Kinoshita Keita, Ozaki Nobuaki, Takagi Yusuke, Murata Yoshiharu, Oshida Yoshiharu, Hayashi Yoshitaka
Research Center of Health, Physical Fitness and Sports (K.K., N.O., Y.T., Y.O.), and Department of Genetics (K.K., Y.T., Y.M., Y.H.), Division of Stress Adaptation and Recognition, Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601, Japan.
Endocrinology. 2014 Sep;155(9):3484-92. doi: 10.1210/en.2014-1175. Epub 2014 Jun 20.
Glucagon, a counterregulatory hormone to insulin, serves as a regulator of glucose homeostasis and acts in response to hypoglycemia. Earlier studies have shown that glucagon administration induces thermogenesis in experimental animal models. However, it is not known whether endogenous glucagon is involved in the regulation of brown adipose tissue (BAT) function. Here we investigated the role of glucagon in cold-induced thermogenesis in male mice deficient in proglucagon-derived peptides (GCGKO mice). Upon exposure to cold, GCGKO mice exhibited a greater decrease in rectal temperature than control mice. The cold exposure-induced increase in oxygen consumption in GCGKO mice was less than that seen in control mice. Moreover, the increase in oxygen consumption after administration of a β3-adrenergic receptor agonist, CL-316,243, was also lesser in GCGKO than in control mice. Expression of thermogenic genes, including the gene encoding uncoupling protein 1 (Ucp1), was reduced in the BAT of GCGKO mice under ambient as well as cold conditions. Administration of glucagon restored the expression of Ucp1 mRNA in the BAT as well as the expression of the fibroblast growth factor 21 gene (Fgf21) in the liver. Supplementation with glucagon for 2 weeks resulted in higher plasma Fgf21 levels and improved responses to CL-316,243 in GCGKO mice. These results indicated that endogenous glucagon is essential for adaptive thermogenesis and that it regulates BAT function, most likely by increasing hepatic Fgf21 production.
胰高血糖素是胰岛素的一种对抗调节激素，作为葡萄糖稳态的调节因子，在低血糖反应中发挥作用。早期研究表明，在实验动物模型中，给予胰高血糖素可诱导产热。然而，内源性胰高血糖素是否参与棕色脂肪组织（BAT）功能的调节尚不清楚。在此，我们研究了胰高血糖素在缺乏胰高血糖素衍生肽的雄性小鼠（GCGKO小鼠）冷诱导产热中的作用。暴露于寒冷环境时，GCGKO小鼠的直肠温度下降幅度比对照小鼠更大。GCGKO小鼠冷暴露诱导的耗氧量增加低于对照小鼠。此外，给予β3-肾上腺素能受体激动剂CL-316,243后，GCGKO小鼠的耗氧量增加也低于对照小鼠。在环境温度和寒冷条件下，GCGKO小鼠BAT中包括解偶联蛋白1（Ucp1）编码基因在内的产热基因表达均降低。给予胰高血糖素可恢复BAT中Ucp1 mRNA的表达以及肝脏中成纤维细胞生长因子21基因（Fgf21）的表达。给GCGKO小鼠补充胰高血糖素2周可导致血浆Fgf21水平升高，并改善其对CL-316,243的反应。这些结果表明，内源性胰高血糖素对适应性产热至关重要，并且它通过增加肝脏Fgf21的产生来调节BAT功能。
