Biology:Agouti-related peptide

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Short description: Mammalian protein found in Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example


Agouti-related protein (AgRP), also called agouti-related peptide, is a neuropeptide produced in the brain by the AgRP/NPY neuron. It is synthesized in neuropeptide Y (NPY)-containing cell bodies located in the ventromedial part of the arcuate nucleus in the hypothalamus.[1] AgRP is co-expressed with NPY and acts to increase appetite and decrease metabolism and energy expenditure. It is one of the most potent and long-lasting of appetite stimulators. In humans, the agouti-related peptide is encoded by the AGRP gene.[2][3]

Structure

AgRP is a paracrine signaling molecule made of 112 amino acids (the gene product of 132 amino acids is processed by removal of the N-terminal 20-residue signal peptide domain). It was independently identified by two teams in 1997 based on its sequence similarity with agouti signalling peptide (ASIP), a protein synthesized in the skin controlling coat colour.[2][3] AgRP is approximately 25% identical to ASIP. The murine homologue of AgRP consists of 111 amino acids (precursor is 131 amino acids) and shares 81% amino acid identity with the human protein. Biochemical studies indicate AgRP to be very stable to thermal denaturation and acid degradation. Its secondary structure consists mainly of random coils and β-sheets[4] that fold into an inhibitor cystine knot motif.[5] AGRP maps to human chromosome 16q22 and Agrp to mouse chromosome 8D1-D2.

Function

Agouti-related protein is expressed primarily in the adrenal gland, subthalamic nucleus, and hypothalamus, with lower levels of expression in the testis, kidneys, and lungs. The appetite-stimulating effects of AgRP are inhibited by the hormone leptin and activated by the hormone ghrelin. Adipocytes secrete leptin in response to food intake. This hormone acts in the arcuate nucleus and inhibits the AgRP/NPY neuron from releasing orexigenic peptides.[6] Ghrelin has receptors on NPY/AgRP neurons that stimulate the secretion of NPY and AgRP to increase appetite. AgRP is stored in intracellular secretory granules and is secreted via a regulated pathway.[7] The transcriptional and secretory action of AgRP is regulated by inflammatory signals.[8] Levels of AgRP are increased during periods of fasting. It has been found that AgRP stimulates the hypothalamic-pituitary-adrenocortical axis to release ACTH, cortisol and prolactin. It also enhances the ACTH response to IL-1-beta, suggesting it may play a role in the modulation of neuroendocrine response to inflammation.[9] Conversely, AgRP-secreting neurons inhibit the release of TRH from the paraventricular nucleus (PVN), which may contribute to conservation of energy in starvation.[10] This pathway is part of a feedback loop, since TRH-secreting neurons from PVN stimulate AgRP neurons.[11]

Mechanism

AGRP has been demonstrated to be a competitive antagonist of melanocortin receptors, specifically MC3-R and MC4-R. The melanocortin receptors, MC3-R and MC4-R, are directly linked to metabolism and body weight control. These receptors are activated by the peptide hormone α-MSH (melanocyte-stimulating hormone) and antagonized by the agouti-related protein.[12] Whereas α-MSH acts broadly on most members of the MCR family (with the exception of MC2-R), AGRP is highly specific for only MC3-R and MC4-R. This inverse agonism not only antagonizes the action of melanocortin agonists such as α-MSH but also further decreases the cAMP produced by the affected cells. The exact mechanism by which AgRP inhibits melanocortin-receptor signalling is not completely clear. It has been suggested that Agouti-related protein binds MSH receptors and acts as a competitive antagonist of ligand binding.[13] Studies of Agouti protein in B16 melanoma cells supported this logic. The expression of AgRP in the adrenal gland is regulated by glucocorticoids. The protein blocks α-MSH-induced secretion of corticosterone.[14]

History

Orthologs of AgRP, ASIP, MCIR, and MC4R have been found in mammalian, teleost fish, and avian genomes. This suggests that the agouti-melanocortin system evolved by gene duplication from individual ligand and receptor genes in the last 500 million years.[12]

Role in obesity

AgRP induces obesity by chronic antagonism of the MC4-R.[15] Overexpression of AgRP in transgenic mice (or intracerebroventricular injection) causes hyperphagia and obesity,[16] whilst AgRP plasma levels have been found to be elevated in obese human males.[17] Understanding the role AgRP plays in weight gain may assist in developing pharmaceutical models for treating obesity. AgRP mRNA levels have been found to be down regulated following an acute stressful event. Studies suggest that systems involved in the regulation of stress response and of energy balance are highly integrated. Loss or gain of AgRP function may result in inadequate adaptive behavioural responses to environmental events, such as stress, and have potential to contribute to the development of eating disorders. It has been shown that polymorphisms in the AgRP gene have been linked with anorexia nervosa[18] as well as obesity. Some studies suggest that inadequate signalling of AgRP during stress may result in binge eating. Starvation-induced hypothalamic autophagy generates free fatty acids, which in turn regulate neuronal AgRP levels.[19]

Agouti protein
1mr0.png
Identifiers
SymbolAgouti
PfamPF05039
Pfam clanCL0083
InterProIPR007733
PROSITEPDOC60024
SCOP21hyk / SCOPe / SUPFAM
OPM superfamily112
OPM protein1mr0

Role in hunger circuitry

According to Mark L. Andermann and Bradford B. Lowell: "...AgRP neurons and the wiring diagram within which they operate can be viewed as the physical embodiment of the intervening variable, hunger."[20] Stimulation of neurons expressing AgRP can induce robust feeding behavior in mice that will trigger: increased food consumption,[21] increased willingness to work for food,[22] and increased investigation of food odors.[23]

Despite this, AgRP neurons are rapidly inhibited upon food presentation and the onset of eating.[24] One mechanism which may account for this discrepancy is the fact that AgRP neurons signal with Neuropeptide Y in order to allow for sustained feeding behavior that outlasts the activation of the neurons.[25]

AgRP neurons are also sensitive to satiety and hunger hormonal signals. One is an appetite stimulant, ghrelin which makes AgRP neurons more excitable through interactions with specialized ghrelin receptors.[26] Another is a satiety signal, leptin, which modulates AgRP activity through inwardly rectifying potassium channels, which alter the excitability of the neurons.[27] Leptin can also decrease the ability of AgRP neurons to carry out other physiological functions, such as triggering Long Term Potentiation of adjacent neurons.[28]

Although AgRP neurons can drive many different phases of feeding behavior, separate AgRP neurons project to different areas of the brain, demonstrating a parallel organizational structure.[29] This is evidenced by different projections of AgRP neurons to various areas of the brain driving different food related behaviors; for example, certain projections will promote increased food consumption, but not increased food odor investigation.[23]

Human proteins containing this domain

AGRP; ASIP

See also

References

  1. ↑ "Down-regulated expression of agouti-related protein (AGRP) mRNA in the hypothalamic arcuate nucleus of hyperphagic and obese tub/tub mice". Brain Research. Molecular Brain Research 125 (1–2): 129–39. June 2004. doi:10.1016/j.molbrainres.2004.03.012. PMID 15193430. 
  2. ↑ 2.0 2.1 "Hypothalamic expression of ART, a novel gene related to agouti, is up-regulated in obese and diabetic mutant mice". Genes & Development 11 (5): 593–602. March 1997. doi:10.1101/gad.11.5.593. PMID 9119224. 
  3. ↑ 3.0 3.1 "Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein". Science 278 (5335): 135–8. October 1997. doi:10.1126/science.278.5335.135. PMID 9311920. 
  4. ↑ "Biochemical, biophysical, and pharmacological characterization of bacterially expressed human agouti-related protein". Biochemistry 37 (46): 16041–52. November 1998. doi:10.1021/bi981027m. PMID 9819197. 
  5. ↑ "Design, pharmacology, and NMR structure of a minimized cystine knot with agouti-related protein activity". Biochemistry 41 (24): 7565–72. June 2002. doi:10.1021/bi012000x. PMID 12056887. 
  6. ↑ "Diet-induced obesity causes severe but reversible leptin resistance in arcuate melanocortin neurons". Cell Metabolism 5 (3): 181–94. March 2007. doi:10.1016/j.cmet.2007.02.004. PMID 17339026. 
  7. ↑ "Agouti-related protein is posttranslationally cleaved by proprotein convertase 1 to generate agouti-related protein (AGRP)83-132: interaction between AGRP83-132 and melanocortin receptors cannot be influenced by syndecan-3". Endocrinology 147 (4): 1621–31. April 2006. doi:10.1210/en.2005-1373. PMID 16384863. 
  8. ↑ "Regulation of agouti-related protein messenger ribonucleic acid transcription and peptide secretion by acute and chronic inflammation". Endocrinology 149 (10): 4837–45. October 2008. doi:10.1210/en.2007-1680. PMID 18583425. 
  9. ↑ "Agouti-related protein stimulates the hypothalamic-pituitary-adrenal (HPA) axis and enhances the HPA response to interleukin-1 in the primate". Endocrinology 144 (5): 1736–41. May 2003. doi:10.1210/en.2002-220013. PMID 12697678. 
  10. ↑ "Regulation of the hypothalamic thyrotropin releasing hormone (TRH) neuron by neuronal and peripheral inputs". Frontiers in Neuroendocrinology 31 (2): 134–56. April 2010. doi:10.1016/j.yfrne.2010.01.001. PMID 20074584. 
  11. ↑ "An excitatory paraventricular nucleus to AgRP neuron circuit that drives hunger". Nature 507 (7491): 238–42. March 2014. doi:10.1038/nature12956. PMID 24487620. Bibcode: 2014Natur.507..238K. 
  12. ↑ 12.0 12.1 "Structural and molecular evolutionary analysis of Agouti and Agouti-related proteins". Chemistry & Biology 13 (12): 1297–305. December 2006. doi:10.1016/j.chembiol.2006.10.006. PMID 17185225. 
  13. ↑ "Interaction of Agouti protein with the melanocortin 1 receptor in vitro and in vivo". Genes & Development 12 (3): 316–30. February 1998. doi:10.1101/gad.12.3.316. PMID 9450927. 
  14. ↑ "Agouti-related protein has an inhibitory paracrine role in the rat adrenal gland". Biochemical and Biophysical Research Communications 301 (1): 102–7. January 2003. doi:10.1016/S0006-291X(02)02991-1. PMID 12535647. 
  15. ↑ "Targeted disruption of the melanocortin-4 receptor results in obesity in mice". Cell 88 (1): 131–41. January 1997. doi:10.1016/S0092-8674(00)81865-6. PMID 9019399. 
  16. ↑ "Overexpression of Agrt leads to obesity in transgenic mice". Nature Genetics 17 (3): 273–4. November 1997. doi:10.1038/ng1197-273. PMID 9354787. 
  17. ↑ "Plasma levels of agouti-related protein are increased in obese men". The Journal of Clinical Endocrinology and Metabolism 86 (5): 1921–4. May 2001. doi:10.1210/jcem.86.5.7458. PMID 11344185. 
  18. ↑ "Association between an agouti-related protein gene polymorphism and anorexia nervosa". Molecular Psychiatry 6 (3): 325–8. May 2001. doi:10.1038/sj.mp.4000854. PMID 11326303. 
  19. ↑ "Autophagy in hypothalamic AgRP neurons regulates food intake and energy balance". Cell Metabolism 14 (2): 173–83. August 2011. doi:10.1016/j.cmet.2011.06.008. PMID 21803288. 
  20. ↑ "Toward a Wiring Diagram Understanding of Appetite Control". Neuron 95 (4): 757–778. August 2017. doi:10.1016/j.neuron.2017.06.014. PMID 28817798. 
  21. ↑ "AGRP neurons are sufficient to orchestrate feeding behavior rapidly and without training". Nature Neuroscience 14 (3): 351–5. March 2011. doi:10.1038/nn.2739. PMID 21209617. 
  22. ↑ "Rapid, reversible activation of AgRP neurons drives feeding behavior in mice". The Journal of Clinical Investigation 121 (4): 1424–8. April 2011. doi:10.1172/JCI46229. PMID 21364278. 
  23. ↑ 23.0 23.1 "Hunger enhances food-odour attraction through a neuropeptide Y spotlight". Nature 592 (7853): 262–266. April 2021. doi:10.1038/s41586-021-03299-4. PMID 33658716. Bibcode: 2021Natur.592..262H. 
  24. ↑ "Sensory detection of food rapidly modulates arcuate feeding circuits". Cell 160 (5): 829–841. February 2015. doi:10.1016/j.cell.2015.01.033. PMID 25703096. 
  25. ↑ "Sustained NPY signaling enables AgRP neurons to drive feeding". eLife 8: e46348. April 2019. doi:10.7554/eLife.46348. PMID 31033437. 
  26. ↑ "Arcuate AgRP neurons mediate orexigenic and glucoregulatory actions of ghrelin". Molecular Metabolism 3 (1): 64–72. February 2014. doi:10.1016/j.molmet.2013.10.001. PMID 24567905. 
  27. ↑ "Leptin modulates the intrinsic excitability of AgRP/NPY neurons in the arcuate nucleus of the hypothalamus". The Journal of Neuroscience 34 (16): 5486–96. April 2014. doi:10.1523/JNEUROSCI.4861-12.2014. PMID 24741039. 
  28. ↑ "AgRP neurons trigger long-term potentiation and facilitate food seeking". Translational Psychiatry 11 (1): 11. January 2021. doi:10.1038/s41398-020-01161-1. PMID 33414382. 
  29. ↑ "Parallel, redundant circuit organization for homeostatic control of feeding behavior". Cell 155 (6): 1337–50. December 2013. doi:10.1016/j.cell.2013.11.002. PMID 24315102. 

Further reading

External links



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