Agouti-related peptide

From WikiMD free medical encyclopedia
Jump to: navigation, search

Template:PBB Template:Pfam box

Agouti-related protein also called Agouti-related peptide (AgRP) is a neuropeptide produced in the brain by the AgRP/NPY neuron. It is only synthesised in NPY-containing cell bodies located in the ventromedial part of the arcuate nucleus in the hypothalamus.[1] AgRP is co-expressed with Neuropeptide Y and works by increasing appetite and decreasing 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 signalling molecule made up of 132 amino acids. It was independently identified by two teams in 1997 based on its sequence similarity with Agouti signalling peptide (ASIP), a protein synthesised in the skin that controls coat colour.[2][3] AgRP is approximately 25% identical to ASIP. The murine homologue of AgRP is made up of 131 amino acids and shares 81% amino acid identity with the human protein. Biochemical studies indicate AgRP is 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 is mapped to human chromosome 16q22 and 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]

Mechanism

AGRP has been demonstrated to be an inverse agonist of melanocortin receptors, to be specific 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.[10] 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.[11] 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.[12]

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.[10]

Role in Obesity

AgRP induces obesity by chronic antagonism of the MC4-R.[13] Overexpression of AgRP in transgenic mice (or intracerebroventricular injection) causes hyperphagia and obesity,[14] whilst AgRP plasma levels have been found to be elevated in obese human males.[15] 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[16] as well as obesity. Some studies suggest that inadequate signalling of AgRP during stress may result in binge eating. Recent studies have shown that autophagy plays a key role in regulation of food intake and energy balance in maintaning neuronal AgRP levels.[17]

Human proteins containing this domain

AGRP; ASIP

See also

References

  1. 2.0 2.1
  2. 3.0 3.1
  3. Template:Cite PMID
  4. 10.0 10.1
  5. Kaushik S, Rodriguez-Navarro JA, Arias E, Kiffin R, Sahu S, Schwartz GJ, Cuervo AM, Singh R. Autophagy in hypothalamic AgRP neurons regulates food intake and energy balance. Cell Metab. 2011 Aug 3;14(2):173-83. PMID 21803288

Further reading

Template:Refbegin

Template:Refend

External links

Template:PDB Gallery Template:Intercellular signaling peptides and proteins Template:Neuropeptidergics Template:Orexigenics

WikiMD Sponsors - W8MD Weight Loss, Sleep and MedSpa Centers

Pronounced weightMD, our state of the art W8MD weight loss, sleep, holistic IV nutrition and aesthetic medicine programs can help you not only to lose weight, and sleep better but also look your best! Since its inception in 2011, W8MD’s insurance physician weight loss program has successfully helped thousands of patients.

W8MD Weight Loss

W8MD’s Physician weight loss is unique in many ways with a comprehensive multidisciplinary approach to weight loss. Weight Loss Success Stories....

W8MD Sleep Services

Sleep medicine program uses state of the art technology to diagnose and treat over 80 different sleep disorders. W8MD Sleep Services…

W8MD Medical Aesthetic Services

Medical aesthetic program offers a wide variety of advanced laser skin treatments including oxygen super facials, photofacials and Affordable Botox. W8MD Aesthetic Services…

IM and IV nutrition therapy includes booster shots for B12, vitamin B complex, Vitamin C, Detox treatments and IV nutrition therapy. W8MD IV Nutrition…

W8MD weight loss | Philadelphia medical weight loss | NYC medical weight loss | NJ medical weight loss

W8MD Weight Loss, Sleep & Medical Aesthetics

Intro to W8MD Weight Loss, Sleep & Medical Aesthetics


Disclaimer: The entire contents of WIKIMD.ORG are for informational purposes only and do not render medical advice or professional services. If you have a medical emergency, you should CALL 911 immediately! Given the nature of the wiki, the information provided may not be accurate and or incorrect. Use the information on this wiki at your own risk! See full Disclaimers.WikiMD is supported by W8MD Weight loss, Poly-Tech Sleep & Medical Aesthetic Centers of America.