GHS-R suppression in adipose tissues protects against obesity and insulin resistance by regulating adipose angiogenesis and fibrosis.
GHS-R suppression in adipose tissues protects against obesity and insulin resistance by regulating adipose angiogenesis and fibrosis.
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DOI：
10.1038/s41366-021-00820-7
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发表时间：
2021-07
期刊：
影响因子：
--
通讯作者：
Sun Y
中科院分区：
文献类型：
--
作者：
Lee JH;Fang C;Li X;Wu CS;Noh JY;Ye X;Chapkin RS;Sun K;Sun Y
Ghrelin是一种促食欲激素，通过其受体生长激素促分泌素受体(GHS-R)增加食物摄入量、肥胖和胰岛素抵抗。我们先前已经证明Ghrelin/GHS-R信号在能量稳态调节中具有重要作用，GHS-R的全局缺失通过增加产热来减少肥胖和改善胰岛素敏感性。然而，GHS-R是否直接调节脂肪组织的生热激活尚不清楚。我们建立了一种新的脂肪组织特异性GHS-R缺失小鼠模型，并对正常饮食(RD)和高脂饮食(HFD)喂养的小鼠进行了表征。用EchoMRI测量体成分。用间接量热法测定代谢谱。使用TH-8温度监测系统评估对环境压力的反应。通过血糖和胰岛素耐量试验评估胰岛素敏感性。苏木精-伊红染色和免疫荧光染色进行组织学分析。实时荧光定量聚合酶链式反应分析脂肪组织中与产热、血管生成和纤维化相关基因的表达。在RD喂养下，脂肪组织特异性GHS-R缺失对代谢参数影响很小或没有影响。然而，在高脂饲料喂养下，脂肪组织特异性GHS-R缺失减轻了饮食诱导的肥胖和胰岛素抵抗，显示出更高的体力活动和热量产生。此外，脂肪组织特异性GHS-R缺失增加了脂肪转录调节因子过氧化物酶体增殖物激活受体γ1、脂联素和成纤维细胞生长因子21的表达，并在基因表达和组织学分析中明显地调控了血管生成和纤维化。这些结果表明，GHS-R在脂肪细胞中具有细胞自主作用，抑制脂肪组织中的GHS-R可以通过调节脂肪血管生成和纤维化来保护饮食诱导的肥胖和胰岛素抵抗。这些发现表明，脂肪GHS-R可能成为治疗肥胖和代谢综合征的新靶点。
Ghrelin is an orexigenic hormone that increases food intake, adiposity, and insulin resistance through its receptor Growth Hormone Secretagogue Receptor (GHS-R). We previously showed that ghrelin/GHS-R signaling has important roles in regulation of energy homeostasis, and global deletion of GHS-R reduces obesity and improves insulin sensitivity by increasing thermogenesis. However, it is unknown whether GHS-R regulates thermogenic activation in adipose tissues directly. We generated a novel adipose tissue-specific GHS-R deletion mouse model and characterized the mice under regular diet (RD) and high-fat diet (HFD) feeding. Body composition was measured by EchoMRI. Metabolic profiling was determined by indirect calorimetry. Response to environmental stress was assessed using a TH-8 temperature monitoring system. Insulin sensitivity was evaluated by glucose and insulin tolerance tests. Tissue histology was analyzed by hematoxylin/eosin and immunofluorescent staining. Expression of genes involved in thermogenesis, angiogenesis and fibrosis in adipose tissues were analyzed by real-time PCR. Under RD feeding, adipose tissue-specific GHS-R deletion had little or no impact on metabolic parameters. However, under HFD feeding, adipose tissue-specific GHS-R deletion attenuated diet-induced obesity and insulin resistance, showing elevated physical activity and heat production. In addition, adipose tissue-specific GHS-R deletion increased expression of master adipose transcription regulator of peroxisome proliferator-activated receptor (PPAR) γ1 and adipokines of adiponectin and fibroblast growth factor (FGF) 21; and differentially modulated angiogenesis and fibrosis evident in both gene expression and histological analysis. These results show that GHS-R has cell-autonomous effects in adipocytes, and suppression of GHS-R in adipose tissues protects against diet-induced obesity and insulin resistance by modulating adipose angiogenesis and fibrosis. These findings suggest adipose GHS-R may constitute a novel therapeutic target for treatment of obesity and metabolic syndrome.
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影响因子：
5.2
作者：
Choe SS;Huh JY;Hwang IJ;Kim JI;Kim JB
通讯作者：
Kim JB
影响因子：
2.9
作者：
Keinicke, Helle;Sunz, Gao;Kjaergaard, Marina
通讯作者：
Kjaergaard, Marina
影响因子：
16.2
作者：
Cowley, MA;Smith, RG;Horvath, TL
通讯作者：
Horvath, TL
影响因子：
12.4
作者：
Downes, Nicholas L.;Laham-Karam, Nihay;Yla-Herttuala, Seppo
通讯作者：
Yla-Herttuala, Seppo
DOI：
10.18632/aging.100888
发表时间：
2016-01
期刊：
Aging
影响因子：
--
作者：
Lin L;Lee JH;Buras ED;Yu K;Wang R;Smith CW;Wu H;Sheikh-Hamad D;Sun Y
通讯作者：
Sun Y