Desacetyl-α-melanocyte stimulating hormone and α-melanocyte stimulating hormone are required to regulate energy balance.
Desacetyl-α-melanocyte stimulating hormone and α-melanocyte stimulating hormone are required to regulate energy balance.
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DOI：
10.1016/j.molmet.2017.11.008
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发表时间：
2018-03
影响因子：
8.1
通讯作者：
Elmquist JK
中科院分区：
文献类型：
--
作者：
Mountjoy KG;Caron A;Hubbard K;Shome A;Grey AC;Sun B;Bould S;Middleditch M;Pontré B;McGregor A;Harris PWR;Kowalczyk R;Brimble MA;Botha R;Tan KML;Piper SJ;Buchanan C;Lee S;Coll AP;Elmquist JK
能量平衡的调节依赖于前阿黑皮素（POMC）衍生肽和黑皮质素-4受体（MC 4 R）。α-黑素细胞刺激激素（α-MSH）是预测的天然POMC衍生肽，可调节能量平衡。脱乙酰-α-MSH是α-MSH的前体，存在于脑和血液中。去乙酰基-α-MSH被认为对调节能量平衡不重要，尽管在体外激活食欲调节MC 4 R方面更有效（与α-MSH相比）。因此，脱乙酰基-α-MSH的生理作用仍不清楚。我们建立了一种新的小鼠模型，以确定脱乙酰基-α-MSH是否在调节能量平衡中发挥作用。我们在POMC蛋白切割位点设计了一个敲入靶向QKQR突变，该突变阻断了促肾上腺皮质激素（ACTH 1 -39）产生脱乙酰基-α-MSH和α-MSH。突变型ACTH 1 -39（ACTHQKQR）在体内黑皮质素2受体（MC 2 R）和体外MC 4 R上的功能与天然ACTH 1 -39（ACTHKKRR）相似。雄性和雌性纯合子突变ACTH 1 -39（Pomctm 1/tm 1）小鼠发展特征性黑皮质素肥胖表型。与野生型（WT）（Pomcwt/wt）小鼠相比，在14天内将脱乙酰基-α-MSH或α-MSH置换到Pomctm 1/tm 1小鼠脑中可显著逆转体重和脂肪量增加。在这里，我们确定了脱乙酰基-α-MSH和α-MSH肽作为能量平衡的调节剂，并强调了脱乙酰基-α-MSH以前未被认识到的生理作用。基于这些数据，我们提出有可能利用天然存在的POMC衍生肽来治疗肥胖，但这依赖于首先理解脱乙酰基-α-MSH和α-MSH的特定功能。小鼠POMC裂解位点KKRR → QKQR突变可阻止脱乙酰-α-MSH和α-MSH的产生。雄性和雌性突变小鼠发生特征性黑皮质素肥胖。α-MSH中枢给药在降低雌性突变小鼠体重方面更有效。在雄性突变小鼠中，去乙酰基-α-MSH和α-MSH的中枢给药在降低体重方面具有相似的效力。
Regulation of energy balance depends on pro-opiomelanocortin (POMC)-derived peptides and melanocortin-4 receptor (MC4R). Alpha-melanocyte stimulating hormone (α-MSH) is the predicted natural POMC-derived peptide that regulates energy balance. Desacetyl-α-MSH, the precursor for α-MSH, is present in brain and blood. Desacetyl-α-MSH is considered to be unimportant for regulating energy balance despite being more potent (compared with α-MSH) at activating the appetite-regulating MC4R in vitro. Thus, the physiological role for desacetyl-α-MSH is still unclear. We created a novel mouse model to determine whether desacetyl-α-MSH plays a role in regulating energy balance. We engineered a knock in targeted QKQR mutation in the POMC protein cleavage site that blocks the production of both desacetyl-α-MSH and α-MSH from adrenocorticotropin (ACTH1-39). The mutant ACTH1-39 (ACTHQKQR) functions similar to native ACTH1-39 (ACTHKKRR) at the melanocortin 2 receptor (MC2R) in vivo and MC4R in vitro. Male and female homozygous mutant ACTH1-39 (Pomctm1/tm1) mice develop the characteristic melanocortin obesity phenotype. Replacement of either desacetyl-α-MSH or α-MSH over 14 days into Pomctm1/tm1 mouse brain significantly reverses excess body weight and fat mass gained compared to wild type (WT) (Pomcwt/wt) mice. Here, we identify both desacetyl-α-MSH and α-MSH peptides as regulators of energy balance and highlight a previously unappreciated physiological role for desacetyl-α-MSH. Based on these data we propose that there is potential to exploit the naturally occurring POMC-derived peptides to treat obesity but this relies on first understanding the specific function(s) for desacetyl-α-MSH and α-MSH. KKRR → QKQR mutation in the cleavage site of POMC prevents the production of desacetyl-α-MSH and α-MSH in mice. Male and female mutant mice develop characteristic melanocortin obesity. Central administration of α-MSH is more potent at reducing body weight in female mutant mice. Central administration of desacetyl-α-MSH and α-MSH are similarly potent at reducing body weight in male mutant mice.
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Melanocortin-4 受体调节的能量稳态。
影响因子：
25
作者：
Krashes MJ;Lowell BB;Garfield AS
通讯作者：
Garfield AS
影响因子：
8.1
作者：
Burke LK;Doslikova B;D'Agostino G;Greenwald-Yarnell M;Georgescu T;Chianese R;Martinez de Morentin PB;Ogunnowo-Bada E;Cansell C;Valencia-Torres L;Garfield AS;Apergis-Schoute J;Lam DD;Speakman JR;Rubinstein M;Low MJ;Rochford JJ;Myers MG;Evans ML;Heisler LK
通讯作者：
Heisler LK
影响因子：
2.8
作者：
Gelez, Helene;Poirier, Sarah;Giuliano, Francois
通讯作者：
Giuliano, Francois
影响因子：
30.8
作者：
Krude, H;Biebermann, H;Grüters, A
通讯作者：
Grüters, A
影响因子：
4.8
作者：
Appleyard, SM;Hayward, M;Low, MJ
通讯作者：
Low, MJ