Antibody-Mediated Targeting of the FGFR1c Isoform Increases Glucose Uptake in White and Brown Adipose Tissue in Male Mice.
Antibody-Mediated Targeting of the FGFR1c Isoform Increases Glucose Uptake in White and Brown Adipose Tissue in Male Mice.
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DOI：
10.1210/en.2017-00591
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发表时间：
2017-10-01
期刊：
影响因子：
4.8
通讯作者：
Tsintzas K
中科院分区：
文献类型：
--
作者：
Lewis JE;Samms RJ;Cooper S;Luckett JC;Perkins AC;Dunbar JD;Smith DP;Emmerson PJ;Adams AC;Ebling FJP;Tsintzas K
肥胖患病率的增加及其对心脏代谢的影响表明，迫切需要确定能够在这一人群中产生有意义的代谢变化的新的治疗靶点。抗体介导靶向成纤维细胞生长因子受体1c亚型(FGFR1c)已被证明可以改善啮齿动物和非人类灵长类动物的高血糖，并保护其免受饮食和遗传诱导的肥胖。然而，目前还不清楚是哪个组织(S)起到了这种降糖作用。因此，为了阐明这一效应，我们用H7(一种选择性靶向FGFR1c的单抗)治疗正常血糖小鼠，并使用葡萄糖示踪剂(18F-氟代脱氧葡萄糖)进行全身正电子发射计算机断层扫描。H7治疗增加了白色脂肪组织(WAT)、棕色脂肪组织(BAT)、大脑和肝脏的基础葡萄糖摄取量，但减少了股四头肌的葡萄糖摄取量。结果，血糖在治疗后显著降低。在胰岛素刺激的条件下，H7的作用在WAT、BAT、肝脏和肌肉中保持不变。H7处理降低了白色脂肪组织中甘油三酯(TG)的含量，增加了脂肪组织中脂肪TG脂肪酶的含量，同时增加了乙酰辅酶A羧基酶的活性，这表明TGS的无用循环，尽管有利于净水解。我们在体外证明，这是治疗对脂肪组织的直接影响，因为治疗后基础细胞呼吸和葡萄糖摄取增加。综上所述，这些数据表明，抗体介导的FGFR1c靶向主要通过增加脂肪组织中的葡萄糖摄取而发挥其强大的降糖效果。靶向FGFR1c亚型通过增加脂肪组织的摄取来降低血糖。这是治疗的直接效果，似乎导致甘油三酯含量的无效(再)循环。
The increased prevalence of obesity and its cardiometabolic implications demonstrates the imperative to identify novel therapeutic targets able to effect meaningful metabolic changes in this population. Antibody-mediated targeting of fibroblast growth factor receptor 1c isoform (FGFR1c) has been shown to ameliorate hyperglycemia and protect from diet- and genetically-induced obesity in rodents and nonhuman primates. However, it is currently unknown which tissue(s) contribute to this glucose-lowering effect. Thus, to elucidate this effect, we treated euglycemic mice with H7, a monoclonal antibody that selectively targets FGFR1c, and used whole-body positron emission computed tomography with a glucose tracer (18F-fluorodeoxyglucose). Treatment with H7 increased basal glucose uptake in white adipose tissue (WAT), brown adipose tissue (BAT), the brain, and liver but reduced it in the quadriceps muscles. Consequentially, blood glucose was significantly reduced in response to treatment. Under insulin-stimulated conditions, the effects of H7 were maintained in WAT, BAT, liver, and muscle. Treatment with H7 decreased triglyceride (TG) content and increased adipose TG lipase content in white adipose tissue, while increasing activation of acetyl coenzyme A carboxylase, suggesting futile cycling of TGs, albeit favoring net hydrolysis. We demonstrated, in vitro, this is a direct effect of treatment in adipose tissue, as basal cellular respiration and glucose uptake were increased in response to treatment. Taken together, these data suggest that antibody-mediated targeting of FGFR1c exerts its powerful glucose-lowering efficacy primarily due to increased glucose uptake in adipose tissue. Targeting the FGFR1c isoform reduces blood glucose via increased uptake in adipose tissue. This is a direct effect of treatment and appears to lead to a futile (re)cycling of triglyceride content.
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影响因子：
7.2
作者：
Belov AA;Mohammadi M
通讯作者：
Mohammadi M
影响因子：
4
作者：
Samms, Ricardo J.;Murphy, Michelle;Tsintzas, Kostas
通讯作者：
Tsintzas, Kostas
DOI：
10.1152/ajpendo.00089.2006
发表时间：
2007-03-01
影响因子：
5.1
作者：
Sun, Haijun D.;Malabunga, Maria;Kussie, Paul
通讯作者：
Kussie, Paul
影响因子：
5.5
作者：
Tsintzas, Kostas;Jewell, Kirsty;Bennett, Andrew
通讯作者：
Bennett, Andrew
影响因子：
5.5
作者：
Blondin, Denis P.;Labbe, Sebastien M.;Haman, Francois
通讯作者：
Haman, Francois