stressful stimuli, circulating levels of both corticosterone and GDF15 rose acutely. In the case of Escherichia coli or lipopolysaccharide injections, the vigorous proinflammatory cytokine response elicited was sufficient to produce a near-maximal HPA response, regardless of the presence or absence of GDF15. In contrast, the activation of the HPA axis seen in wild-type mice in response to the administration of genotoxic or endoplasmic reticulum toxins, which do not provoke a marked rise in cytokines, was absent in Gdf15−/− mice. In conclusion, consistent with its proposed role as a sentinel hormone, endogenous GDF15 is required for the activation of the protective HPA response to toxins that do not induce a substantial cytokine response. In the context of efforts to develop GDF15 as an antiobesity therapeutic, these findings identify a biomarker of target engagement and a previously unrecognized pharmacodynamic effect, which will require monitoring in human studies.

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Temporal Stability of the dex/CRH Test in Patients with Rapid-Cycling Bipolar I Disorder: A Pilot Study

Australian & New Zealand Journal of Psychiatry ◽

10.1080/j.1440-1614.2005.01560.x ◽

2005 ◽

Vol 39 (4) ◽

pp. 244-248 ◽

Cited By ~ 13

Author(s):

Stuart Watson ◽

Jill M. Thompson ◽

Navdeep Malik ◽

I. Nicol Ferrier ◽

Allan H. Young

Keyword(s):

Bipolar Disorder ◽

Pilot Study ◽

Hpa Axis ◽

Mood State ◽

Temporal Stability ◽

Cortisol Response ◽

Rapid Cycling ◽

Corticotropin Releasing Hormone ◽

Hypothalamic Pituitary Adrenal ◽

Over Time

Objective: To examine the hypothesis that hypothalamic-pituitary-adrenal (HPA) axis function is a trait abnormality in bipolar disorder. Method: We examined HPA axis function in a pilot study of five patients with rapid-cycling bipolar disorder in both relapse and remission using the dexamethasone/corticotropin releasing hormone (dex/CRH) test. Results: The cortisol response to the dex/CRH test correlated significantly between the 2 tests (r = 0.997; p < 0.0005). Conclusion: The data suggests that the cortisol response to the dex/CRH test is stable over time and independent of mood state.

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Glucose injection reduces neuropeptide Y and agouti-related protein expression in the arcuate nucleus: A possible physiological role in eating behavior

Molecular Brain Research ◽

10.1016/j.molbrainres.2004.12.017 ◽

2005 ◽

Vol 135 (1-2) ◽

pp. 69-80 ◽

Cited By ~ 22

Author(s):

Guo-Qing Chang ◽

Olga Karatayev ◽

Zoya Davydova ◽

Katherine Wortley ◽

Sarah F. Leibowitz

Keyword(s):

Protein Expression ◽

Neuropeptide Y ◽

Eating Behavior ◽

Arcuate Nucleus ◽

Physiological Role ◽

Related Protein ◽

Glucose Injection ◽

Agouti Related Protein

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Neonatal Gonadectomy and Adult Testosterone Replacement Suggest an Involvement of Limbic Arginine Vasopressin and Androgen Receptors in the Organization of the Hypothalamic-Pituitary-Adrenal Axis

Endocrinology ◽

10.1210/en.2007-1796 ◽

2008 ◽

Vol 149 (7) ◽

pp. 3581-3591 ◽

Cited By ~ 31

Author(s):

Brenda Bingham ◽

Victor Viau

Keyword(s):

Androgen Receptor ◽

Hpa Axis ◽

Paraventricular Nucleus ◽

Arginine Vasopressin ◽

Androgen Receptors ◽

Male Rats ◽

Testosterone Replacement ◽

Testosterone Treatment ◽

Hypothalamic Pituitary Adrenal ◽

Hpa Response

Testosterone exposure during critical periods of development exerts major organizing effects on the hypothalamic-pituitary-adrenal (HPA) axis. Here we examined how neonatal gonadectomy (GDX) with or without testosterone treatment during the first week of life alters the HPA response to adult testosterone replacement in 65-d-old male rats. As adults, neonatal GDX rats showed higher levels of plasma corticosterone and Fos activation in medial parvocellular part of the paraventricular nucleus of the hypothalamus under basal conditions and during 30 min of restraint exposure. These responses were normalized with testosterone treatment on postnatal d 1–5 but were not restored with adult testosterone replacement. As adults, neonatal GDX rats also showed a decrease in the number of androgen receptor and arginine vasopressin-positive cells in the bed nucleus of the stria terminalis and in the medial nucleus of the amygdala, and both of these responses were reversed with postnatal testosterone treatment. In stressed and unstressed animals, the number of androgen receptors and arginine vasopressin-expressing neurons in both of these nuclei correlated negatively with corticosterone concentrations in plasma and Fos levels in the paraventricular nucleus. Taken together, our findings suggest that testosterone exposure during the neonatal period primes the adult HPA response to testosterone by altering androgen receptor levels and function within afferent mediators of basal and stress-related input to the HPA axis.

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