Insulin Action on GABA Neurons Is a Critical Regulator of Energy Balance But Not Fertility in Mice
Insulin Action on GABA Neurons Is a Critical Regulator of Energy Balance But Not Fertility in Mice
复制标题
DOI：
10.1210/en.2014-1412
复制
发表时间：
2014-11-01
期刊：
影响因子：
4.8
通讯作者：
Anderson, Greg M.
中科院分区：
文献类型：
--
作者：
Evans, Maggie C.;Rizwan, Mohammed Z.;Anderson, Greg M.
大脑中的胰岛素信号在能量稳态和生育的中枢调节中起着重要作用，因此表现出脑特异性胰岛素受体缺失（InsRs）的小鼠表现出饮食敏感的肥胖表型和下丘脑性腺功能减退。然而，介导胰岛素对生育的中枢作用的特定神经元在很大程度上仍未确定。神经递质γ -氨基丁酸（GABA）和谷氨酸是生殖能力和能量稳态的重要调节剂，广泛分布于下丘脑。因此，我们研究了胰岛素信号是否通过gaba能或谷氨酸能神经元在生育的代谢调节中发挥重要作用。我们使用Cre-loxP系统，通过将Insr-flox小鼠分别与Vgat- cre或Vglut2- cre小鼠杂交，从gaba能（Vgat(+)）或谷氨酸能（Vglut2(+)）细胞中产生选择性失活Insr基因的小鼠。然后比较雄性和雌性Insr-flox/Vgat-Cre(+) （Vgat-IRKO）、Insr-flox/Vglut2-Cre(+) （VglutIRKO）和Insr-flox/ cre阴性对照（CON）小鼠的多项生殖和代谢参数。与对照组小鼠相比，雌性VgatIRKO小鼠的成年体重、腹部脂肪量、空腹血浆胰岛素和瘦素浓度显著增加，但空腹葡萄糖浓度和葡萄糖耐量正常。令人惊讶的是，与对照组相比，VgatIRKO和VglutIRKO小鼠表现出正常的生殖成熟和功能。VgatIRKO、VglutIRKO和对照组小鼠在青春期开始年龄、发情周期或生育能力方面没有差异。然而，与对照组相比，雄性VgatIRKO小鼠表现出LH浓度显著增加和精囊重量减少的趋势，这可能表明原发性性腺功能减退。因此，我们的研究结果表明，通过gaba能细胞和谷氨酸能细胞的胰岛素信号传导并不是小鼠生育所必需的，但表明gaba能神经元包含胰岛素调节能量稳态的电路。
Insulin signaling in the brain plays an important role in the central regulation of energy homeostasis and fertility, such that mice exhibiting brain-specific deletion of insulin receptors (InsRs) display a diet-sensitive obesogenic phenotype and hypothalamic hypogonadism. However, the specific neurons mediating insulin's central effects on fertility remain largely unidentified. The neurotransmitters gamma-aminobutyric acid (GABA) and glutamate are important modulators of fertility and energy homeostasis and are widely distributed in the hypothalamus. We therefore investigated whether insulin signaling via GABAergic or glutamatergic neurons plays an important role in the metabolic regulation of fertility. We used the Cre-loxP system to generate mice with a selective inactivation of the Insr gene from GABAergic (Vgat(+)) or glutamatergic (Vglut2(+)) cells by crossing Insr-flox mice with Vgat-Cre or Vglut2-Cre mice, respectively. Multiple reproductive and metabolic parameters were then compared between male and female Insr-flox/Vgat-Cre(+) (Vgat-IRKO), Insr-flox/Vglut2-Cre(+) (VglutIRKO), and Insr-flox/Cre-negative control (CON) mice. Female VgatIRKO mice exhibited a significant increase in adult body weight, abdominal fat mass, and fasting plasma insulin and leptin concentrations, but normal fasting glucose concentration and glucose tolerance compared with CON mice. Surprisingly, VgatIRKO and VglutIRKO mice exhibited normal reproductive maturation and function compared with CONs. No differences in the age of puberty onset, estrous cyclicity, or fertility were observed between VgatIRKO, VglutIRKO, and CON mice. However, male VgatIRKO mice exhibited significantly augmented LH concentration and a trend toward reduced seminal vesicle weight compared with CON mice, which may be indicative of primary hypogonadism. Our results therefore demonstrate that insulin signaling via GABAergic and glutamatergic cells is not required for fertility in mice, but show that GABAergic neurons encompass circuitry through which insulin acts to modulate energy homeostasis.