Activating Connexin43 gap junctions primes adipose tissue for therapeutic intervention.
Activating Connexin43 gap junctions primes adipose tissue for therapeutic intervention.
复制标题
激活连接蛋白43间隙连接为治疗性干预准备脂肪组织。
DOI：
10.1016/j.apsb.2022.02.020
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发表时间：
2022-07
影响因子：
14.5
通讯作者：
Scherer, Philipp E.
中科院分区：
文献类型：
--
作者：
Zhu, Yi;Li, Na;Huang, Mingyang;Chen, Xi;An, Yu A.;Li, Jianping;Zhao, Shangang;Funcke, Jan-Bernd;Cao, Jianhong;He, Zhenyan;Zhu, Qingzhang;Zhang, Zhuzhen;Wang, Zhao, V;Xu, Lin;Williams, Kevin W.;Li, Chien;Grove, Kevin;Scherer, Philipp E.
关键词：
脂肪组织是治疗肥胖和代谢性疾病的一个有前途的靶点。然而，药理学试剂通常不能有效地接合脂肪细胞，由于它们非常大的尺寸和不足的血管化，特别是在肥胖受试者中。我们以前已经表明，在冷暴露期间，连接蛋白43（Cx43）间隙连接被诱导和激活，以连接相邻的脂肪细胞，从而在多个细胞之间共享有限的交感神经元输入。我们认为，同样的机制可以用来提高针对脂肪组织的各种药物的疗效。使用脂肪组织特异性Cx43过表达小鼠模型，我们证明了连接脂肪细胞以增强β3-肾上腺素能受体激动剂Mirabegron和FGF 21的代谢功效的有效性。此外，将这些分子与Cx43间隙连接通道激活剂达奈肽组合显示出类似的增强功效。鉴于这些发现，我们提出了一个模型，其中连接脂肪细胞通过Cx43缝隙连接通道启动脂肪组织的药理学代理设计engage it. Thus，Cx43缝隙连接激活剂具有很大的潜力，与其他药物靶向脂肪组织的组合。肥大的脂肪细胞是药物干预难治的。增强连接蛋白43间隙连接通道促进来自治疗剂的信号的传播，从而重新实现脂肪组织的有效靶向。
Adipose tissue is a promising target for treating obesity and metabolic diseases. However, pharmacological agents usually fail to effectively engage adipocytes due to their extraordinarily large size and insufficient vascularization, especially in obese subjects. We have previously shown that during cold exposure, connexin43 (Cx43) gap junctions are induced and activated to connect neighboring adipocytes to share limited sympathetic neuronal input amongst multiple cells. We reason the same mechanism may be leveraged to improve the efficacy of various pharmacological agents that target adipose tissue. Using an adipose tissue-specific Cx43 overexpression mouse model, we demonstrate effectiveness in connecting adipocytes to augment metabolic efficacy of the β3-adrenergic receptor agonist Mirabegron and FGF21. Additionally, combing those molecules with the Cx43 gap junction channel activator danegaptide shows a similar enhanced efficacy. In light of these findings, we propose a model in which connecting adipocytes via Cx43 gap junction channels primes adipose tissue to pharmacological agents designed to engage it. Thus, Cx43 gap junction activators hold great potential for combination with additional agents targeting adipose tissue. Hypertrophied adipocytes are refractory to pharmaceutical intervention. Enhancing the Connexin43 gap junction channel facilitates the dissemination of signals from therapeutic agents and thus re-enables efficient targeting of adipose tissue.
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影响因子：
4.6
作者：
Lewis JE;Samms RJ;Cooper S;Luckett JC;Perkins AC;Adams AC;Tsintzas K;Ebling FJP
通讯作者：
Ebling FJP
影响因子：
5.8
作者：
Burke, Shoshana;Nagajyothi, Fnu;Spray, David C.
通讯作者：
Spray, David C.
影响因子：
29
作者：
Holland WL;Adams AC;Brozinick JT;Bui HH;Miyauchi Y;Kusminski CM;Bauer SM;Wade M;Singhal E;Cheng CC;Volk K;Kuo MS;Gordillo R;Kharitonenkov A;Scherer PE
通讯作者：
Scherer PE
影响因子：
29
作者：
Cypess AM;Weiner LS;Roberts-Toler C;Franquet Elía E;Kessler SH;Kahn PA;English J;Chatman K;Trauger SA;Doria A;Kolodny GM
通讯作者：
Kolodny GM
DOI：
10.1073/pnas.1006962107
发表时间：
2010-07-13
影响因子：
11.1
作者：
Chau, Mary D. L.;Gao, Jiaping;Gromada, Jesper
通讯作者：
Gromada, Jesper