Briski K P, Napit Prabhat R, Md Haider Ali, Alshamrani A A, Alhamyani A R, Bheemanapally Khaggeswar, Ibrahim Mostafa M H
School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana Monroe, Monroe, LA 71201, United States.
Endocr Metab Sci. 2021 Jun 30;3. doi: 10.1016/j.endmts.2021.100087. Epub 2021 Feb 13.
Ventromedial hypothalamic nucleus (VMN) glycogen metabolism affects local glucoregulatory signaling. The hindbrain metabolic-sensitive catecholamine (CA) neurotransmitter norepinephrine controls VMN glycogen phosphorylase (GP)-muscle (GPmm) and -brain (GPbb) type expression in male rats. Present studies addressed the premise that CA regulation of hypoglycemic patterns of VMN glycogen metabolic enzyme protein expression is sex-dimorphic, and that this signal is responsible for sex differences in acclimation of these profiles to recurrent insulin-induced hypoglycemia (RIIH). VMN tissue was acquired by micropunch-dissection from male and female rats pretreated by caudal fourth ventricular administration of the CA neurotoxin 6-hydroxydopamine (6OHDA) before single or serial insulin injection. 6-OHDA averted acute hypoglycemic inhibition of VMN glycogen synthase (GS) and augmentation of GPmm and GPbb protein expression in males, and prevented GPmm and -bb down-regulation in females. Males recovered from antecedent hypoglycemia (AH) exhibited neurotoxin-preventable diminution of baseline GS profiles, whereas acclimated GPmm and -bb expression in females occurred irrespective of pretreatment. RIIH did not alter VMN GS, GPmm, and GPbb expression in vehicle- or 6-OHDA-pretreated animals of either sex. VMN glycogen content was correspondingly unchanged or increased in males versus females following AH; 6-OHDA augmented glycogen mass in AH-exposed animals of both sexes. RIIH did not alter VMN glycogen accumulation in vehicle-pretreated rats of either sex, but diminished glycogen in neurotoxin-pretreated animals. AH suppresses baseline GS (CA-dependent) or GPmm/GPbb (CA-independent) expression in male and female rats, respectively, which corresponds with unaltered or augmented VMN glycogen content in those sexes. AH-associated loss of sex-distinctive CA-mediated enzyme protein sensitivity to hypoglycemia (male: GS, GPmm, GPbb; female: GPmm, Gpbb) may reflect, in part, VMN target desensitization to noradrenergic input.
腹内侧下丘脑核（VMN）的糖原代谢影响局部葡萄糖调节信号。后脑代谢敏感的儿茶酚胺（CA）神经递质去甲肾上腺素控制雄性大鼠VMN糖原磷酸化酶（GP）的肌肉型（GPmm）和脑型（GPbb）表达。目前的研究探讨了以下前提：CA对VMN糖原代谢酶蛋白表达的降血糖模式的调节具有性别差异，并且该信号负责这些模式对反复胰岛素诱导的低血糖（RIIH）适应过程中的性别差异。在单次或连续注射胰岛素之前，通过尾侧第四脑室注射CA神经毒素6-羟基多巴胺（6OHDA）预处理雄性和雌性大鼠，然后通过微量穿刺解剖获取VMN组织。6-OHDA避免了雄性大鼠VMN糖原合酶（GS）的急性低血糖抑制以及GPmm和GPbb蛋白表达的增加，并防止了雌性大鼠中GPmm和GPbb的下调。从先前低血糖（AH）中恢复的雄性大鼠表现出神经毒素可预防的基线GS水平降低，而雌性大鼠中适应性的GPmm和GPbb表达则不受预处理的影响。RIIH并未改变两性中接受载体或6-OHDA预处理动物的VMN GS、GPmm和GPbb表达。AH后，雄性大鼠的VMN糖原含量相应未变或增加，而雌性大鼠则相反；6-OHDA增加了两性中暴露于AH的动物的糖原量。RIIH并未改变两性中接受载体预处理大鼠的VMN糖原积累，但减少了接受神经毒素预处理动物的糖原。AH分别抑制雄性和雌性大鼠的基线GS（CA依赖性）或GPmm/GPbb（CA非依赖性）表达，这与这些性别中VMN糖原含量未变或增加相对应。AH相关的性别特异性CA介导的酶蛋白对低血糖敏感性的丧失（雄性：GS、GPmm、GPbb；雌性：GPmm、Gpbb）可能部分反映了VMN靶标对去甲肾上腺素能输入的脱敏。
