Alternative titles; symbols
HGNC Approved Gene Symbol: AGRP
Cytogenetic location: 16q22.1 Genomic coordinates (GRCh38): 16:67,482,571-67,483,547 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16q22.1 | {Leanness, inherited} | 601665 | Autosomal dominant; Autosomal recessive; Multifactorial | 3 |
| {Obesity, late-onset} | 601665 | Autosomal dominant; Autosomal recessive; Multifactorial | 3 |
The hypothalamic agouti-related protein (AGRP) regulates body weight via central melanocortin receptors (see 155555).
The agouti gene in mice (see 600201) encodes a cell-signaling protein that acts as an antagonist at the melanocortin-1 receptor (MC1R; 155555). Shutter et al. (1997) cloned a gene, which they designated ART for 'agouti-related transcript,' whose sequence predicted a 132-amino acid protein with 25% identity to human agouti. Northern blot analysis of human tissues showed that ART is expressed most abundantly in the adrenal gland, hypothalamus, and subthalamic nucleus, with weaker expression in the testis, lung, and kidney. The ART gene is alternatively spliced; Northern blot analysis revealed a 0.7-kb mRNA with a noncoding 5-prime exon in brain and a 0.5-kb mRNA in peripheral tissues.
Because Shutter et al. (1997) observed hypothalamic ART expression to be elevated 10-fold in the mouse models of obesity ob/ob (164160) and db/db (601007), they suggested that ART is a participant in the hypothalamic control of feeding.
From an expressed sequence tag database, Ollmann et al. (1997) isolated a protein that they named Agrp for 'Agouti-related protein' and showed that Agrp expression is reduced 5-fold in the hypothalamus of agouti mutant mice. Ollmann et al. (1997) demonstrated that, in vitro, AGRP was a potent, selective antagonist of MC3R (155540) and MC4R (155541). Ubiquitous expression of human AGRP in transgenic mice led to obesity, but had no effect on pigmentation. Therefore, Ollmann et al. (1997) concluded that AGRP normally regulates body weight via central melanocortin receptors, analogous to the relation between agouti and MC1R for regulation of pigmentation.
Graham et al. (1997) found that overexpression of Agrt recapitulated many unique features of obese yellow and MC4R-deficient mice, including obesity, increased body length, hyperinsulinemia, late-onset hyperglycemia, pancreatic islet hyperplasia, and lack of elevated corticosterone. The fact that Agrt is expressed in the arcuate nucleus, is regulated by leptin (164160), and is a potent antagonist of MC3R and MC4R, suggested that Agrt is an endogenous regulator of melanocortinergic neurons in the brain. Graham et al. (1997) stated that the ectopic expression of agouti produces obesity by mimicking the normal action of Agrt in the hypothalamus.
To investigate the relationship between peripheral blood levels of AGRP and various parameters of obesity, Katsuki et al. (2001) measured the plasma level of AGRP in 15 obese and 15 nonobese men and evaluated its relationship with body mass index (BMI); body fat weight; visceral, subcutaneous, and total fat areas; fasting insulin (176730) levels; glucose infusion rate; serum leptin; and plasma alpha-MSH (see 176830). Obese men had significantly higher plasma concentrations of AGRP than nonobese men. Univariate analysis showed that plasma levels of AGRP are proportionally correlated with BMI, body fat weight, and subcutaneous fat area in obese men. In all men, the plasma levels of AGRP were significantly correlated with the visceral fat area, total fat area, fasting insulin level, glucose infusion rate, serum level of leptin, and the plasma level of alpha-MSH. The authors concluded that the circulating levels of AGRP are increased in obese men and that they are correlated with various parameters of obesity.
To determine whether neurons that express neuropeptide Y (NPY; 162640) and Agrp are essential in mice, Luquet et al. (2005) targeted the human diphtheria toxin receptor (126150) to the Agrp locus, which allows temporally controlled ablation of Npy/Agrp neurons to occur after an injection of diphtheria toxin. Neonatal ablation of Npy/Agrp neurons had minimal effects on feeding, whereas their ablation in adults caused rapid starvation. Luquet et al. (2005) concluded that network-based compensatory mechanisms can develop after the ablation of Npy/Agrp neurons in neonates but do not readily occur when these neurons become essential in adults.
Kitamura et al. (2006) delivered adenovirus encoding a constitutively nuclear mutant Foxo1a (136533) to the hypothalamic arcuate nucleus of rodents and observed a loss of the ability of leptin to curtail food intake or to suppress expression of Agrp. Conversely, a transactivation-deficient Foxo1a mutant prevented induction of Agrp by fasting. Using reporter gene, gel shift, and immunoprecipitation assays, Kitamura et al. (2006) demonstrated that Foxo1a and Stat3 (102582) exerted opposing actions on the expression of Agrp and Pomc (176830) through transcriptional interference. Foxo1a promoted opposite patterns of coactivator-corepressor exchange at the Pomc and Agrp promoters, resulting in activation of Agrp and inhibition of Pomc. Kitamura et al. (2006) concluded that Foxo1a mediates the Agrp-dependent effects of leptin on food intake.
Andrews et al. (2008) showed that ghrelin (605353) initiates robust changes in hypothalamic mitochondrial respiration in mice that are dependent on uncoupling protein-2 (UCP2; 601693). Activation of this mitochondrial mechanism is critical for ghrelin-induced mitochondrial proliferation and electric activation of NPY/AgRP neurons, for ghrelin-triggered synaptic plasticity of POMC-expressing neurons, and for ghrelin-induced food intake. The UCP2-dependent action of ghrelin on NPY/AgRP neurons is driven by a hypothalamic fatty acid oxidation pathway involving AMPK (see 602739), CPT1 (600528), and free radicals that are scavenged by UCP2. Andrews et al. (2008) concluded that their results revealed a signaling modality connecting mitochondria-mediated effects of G protein-coupled receptors on neuronal function and associated behavior.
Atasoy et al. (2012) mapped synaptic interactions of AGRP neurons with multiple cell populations in mice and probed the contribution of these distinct circuits to feeding behavior using optogenetic and pharmacogenetic techniques. An inhibitory circuit with paraventricular hypothalamus (PVH) neurons substantially accounted for acute AGRP neuron-evoked eating, whereas 2 other prominent circuits (the hypothalamic arcuate nucleus and the parabrachial nucleus) were insufficient. Within the PVH, Atasoy et al. (2012) found that AGRP neurons target and inhibit oxytocin neurons, a small population that is selectively lost in Prader-Willi syndrome (176270), a condition involving insatiable hunger. By developing strategies for evaluating molecularly defined circuits, Atasoy et al. (2012) showed that AGRP neuron suppression of oxytocin neurons is critical for evoked feeding.
Using Cre-recombinase-enabled cell-specific neuron mapping techniques in mice, Krashes et al. (2014) discovered strong excitatory drive that, unexpectedly, emanates from the hypothalamic paraventricular nucleus, specifically from subsets of neurons expressing thyrotropin-releasing hormone (TRH; 613879) and pituitary adenylate cyclase-activating polypeptide (PACAP; 102980). Chemogenetic stimulation of these afferent neurons in sated mice markedly activated Agrp neurons and induced intense feeding. Conversely, acute inhibition in mice with caloric deficiency-induced hunger decreased feeding. Krashes et al. (2014) concluded that discovery of these afferent neurons capable of triggering hunger advances understanding of how this intense motivational state is regulated.
Brown et al. (2001) determined that the AGRP gene contains 4 exons and spans 1.2 kb. Exon 1 is noncoding and contains a canonical TATA box and 2 CACCC boxes. In the region upstream of exon 1, they identified a noncanonical TATA box, a CCAAT box, a CACCC box, a portion of a putative insulin response element, and STAT (see STAT1; 600555)-recognition sites.
Shutter et al. (1997) mapped the AGRP gene to chromosome 16q22 by fluorescence in situ hybridization.
Brown et al. (2001) reported a polymorphism in the third exon of the AGRP gene, 199G-A, that resulted in a nonconservative ala67-to-thr (A67T) substitution. Argyropoulos et al. (2002) examined the association of this polymorphism with body mass index, adiposity, and abdominal fat in members of the HERITAGE (HEalth, RIsk factors, exercise Training, And GEnetics) Family Study cohort. Computational analysis of the protein showed significant differences in the coils of the 2 polymorphic isoforms of the protein. Human studies showed no genotype effects in individuals with a mean age of 25 years. However, the G/G genotype was significantly associated with fatness and abdominal adiposity in the parental population with a mean age of 53 years. The authors concluded that the 199G-A polymorphism in AGRP could, therefore, play a role in the development of human obesity (601665) in an age-dependent fashion.
Haploinsufficiency of the type 4 melanocortin receptor (155541) is associated with early-onset obesity, implying that this receptor provides an important tonic inhibition of weight gain. AGRP is an endogenous antagonist of melanocortin signaling. Therefore, Marks et al. (2004) reasoned that loss of AGRP function could lead to the expression of a lean phenotype. They investigated the potential role of AGRP in human weight regulation by examining the association between the A67T AGRP polymorphism and indices of body composition phenotype in 874 subjects of the Quebec family study. In this group they found 8 individuals who were homozygous for the thr67 allele. These 8 had lower weight, body mass index (BMI), fat free mass, fat mass, and leptin (164160) when compared to those carrying at least 1 ala67 allele. Individuals homozygous for the thr67 allele had a BMI that was either at or slightly below an ideal range for their age. Thus, the A67T AGRP polymorphism is associated with lower body weight in humans, with the largest effect being observed on body fat mass. The authors did not observe any difference in the stability or cellular distribution of the mutant protein in a heterologous expression system; thus, the mechanism of this effect required further investigation. It is noteworthy that no homozygotes for thr67 were found in the individuals registered in the San Antonio Family Heart Study (SAFHS).
Andrews, Z. B., Liu, Z.-W., Wallingford, N., Erion, D. M., Borok, E., Friedman, J. M., Tschop, M. H., Shanabrough, M., Cline, G., Shulman, G. I., Coppola, A., Gao, X.-B., Horvath, T. L., Diano, S. UCP2 mediates ghrelin's action on NPY/AgRP neurons by lowering free radicals. Nature 454: 846-851, 2008. Note: Erratum: Nature 459: 736 only, 2009. [PubMed: 18668043] [Full Text: https://doi.org/10.1038/nature07181]
Argyropoulos, G., Rankinen, T., Neufeld, D. R., Rice, T., Province, M. A., Leon, A. S., Skinner, J. S., Wilmore, J. H., Rao, D. C., Bouchard, C. A polymorphism in the human agouti-related protein is associated with late-onset obesity. J. Clin. Endocr. Metab. 87: 4198-4202, 2002. [PubMed: 12213871] [Full Text: https://doi.org/10.1210/jc.2002-011834]
Atasoy, D., Betley, J. N., Su, H. H., Sternson, S. M. Deconstruction of a neural circuit for hunger. Nature 488: 172-177, 2012. [PubMed: 22801496] [Full Text: https://doi.org/10.1038/nature11270]
Brown, A. M., Mayfield, D. K., Volaufova, J., Argyropoulos, G. The gene structure and minimal promoter of the human agouti related protein. Gene 277: 231-238, 2001. [PubMed: 11602360] [Full Text: https://doi.org/10.1016/s0378-1119(01)00705-3]
Graham, M., Shutter, J. R., Sarmiento, U., Sarosi, I., Stark, K. L. Overexpression of Agrt leads to obesity in transgenic mice. (Letter) Nature Genet. 17: 273-274, 1997. [PubMed: 9354787] [Full Text: https://doi.org/10.1038/ng1197-273]
Katsuki, A., Sumida, Y., Gabazza, E. C., Murashima, S., Tanaka, T., Furuta, M., Araki-Sasaki, R., Hori, Y., Nakatani, K., Yano, Y., Adachi, Y. Plasma levels of agouti-related protein are increased in obese men. J. Clin. Endocr. Metab. 86: 1921-1924, 2001. [PubMed: 11344185] [Full Text: https://doi.org/10.1210/jcem.86.5.7458]
Kitamura, T., Feng, Y., Kitamura, Y. I., Chua, S. C., Jr., Xu, A. W., Barsh, G. S., Rossetti, L., Accili, D. Forkhead protein FoxO1 mediates Agrp-dependent effects of leptin on food intake. Nature Med. 12: 534-540, 2006. [PubMed: 16604086] [Full Text: https://doi.org/10.1038/nm1392]
Krashes, M. J., Shah, B. P., Madara, J. C., Olson, D. P., Strochlic, D. E., Garfield, A. S., Vong, L., Pei, H., Watabe-Uchida, M., Uchida, N., Liberles, S. D., Lowell, B. B. An excitatory paraventricular nucleus to AgRP neuron circuit that drives hunger. Nature 507: 238-242, 2014. [PubMed: 24487620] [Full Text: https://doi.org/10.1038/nature12956]
Luquet, S., Perez, F. A., Hnasko, T. S., Palmiter, R. D. NPY/AgRP neurons are essential for feeding in adult mice but can be ablated in neonates. Science 310: 683-685, 2005. [PubMed: 16254186] [Full Text: https://doi.org/10.1126/science.1115524]
Marks, D. L., Boucher, N., Lanouette, C.-M., Perusse, L., Brookhart, G., Comuzzie, A. G., Chagnon, Y. C., Cone, R. D. Ala67-to-thr polymorphism in the agouti-related peptide gene is associated with inherited leanness in humans. Am. J. Med. Genet. 126A: 267-271, 2004. [PubMed: 15054840] [Full Text: https://doi.org/10.1002/ajmg.a.20600]
Ollmann, M. M., Wilson, B. D., Yang, Y.-K., Kerns, J. A., Chen, Y., Gantz, I., Barsh, G. S. Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science 278: 135-138, 1997. Note: Erratum: Science 281: 1615 only, 1998. [PubMed: 9311920] [Full Text: https://doi.org/10.1126/science.278.5335.135]
Shutter, J. R., Graham, M., Kinsey, A. C., Scully, S., Luthy, R., Stark, K. L. Hypothalamic expression of ART, a novel gene related to agouti, is up-regulated in obese and diabetic mutant mice. Genes Dev. 11: 593-602, 1997. [PubMed: 9119224] [Full Text: https://doi.org/10.1101/gad.11.5.593]