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刺鼠相关蛋白(刺鼠相关肽AgRP)是大脑内AgRP/NPY神经元产生的神经肽。刺鼠相关肽只在下丘脑中弓状核的腹内侧部分含有NPY的细胞体中合成。
编号:432872
CAS号:
单字母:H2N-LAPMEGIRRPDQALLPELPGLGLRAPLKKTTAEQAEEDLLQEAQALAEVLDLQDREPR-OH
背景
刺鼠相关蛋白(刺鼠相关肽AgRP)是大脑内AgRP/NPY神经元产生的神经肽。刺鼠相关肽只在下丘脑中弓状核的腹内侧部分含有NPY的细胞体中合成。刺鼠相关蛋白主要在肾上腺、丘脑底核和下丘脑中表达,在睾丸、肾和肺中的表达水平相对较低(1)。AgRP具有刺激食欲的作用,这种作用可以被瘦素抑制,被生长素激活。脂肪细胞响应于食物摄取,分泌瘦素。这种激素作用于弓状核,抑制AgRP / NPY神经元释放开胃肽(2)。NPY / AgRP神经元中含有生长素受体,可以刺激NPY和AgRP的分泌,增进食欲。AgRP存储在细胞内的分泌颗粒中,通过可调节的通路进行分泌。AgRP的转录和分泌作用可由炎症信号调节。在禁食期间,AgRP的表达增加。研究发现,AgRP刺激下丘脑-垂体-肾上腺皮质轴释放促肾上腺皮质激素、皮质醇和催乳素。它还增强促肾上腺皮质激素对IL-1β的应答,表明AgRP可能在神经内分泌对炎症的响应中发挥调节作用(3)。
参考文献:
1. Bäckberg M, Madjid N, Ogren SO, Meister B (June 2004). "Down-regulated expression of agouti-related protein (AGRP) mRNA in the hypothalamic arcuate nucleus of hyperphagic and obese tub/tub mice". Brain Res. Mol. Brain Res. 125 (1-2): 129–39.
2. Enriori PJ, Evans AE, Sinnayah P, Jobst EE, Tonelli-Lemos L, Billes SK, Glavas MM, Grayson BE, Perello M, Nillni EA, Grove KL, Cowley MA (March 2007). "Diet-induced obesity causes severe but reversible leptin resistance in arcuate melanocortin neurons". Cell Metabolism 5 (3): 181–94.
3. Xiao E, Xia-Zhang L, Vulliémoz NR, Ferin M, Wardlaw SL (May 2003). "Agouti-related protein stimulates the hypothalamic-pituitary-adrenal (HPA) axis and enhances the HPA response to interleukin-1 inthe primate". Endocrinology 144 (5): 1736–41.
Definition
Agouti-related peptide (AgRP) is a neuropeptide produced in the brain in the arcuate nucleus of the hypothalamus. It is an endogenous antagonist of melanocortin receptors (MC3-R and MC4-R) which plays a critical role in energy balance.
Discovery
It was identified independently by two teams based on sequence similarity with Agouti signalling peptide, a protein synthesized in the skin that controls coat color1,2.
Classification
There are 3 synthetic AgRP fragments in humans, viz AgRP (25-51), AgRP (54-82) and AgRP (83-132). Amino-terminal fragments AgRP (25-51) and (54-82) were devoid of significant antagonist activity, whereas the amidated carboxyl-terminal AGRP fragment (83-132)-NH2 is potently active3.
Structural characteristics
The human AgRP is 132 amino acids in length, and is about 25 percent identical to agouti polypeptide. It contains 11 cysteines, the majority of which are located at the carboxyl terminal end of the polypeptide, and form 5 disulfide bridges4. The C-terminal portion of the peptide (87-132) is believed to be necessary for optimal binding and contains a five fingered spider-toxin motif with an eight amino acid portion mimicking alpha -MSH.
Mode of action
AgRP binds specifically to MC3-R and MC4-R as an inverse agonist. This inverse agonism antagonizes the action of alpha-MSH and also brings down the level of cAMP (secondary messenger) produced in the affected cells.
Functions
The major function of AgRP is to increase appetite and decrease metabolism. It is one of the most potent and longest appetite stimulator. It can used in treatment of obesity and is particularly beneficial in the prevention and treatment of type 2 diabetes5.