LEAP2 deletion in mice enhances ghrelin's actions as an orexigen and growth hormone secretagogue.
LEAP2 deletion in mice enhances ghrelin's actions as an orexigen and growth hormone secretagogue.
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小鼠体内 LEAP2 缺失增强了 ghrelin 作为食欲原和生长激素促分泌素的作用。
DOI：
10.1016/j.molmet.2021.101327
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发表时间：
2021-11
影响因子：
8.1
通讯作者：
Zigman JM
中科院分区：
文献类型：
--
作者：
Shankar K;Metzger NP;Singh O;Mani BK;Osborne-Lawrence S;Varshney S;Gupta D;Ogden SB;Takemi S;Richard CP;Nandy K;Liu C;Zigman JM
肝脏表达的抗菌肽2（LEAP 2）是最近发现的生长激素促分泌素受体（GHSR）的拮抗剂和反向激动剂。GHSR的另一个众所周知的内源性配体酰基-生长激素释放肽增加食物摄入量，体重和GH分泌，在肥胖症中降低，但在禁食时升高。相比之下，LEAP 2减少酰基-生长激素释放肽诱导的食物摄入和GH分泌，并且发现在肥胖症中升高，但在禁食时降低。因此，血浆LEAP 2/酰基-ghrelin摩尔比可能是响应于体重和进食状态的变化而调节GHSR信号传导的关键决定因素。特别地，LEAP 2可以用于在肥胖的情况下抑制酰基-生长素释放肽作用，这与生长素释放肽抗性相关。在这里，我们试图确定遗传LEAP 2缺失的代谢效应。我们产生了第一个已知的LEAP2-KO小鼠系。s.c.后不同脑区的食物摄入、GH分泌和细胞活化（c-fos诱导）测定了LEAP 2-KO小鼠和野生型同窝仔中的酰基-生长素释放肽给药。在16周的高脂肪饮食和/或标准食物喂养的过程中，对LEAP 2-KO小鼠和野生型同窝小鼠进行一系列测试（例如体重、食物摄入和身体组成的测量;间接量热法，运动活性的测定，以及在代谢笼中饲养时的膳食模式）。在来自这些小鼠的苏木精和伊红染色和油红0染色的肝切片中评估脂肪积累。LEAP 2-KO小鼠对s.c.胃饥饿素特别是，在标准饲料喂养的LEAP 2-KO小鼠中，0.5 mg/kg BW剂量的酰基-ghrelin急性刺激摄食量，而野生型同窝小鼠需要2倍更高的剂量。此外，在高脂饮食喂养的LEAP 2-KO小鼠中，酰基-ghrelin以1 mg/kg BW的剂量刺激食物摄入，而在野生型同窝出生的小鼠中，甚至10倍的高剂量也无效。与野生型同窝小鼠相比，酰基-ghrelin诱导LEAP 2-KO小鼠的血浆GH水平升高90.9%，弓状核和嗅球中c-fos免疫反应阳性细胞的数量分别增加77.2 - 119.7%。与野生型同窝仔相比，LEAP 2缺失使长期高脂饮食雌性动物的体重（15.0%）、摄食量（18.4%）、瘦体重（6.1%）、肝脂肪（42.1%）和体长（1.7%）增加。在高脂饮食仅4周后，雌性LEAP 2-KO小鼠在黑暗期的第一部分表现出比野生型同窝小鼠更低的O2消耗量（13%），产热量（9.5%）和运动活动（49%）。在高脂饮食暴露的雄性或长期暴露于标准饲料的雌性和雄性小鼠中未观察到这些基因型依赖性差异。LEAP 2缺失使瘦小鼠和肥胖小鼠对施用酰基-生长激素释放肽对食物摄入和GH分泌的急性作用敏感。LEAP2缺失增加了长期喂食高脂肪饮食的雌性动物的体重，这是由于能量消耗降低、运动活动减少和食物摄入增加。此外，在雌性小鼠中，LEAP 2缺失增加了体长，并夸大了通常与慢性高脂饮食喂养相关的肝脏脂肪积累。产生了LEAP 2敲除小鼠的新品系。LEAP 2缺失使小鼠对施用的ghrelin的GH分泌作用敏感。LEAP2缺失降低饮食诱导的肥胖小鼠的ghrelin抵抗HFD喂养的雌性LEAP 2-KO小鼠吃得更多，体重和肝脏脂肪增加更多。HFD喂养的雌性LEAP 2-KO小鼠表现出较低的能量消耗和活动。
The hormone liver-expressed antimicrobial peptide-2 (LEAP2) is a recently identified antagonist and an inverse agonist of the growth hormone secretagogue receptor (GHSR). GHSR's other well-known endogenous ligand, acyl-ghrelin, increases food intake, body weight, and GH secretion and is lowered in obesity but elevated upon fasting. In contrast, LEAP2 reduces acyl-ghrelin-induced food intake and GH secretion and is found elevated in obesity but lowered upon fasting. Thus, the plasma LEAP2/acyl-ghrelin molar ratio could be a key determinant modulating GHSR signaling in response to changes in body mass and feeding status. In particular, LEAP2 may serve to dampen acyl-ghrelin action in the setting of obesity, which is associated with ghrelin resistance. Here, we sought to determine the metabolic effects of genetic LEAP2 deletion. We generated the first known LEAP2-KO mouse line. Food intake, GH secretion, and cellular activation (c-fos induction) in different brain regions following s.c. acyl-ghrelin administration in LEAP2-KO mice and wild-type littermates were determined. LEAP2-KO mice and wild-type littermates were submitted to a battery of tests (such as measurements of body weight, food intake, and body composition; indirect calorimetry, determination of locomotor activity, and meal patterning while housed in metabolic cages) over the course of 16 weeks of high-fat diet and/or standard chow feeding. Fat accumulation was assessed in hematoxylin & eosin-stained and oil red O-stained liver sections from these mice. LEAP2-KO mice were more sensitive to s.c. ghrelin. In particular, acyl-ghrelin acutely stimulated food intake at a dose of 0.5 mg/kg BW in standard chow-fed LEAP2-KO mice while a 2× higher dose was required by wild-type littermates. Also, acyl-ghrelin stimulated food intake at a dose of 1 mg/kg BW in high-fat diet-fed LEAP2-KO mice while not even a 10× higher dose was effective in wild-type littermates. Acyl-ghrelin induced a 90.9% higher plasma GH level and 77.2–119.7% higher numbers of c-fos-immunoreactive cells in the arcuate nucleus and olfactory bulb, respectively, in LEAP2-KO mice than in wild-type littermates. LEAP2 deletion raised body weight (by 15.0%), food intake (by 18.4%), lean mass (by 6.1%), hepatic fat (by 42.1%), and body length (by 1.7%) in females on long-term high-fat diet as compared to wild-type littermates. After only 4 weeks on the high-fat diet, female LEAP2-KO mice exhibited lower O2 consumption (by 13%), heat production (by 9.5%), and locomotor activity (by 49%) than by wild-type littermates during the first part of the dark period. These genotype-dependent differences were not observed in high-fat diet-exposed males or female and male mice exposed for long term to standard chow diet. LEAP2 deletion sensitizes lean and obese mice to the acute effects of administered acyl-ghrelin on food intake and GH secretion. LEAP2 deletion increases body weight in females chronically fed a high-fat diet as a result of lowered energy expenditure, reduced locomotor activity, and increased food intake. Furthermore, in female mice, LEAP2 deletion increases body length and exaggerates the hepatic fat accumulation normally associated with chronic high-fat diet feeding. A novel line of LEAP2-knockout mice was generated. LEAP2 deletion sensitizes mice to the GH secretory effects of administered ghrelin. LEAP2 deletion reduces ghrelin resistance in diet-induced obese mice. HFD-fed female LEAP2-KO mice eat more and gain more body weight and hepatic fat. HFD-fed female LEAP2-KO mice exhibit lowered energy expenditure and activity.
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影响因子：
4.8
作者：
Li, Robert Lin;Sherbet, Daniel P.;Zhao, Tong-Jin
通讯作者：
Zhao, Tong-Jin
影响因子：
5.8
作者：
Fittipaldi, Antonela S.;Hernandez, Julieta;Perello, Mario
通讯作者：
Perello, Mario
影响因子：
5.9
作者：
Francisco, Vera;Tovar, Sulay;Gualillo, Oreste
通讯作者：
Gualillo, Oreste
Ghrelin 通过激活 mTOR-PPAR gamma 信号通路促进肝脏脂肪生成
DOI：
10.1073/pnas.1411571111
发表时间：
2014-09-09
影响因子：
11.1
作者：
Li, Ziru;Xu, Geyang;Zhang, Weizhen
通讯作者：
Zhang, Weizhen
影响因子：
4.3
作者：
Howard, Alison;Townes, Claire;Hall, Judith
通讯作者：
Hall, Judith