Peroxisome Proliferator-Activated Receptor   Controls Ingestive Behavior, Agouti-Related Protein, and Neuropeptide Y mRNA in the Arcuate Hypothalamus

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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Estradiol decreases the orexigenic effect of neuropeptide Y, but not agouti-related protein, in ovariectomized rats

Behavioural Brain Research ◽

10.1016/j.bbr.2008.03.019 ◽

2008 ◽

Vol 191 (2) ◽

pp. 173-177 ◽

Cited By ~ 62

Author(s):

Jessica Santollo ◽

Lisa A. Eckel

Keyword(s):

Neuropeptide Y ◽

Ovariectomized Rats ◽

Related Protein ◽

Agouti Related Protein

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Hypophysiotropic Thyrotropin-Releasing Hormone-Synthesizing Neurons in the Human Hypothalamus Are Innervated by Neuropeptide Y, Agouti-Related Protein, and -Melanocyte-Stimulating Hormone

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.85.7.2596 ◽

2000 ◽

Vol 85 (7) ◽

pp. 2596-2603 ◽

Cited By ~ 27

Author(s):

E. Mihaly

Keyword(s):

Neuropeptide Y ◽

Thyrotropin Releasing Hormone ◽

Related Protein ◽

Human Hypothalamus ◽

Releasing Hormone ◽

Melanocyte Stimulating Hormone ◽

Agouti Related Protein ◽

Stimulating Hormone

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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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Association of PPARγ2(Pro12Ala) and Neuropeptide Y (Leu7Pro) Gene Polymorphisms with Obstructive Sleep Apnea in Obese Asian Indians

Disease Markers ◽

10.1155/2011/410397 ◽

2011 ◽

Vol 30 (1) ◽

pp. 31-38 ◽

Cited By ~ 5

Author(s):

Bharat Bhushan ◽

Randeep Guleria ◽

Anoop Misra ◽

Kalpana Luthra ◽

Guresh Kumar

Keyword(s):

Obstructive Sleep Apnea ◽

Sleep Apnea ◽

Neuropeptide Y ◽

Gene Polymorphisms ◽

Asian Indians ◽

Fasting Blood Glucose ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Skin Fold ◽

Obstructive Sleep

Background:Obstructive sleep apnea (OSA) is prevalent in 7.5% in urban Asian Indians.Peroxisome proliferator activated receptor gamma2 (PPARγ2)has been implicated in adipocyte differentiation.Neuropeptide Y (NPY)is also considered as a candidate gene for excess body fat accumulation. The association ofPPARγ2 (Pro12Ala)andNPY (Leu7Pro)gene polymorphisms with OSA has not been studied in Asian Indians.Objective:To study the distribution ofPPARγ2 (Pro12Ala)andNPY (Leu7Pro)polymorphism in Asian Indians with and without OSA.Methods and results:This study was carried out in 252 obese subjects [(body mass index (BMI > 25 kg/m2)]; 142 with OSA and 110 without OSA. Measurements included anthropometric and biochemical parameters (fasting blood glucose, lipid profile, various circumferences and skin-fold thicknesses).PPARγ2 (Pro12Ala) and NPY (Leu7Pro) genepolymorphisms were studied in all subjects. The frequency of the variantallele (Ala12) of PPARγ2 genewas significantly higher in subjects with OSA (14.4%) when compared with subjects without OSA (5.5%; χ2= 9.7;p= 0.001). The distribution of the variantallele (Pro7)ofNPY genewas comparable in subjects with OSA (3.5%) and without OSA (3.6%; χ2= 0.001,p= 0.94).Conclusion:This study reveals a significantly higher frequency ofPPARγ2 (Ala12) allelein obese Asian Indians with OSA when compared to obese Asian Indians without OSA.

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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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