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

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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Altered Expression of Agouti-Related Protein and Its Colocalization with Neuropeptide Y in the Arcuate Nucleus of the Hypothalamus during Lactation*

Endocrinology ◽

10.1210/endo.140.6.6829 ◽

1999 ◽

Vol 140 (6) ◽

pp. 2645-2650 ◽

Cited By ~ 59

Author(s):

Peilin Chen ◽

Chien Li ◽

Carrie Haskell-Luevano ◽

Roger D. Cone ◽

M. Susan Smith

Keyword(s):

In Situ Hybridization ◽

Food Intake ◽

Neuropeptide Y ◽

Arcuate Nucleus ◽

Mrna Levels ◽

Related Protein ◽

Altered Expression ◽

Caudal Portion ◽

Agouti Related Protein

Abstract During lactation, the levels of neuropeptide Y (NPY), which plays an important role in mediating food intake, are significantly elevated in a number of hypothalamic areas, including the arcuate nucleus (ARH). To identify additional hypothalamic systems that might be important in mediating the increase in food intake and alterations in energy homeostasis during lactation, the present studies examined the expression of agouti-related protein (AGRP), a recently described homologue of the skin agouti protein. AGRP is found in the hypothalamus and has been suggested to play an important role in the regulation of food intake. In the first experiment, animals were studied during diestrus of the estrous cycle, a stage of the cycle when estrogen levels are basal and similar to lactation, or during days 12–13 postpartum. Lactating animals had their litters adjusted to eight pups on day 2 postpartum. Brain tissue sections were used to measure AGRP messenger RNA (mRNA) levels by in situ hybridization. AGRP mRNA signal was found mostly in the ventromedial portion of the ARH, which has been shown to contain a high density of NPY neurons. A significant increase in AGRP mRNA content was observed in the mid- to caudal portion of the ARH of lactating animals compared with diestrous females. No difference was found in the rostral portion of the ARH. In the second experiment, double-label in situ hybridization for AGRP and NPY was performed in lactating animals to determine the extent of colocalization of the two peptides in the ARH, using 35S-labeled and digoxigenin-labeled antisense complementary RNA probes. It was found that almost all of the NPY-positive neurons throughout the ARH also expressed AGRP mRNA signal. Furthermore, AGRP expression was confined almost exclusively to NPY-positive neurons. Thus, the present study showed that during lactation, AGRP gene expression was significantly elevated in a subset of the AGRP neurons in the ARH. The high degree of colocalization of AGRP and NPY, coupled with previous reports from our laboratory demonstrating increased NPY expression in the ARH in response to suckling, suggests that AGRP and NPY are coordinately regulated and may be involved in the increase in food intake during lactation.

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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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Effects of neuropeptide Y deficiency on hypothalamic agouti-related protein expression and responsiveness to melanocortin analogues

Brain Research ◽

10.1016/s0006-8993(99)01962-9 ◽

1999 ◽

Vol 848 (1-2) ◽

pp. 66-77 ◽

Cited By ~ 89

Author(s):

Donald J Marsh ◽

Grant I Miura ◽

Keith A Yagaloff ◽

Michael W Schwartz ◽

Gregory S Barsh ◽

...

Keyword(s):

Protein Expression ◽

Neuropeptide Y ◽

Related Protein ◽

Agouti Related Protein

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Fasting Induces a Large, Leptin-Dependent Increase in the Intrinsic Action Potential Frequency of Orexigenic Arcuate Nucleus Neuropeptide Y/Agouti-Related Protein Neurons

Endocrinology ◽

10.1210/en.2004-1397 ◽

2005 ◽

Vol 146 (3) ◽

pp. 1043-1047 ◽

Cited By ~ 159

Author(s):

Kanji A. Takahashi ◽

Roger D. Cone

Keyword(s):

Action Potential ◽

Neuropeptide Y ◽

Arcuate Nucleus ◽

Related Protein ◽

Action Potential Frequency ◽

Agouti Related Protein ◽

Potential Frequency

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Contribution of Noradrenergic and Adrenergic Cell Groups of the Brainstem and Agouti-Related Protein-Synthesizing Neurons of the Arcuate Nucleus to Neuropeptide-Y Innervation of Corticotropin-Releasing Hormone Neurons in Hypothalamic Paraventricular Nucleus of the Rat

Endocrinology ◽

10.1210/en.2007-0732 ◽

2007 ◽

Vol 148 (11) ◽

pp. 5442-5450 ◽

Cited By ~ 43

Author(s):

Tamás Füzesi ◽

Gábor Wittmann ◽

Zsolt Liposits ◽

Ronald M. Lechan ◽

Csaba Fekete

Keyword(s):

Neuropeptide Y ◽

Paraventricular Nucleus ◽

Arcuate Nucleus ◽

Protein A ◽

Hypothalamic Paraventricular Nucleus ◽

Related Protein ◽

Cell Groups ◽

Hypothalamic Arcuate Nucleus ◽

Agouti Related Protein ◽

Pituitary Adrenal Axis

CRH-synthesizing neurons in the hypothalamic paraventricular nucleus (PVN) integrate neuronal and hormonal inputs and serve as a final common pathway to regulate the hypothalamic-pituitary-adrenal axis. One of the neuronal regulators of CRH neurons is neuropeptide Y (NPY) contained in axons that densely innervate CRH neurons. The three main sources of NPY innervation of the PVN are the hypothalamic arcuate nucleus and the noradrenergic and adrenergic neurons of the brainstem. To elucidate the origin of the NPY-immunoreactive (NPY-IR) innervation to hypophysiotropic CRH neurons, quadruple-labeling immunocytochemistry for CRH, NPY, dopamine-β-hydroxylase, and phenylethanolamine-N-methyltransferase was performed. Approximately 63% of NPY-IR varicosities on the surface of CRH neurons were catecholaminergic (22% noradrenergic and 41% adrenergic), and 37% of NPY-IR boutons were noncatecholaminergic. By triple-labeling immunofluorescence detection of NPY, CRH, and agouti-related protein, a marker of NPY axons projecting from the arcuate nucleus, the noncatecholaminergic, NPY-ergic axon population was shown to arise primarily from the arcuate nucleus. When NPY was administered chronically into the cerebral ventricle of fed animals, a dramatic reduction of CRH mRNA was observed in the PVN (NPY vs. control integrated density units, 23.9 ± 2.7 vs. 77.09 ± 15.9). We conclude that approximately two thirds of NPY-IR innervation to hypophysiotropic CRH neurons originates from catecholaminergic neurons of the brainstem, whereas the remaining one third arises from the arcuate nucleus. The catecholaminergic NPY innervation seems to modulate the activation of CRH neurons in association with glucoprivation and infection, whereas the NPY input from the arcuate nucleus may contribute to inhibition of CRH neurons during fasting.

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