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
Touchstone Diabetes Center, Department of Internal Medicine, the University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Acta Pharm Sin B. 2022 Jul;12(7):3063-3072. doi: 10.1016/j.apsb.2022.02.020. Epub 2022 Feb 26.
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 -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 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.
脂肪组织是治疗肥胖症和代谢性疾病的一个有前景的靶点。然而，由于脂肪细胞体积异常大且血管化不足，药物通常无法有效地作用于脂肪细胞，尤其是在肥胖个体中。我们之前已经表明，在冷暴露期间，连接蛋白43（Cx43）间隙连接被诱导并激活，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输入。我们推断，同样的机制可用于提高各种靶向脂肪组织的药物的疗效。使用脂肪组织特异性Cx43过表达小鼠模型，我们证明了在连接脂肪细胞以增强β-肾上腺素能受体激动剂米拉贝隆和FGF21的代谢功效方面的有效性。此外，将这些分子与Cx43间隙连接通道激活剂达奈普肽联合使用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，其中通过Cx43间隙连接通道连接脂肪细胞可使脂肪组织对旨在作用于它的药物产生预适应。因此，Cx43间隙连接激活剂与其他靶向脂肪组织的药物联合使用具有巨大潜力。
