Department of Anesthesiology and Critical Care Medicine, George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, United States.
Department of Environmental and Occupational Health, University of Pittsburgh School of Public Health, Pittsburgh, Pennsylvania, United States.
J Appl Physiol (1985). 2024 Feb 1;136(2):233-243. doi: 10.1152/japplphysiol.00215.2023. Epub 2023 Dec 21.
The carotid bodies (CBs) have been implicated in glucose abnormalities in obesity via elevation of activity of the sympathetic nervous system. Obesity-induced hypertension is mediated by insulin receptor (INSR) signaling and by leptin, which binds to the leptin receptor (LEPR) in CB and activates transient receptor potential channel subfamily M member 7 (TRPM7). We hypothesize that in mice with diet-induced obesity, hyperglycemia, glucose intolerance, and insulin resistance will be attenuated by the CB denervation (carotid sinus nerve dissection, CSND) and by knockdown of , and gene expression in CB. In series of experiments in 75 male diet-induced obese (DIO) mice, we performed either CSND (vs. sham) surgeries or shRNA-induced suppression of , , or gene expression in CB, followed by blood pressure telemetry, intraperitoneal glucose tolerance and insulin tolerance tests, and measurements of fasting plasma insulin, leptin, corticosterone, glucagon and free fatty acids (FFAs) levels, hepatic expression of gluconeogenesis enzymes phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G-6-Pase) mRNA and liver glycogen levels. CSND decreased blood pressure, fasting blood glucose levels and improved glucose tolerance without any effect on insulin resistance. CSND did not affect any hormone levels and gluconeogenesis enzymes, but increased liver glycogen level. Genetic knockdown of CB , and had no effect on glucose metabolism. We conclude that CB contributes to hyperglycemia of obesity, probably by modulation of the glycogen-glucose equilibrium. Diabetogenic effects of obesity on CB in mice do not occur via activation of CB , and . This paper provides first evidence that carotid body denervation abolishes hypertension and improves fasting blood glucose levels and glucose tolerance in mice with diet-induced obesity. Furthermore, we have shown that this phenomenon is associated with increased liver glycogen content, whereas insulin sensitivity and enzymes of gluconeogenesis were not affected.
颈动脉体 (CBs) 通过交感神经系统活性的升高被牵连到肥胖中的葡萄糖异常。肥胖诱导的高血压是由胰岛素受体 (INSR) 信号和瘦素介导的，瘦素在 CB 中结合瘦素受体 (LEPR) 并激活瞬时受体电位通道亚家族 M 成员 7 (TRPM7)。我们假设，在饮食诱导肥胖的小鼠中，CB 去神经支配（颈动脉窦神经解剖术，CSND）和 CB 中基因表达的 knockdown 将减轻高血糖、葡萄糖耐量受损和胰岛素抵抗。在一系列 75 只雄性饮食诱导肥胖 (DIO) 小鼠的实验中，我们进行了 CSND（与假手术）手术或 CB 中基因表达的 shRNA 诱导抑制，随后进行血压遥测、腹腔内葡萄糖耐量和胰岛素耐量测试以及空腹血浆胰岛素、瘦素、皮质酮、胰高血糖素和游离脂肪酸 (FFAs) 水平、肝脏糖异生酶磷酸烯醇丙酮酸羧激酶 (PEPCK) 和葡萄糖 6-磷酸酶 (G-6-Pase) mRNA 的表达和肝糖原水平的测量。CSND 降低了血压、空腹血糖水平并改善了葡萄糖耐量，而对胰岛素抵抗没有影响。CSND 不影响任何激素水平和糖异生酶，但增加了肝糖原水平。CB 的基因敲低没有对葡萄糖代谢产生影响。我们得出结论，CB 可能通过调节糖原-葡萄糖平衡对肥胖中的高血糖做出贡献。肥胖对 CB 的致糖尿病作用不是通过 CB 的激活发生的， 而且 。本文首次提供证据表明，颈动脉体去神经支配可消除饮食诱导肥胖小鼠的高血压并改善空腹血糖水平和葡萄糖耐量。此外，我们已经表明，这种现象与增加肝糖原含量有关，而胰岛素敏感性和糖异生酶不受影响。
