USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
Department of Marine Bio and Medical Sciences, Hanseo University, Seosan, Korea.
Int J Obes (Lond). 2021 Jul;45(7):1565-1575. doi: 10.1038/s41366-021-00820-7. Epub 2021 Apr 26.
BACKGROUND/OBJECTIVES: 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 Echo MRI. 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.
背景/目的：Ghrelin 是一种食欲激素，通过其受体生长激素促分泌素受体（GHS-R）增加食物摄入、肥胖和胰岛素抵抗。我们之前的研究表明，ghrelin/GHS-R 信号在调节能量平衡方面起着重要作用，而 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，尚不清楚 GHS-R 是否直接调节脂肪组织中的产热激活。
我们构建了一种新型脂肪组织特异性 GHS-R 缺失小鼠模型，并在常规饮食（RD）和高脂肪饮食（HFD）喂养条件下对其进行了特征描述。采用 Echo MRI 测量身体成分。通过间接热量法测定代谢谱。使用 TH-8 温度监测系统评估对环境应激的反应。通过葡萄糖和胰岛素耐量试验评估胰岛素敏感性。通过苏木精/伊红和免疫荧光染色分析组织学。通过实时 PCR 分析脂肪组织中与产热、血管生成和纤维化相关的基因表达。
在 RD 喂养下，脂肪组织特异性 GHS-R 缺失对代谢参数几乎没有影响。然而，在 HFD 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，表现为体力活动和产热量增加。此外，脂肪组织特异性 GHS-R 缺失增加了过氧化物酶体增殖物激活受体（PPAR）γ1 的主要脂肪转录调节因子和脂联素和成纤维细胞生长因子（FGF）21 等脂肪细胞因子的表达；并通过基因表达和组织学分析显示，血管生成和纤维化的差异调节。
这些结果表明，GHS-R 在脂肪细胞中有细胞自主效应，而脂肪组织中 GHS-R 的抑制通过调节脂肪组织的血管生成和纤维化，可预防饮食诱导的肥胖和胰岛素抵抗。这些发现表明脂肪 GHS-R 可能成为治疗肥胖症和代谢综合征的新型治疗靶点。
