Disease relevance of Agrp

• Agrp and Mc4r are excellent candidates for human disorders of body weight regulation and represent promising targets for pharmacological intervention in the treatment of these disorders [1].
• Agouti-related protein (AGRP) is a homologue of the agouti gene product and, when overexpressed, promotes obesity [2].
• Likewise, treatment of WT mice with intracranial agouti-related peptide reversed the cachexic effects of uremia on appetite, weight gain, body composition, and metabolic rate [3].
• Administering a melanocortin-3/4 receptor agonist abrogated the hyperphagia and hypothalamic immunohistochemistry showed a marked reduction in proopiomelanocortin with an increase in neuropeptide Y and agouti-related protein [4].

Psychiatry related information on Agrp

• Agrp(-/-) mice are viable and exhibit normal locomotor activity, growth rates, body composition, and food intake [5].
• To determine whether the change in Agrp expression that occurs with food deprivation in lean rats could be prevented by leptin replacement, Sprague-Dawley rats were fasted and infused via subcutaneous osmotic micropumps for 48 h with either saline or recombinant mouse leptin [6].
• We report data herein supporting an alternative mechanism for AGRP involvement in feeding behavior [7].
• Since agouti-related protein suppresses the activity of the melanocortin system, the AgRP gene was investigated as candidate gene in anorexia nervosa [8].

High impact information on Agrp

• Here we demonstrate in transgenic, biochemical and genetic-interaction experiments that attractin is a low-affinity receptor for agouti protein, but not Agrp, in vitro and in vivo [9].
• Overexpression of Agrt leads to obesity in transgenic mice [10].
• Intra-cerebroventricular injection studies show that an agouti-related peptide analogue lacked orexigenic (appetite-stimulating) activity in M3R-/- mice [11].
• Thus, Agouti-related protein is a neuropeptide implicated in the normal control of body weight downstream of leptin signaling [12].
• Central control of energy balance depends on the ability of proopiomelanocortin (POMC) or agouti-related protein (Agrp) hypothalamic neurons to sense and respond to changes in peripheral energy stores [13].

Chemical compound and disease context of Agrp

• Nicotine withdrawal increases body weight, neuropeptide Y and Agouti-related protein expression in the hypothalamus and decreases uncoupling protein-3 expression in the brown adipose tissue in high-fat fed mice [14].

Biological context of Agrp

• By contrast, the absence of a functional leptin receptor results in the upregulation of Npy but not Agrp mRNA [6].
• An expressed sequence tag was identified that encodes Agouti-related protein, whose RNA is normally expressed in the hypothalamus and whose levels were increased eightfold in ob/ob mice [12].
• Neither agouti-related protein nor neuropeptide Y is critically required for the regulation of energy homeostasis in mice [5].
• The central administration of AGRP not only stimulates food intake, but also inhibits the hypothalamic-pituitary-thyroid axis (HPT) axis, closely replicating the central hypothyroid state induced by fasting [15].
• Structure activity studies of the melanocortin-4 receptor by in vitro mutagenesis: identification of agouti-related protein (AGRP), melanocortin agonist and synthetic peptide antagonist interaction determinants [16].

Anatomical context of Agrp

• Leptin regulation of Agrp and Npy mRNA in the rat hypothalamus [6].
• To test this hypothesis we evaluated mRNA expression of Npy, Agrp, and Pomc by in situ hybridization in the hypothalamic arcuate nucleus (ARC) of 3-day-old female and male PWS neonates [17].
• AGRP or artificial cerebrospinal fluid was administered daily into the lateral ventricle of adult, male MC4-R knockout and wild-type (WT) mice for 3 d [15].
• In the ARC of young mice, NPY and AGRP expression increased and POMC and CART expression decreased with body fat content [18].
• However, in vitro AgRP can decrease leptin secretion, by approximately 40%, from adipocytes into culture medium and may via this axis have an effect on energy metabolism during prolonged caloric restriction [19].

Associations of Agrp with chemical compounds

• Hypothalamic mRNA levels of agouti- related protein (AGRP), an orexigenic melanocortin receptor antagonist, increased after GHRP-2 treatment [20].
• In addition, the present results confirmed the downregulating effects of leptin on the expression of AGRP mRNA in the hypothalamic arcuate nucleus (ARC), and demonstrated that this effect was more apparent in ADX mice treated with corticosterone than in ADX mice not supplemented with corticosterone [21].
• In muscle, however, 2 weeks of high fat feeding did not result in changes in insulin sensitivity or in triglyceride content. mRNA expression levels of NPY, AgRP, POMC, and CART in the hypothalamus were not different between the groups [22].
• The persistent effect seems to be due to inhibition of the fasting-induced up-regulation of expression of hypothalamic orexigenic neuropeptides neuropeptide Y and agouti-related protein and down-regulation of expression of anorexigenic neuropeptides pro-opiomelanocortinalpha-melanocyte-stimulating hormone and cocaine-amphetamine-related transcript [23].
• ASIP adopts the inhibitor cystine knot fold and, along with AgRP, are the only known mammalian proteins in this structure class [24].

Physical interactions of Agrp

• AGRP binds as an endogenous antagonist or inverse agonist of the central melanocortin receptors but has also been hypothesized to have melanocortin receptor-independent effects [15].
• Syndecan-3 modulates food intake by interacting with the melanocortin/AgRP pathway [25].

Regulatory relationships of Agrp

• These studies demonstrate that hypothalamic AgRP mRNA and immunoreactivity are upregulated with fasting and that these increases are not affected by NPY deficiency [26].
• Hypothalamic agouti-related protein messenger ribonucleic acid is inhibited by leptin and stimulated by fasting [2].

Other interactions of Agrp

• In contrast, no significant effects of AGRP were observed in any of these parameters in the MC4-R knockout mice [15].
• Novel agouti-related-protein-based melanocortin-1 receptor antagonist [27].
• Moreover, mutant mice that ectopically express either agouti (Ay/a mice) or agouti-related protein (Agrp), antagonists of melanocortin signalling, become obese [28].
• The results showed that Agrp mRNA expression was decreased relative to wild-type (WT) controls in neonates of both sexes, while mRNA expression of Pomc was upregulated in PWS neonates [17].
• Elongation studies of the human agouti-related protein (AGRP) core decapeptide (Yc[CRFFNAFC]Y) results in antagonism at the mouse melanocortin-3 receptor [29].

Analytical, diagnostic and therapeutic context of Agrp

• To investigate the potential role of the amino-terminal residues, we compared the function of full-length and carboxyl-terminal fragments of Agrp and Agouti protein in a sensitive bioassay based on pigment dispersion in Xenopus melanophores [30].
• Using a sensitive solution hybridization/S1 nuclease protection assay, we found no significant difference in Agrp messenger RNA (mRNA) levels (pg/microg total RNA +/- SEM) in obese rats (n = 5), compared with lean controls (n = 5): 0.46 +/- 0.06 vs. 0.47 +/- 0.06 (P = 0.9) [31].
• Similarly, no difference in Agrp expression was found using in situ hybridization or semiquantitative RT-PCR [31].
• Sequence analysis of this gene, named ART, for agouti-related transcript, predicts a 132-amino-acid protein that is 25% identical to human agouti [32].
• All of these residues are conserved in the agouti-related transcript, ART, whose expression is up-regulated in animal models of obesity [33].

References