性别二态性后脑对腹内侧下丘脑核糖调节神经元 5'-AMP 激活蛋白激酶活性和递质标记蛋白表达的调节作用。
Sex-dimorphic hindbrain lactate regulation of ventromedial hypothalamic nucleus glucoregulatory neuron 5'-AMP-activated protein kinase activity and transmitter marker protein expression.
机构信息
School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71201, United States.
School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71201, United States.
出版信息
Neuropeptides. 2023 Jun;99:102324. doi: 10.1016/j.npep.2023.102324. Epub 2023 Feb 2.
BACKGROUND
The oxidizable glycolytic end-product L-lactate is a gauge of nerve cell metabolic fuel stability that metabolic-sensory hindbrain A2 noradrenergic neurons impart to the brain glucose-regulatory network. Current research investigated the premise that hindbrain lactate deficiency exerts sex-specific control of energy sensor and transmitter marker protein responses to hypoglycemia in ventromedial hypothalamic nucleus (VMN) glucose-regulatory nitrergic and γ-aminobutyric acid (GABA) neurons.
METHODS
Nitric oxide synthase (nNOS)- or glutamate decarboxylase (GAD)-immunoreactive neurons were laser-catapult-microdissected from male and female rat VMN after subcutaneous insulin injection and caudal fourth ventricular L-lactate or vehicle infusion for Western blot protein analysis.
RESULTS
Hindbrain lactate repletion reversed hypoglycemia-associated augmentation (males) or inhibition (females) of nitrergic neuron nNOS expression, and prevented up-regulation of phosphorylated AMPK 5'-AMP-activated protein kinase (pAMPK) expression in those neurons. Hypoglycemic suppression of GABAergic neuron GAD protein was averted by exogenous lactate over the rostro-caudal length of the male VMN and in the middle region of the female VMN. Lactate normalized GABA neuron pAMPK profiles in hypoglycemic male (caudal VMN) and female (all VMN segments) rats. Hypoglycemic patterns of norepinephrine (NE) signaling were lactate-dependent throughout the male VMN, but confined to the rostral and middle female VMN.
CONCLUSIONS
Results document, in each sex, regional VMN glucose-regulatory transmitter responses to hypoglycemia that are controlled by hindbrain lactate status. Hindbrain metabolic-sensory regulation of hypoglycemia-correlated nitric oxide or GABA release may entail AMPK-dependent mechanisms in specific VMN rostro-caudal segments in each sex. Additional effort is required to examine the role of hindbrain lactoprivic-sensitive VMN neurotransmitters in lactate-mediated attenuation of hypoglycemic hyperglucagonemia and hypercorticosteronemia in male and female rats.
背景
可氧化的糖酵解终产物 L-乳酸是衡量神经细胞代谢燃料稳定性的指标，代谢-感觉后脑 A2 去甲肾上腺素能神经元将其赋予大脑葡萄糖调节网络。目前的研究假设，后脑乳酸缺乏对腹内侧下丘脑核（VMN）葡萄糖调节性硝化和γ-氨基丁酸（GABA）神经元的能量传感器和递质标记蛋白对低血糖的反应具有性别特异性控制。
方法
皮下注射胰岛素后，雄性和雌性大鼠 VMN 中的一氧化氮合酶（nNOS）或谷氨酸脱羧酶（GAD）免疫反应性神经元经激光弹射微切割，进行 Western blot 蛋白分析。
结果
后脑乳酸补充逆转了低血糖相关的硝化神经元 nNOS 表达增加（雄性）或抑制（雌性），并防止了这些神经元中磷酸化 AMPK 5'-AMP 激活蛋白激酶（pAMPK）表达的上调。雄性 VMN 头尾部和雌性 VMN 中部的外源性乳酸避免了 GABA 能神经元 GAD 蛋白的抑制。乳酸使低血糖雄性（尾侧 VMN）和雌性（所有 VMN 节段）大鼠的 GABA 神经元 pAMPK 谱正常化。雄性 VMN 中的去甲肾上腺素（NE）信号传递模式依赖于乳酸，但仅限于雌性 VMN 的头侧和中间区域。
结论
结果表明，在每个性别中，VMN 葡萄糖调节性递质对低血糖的反应都受到后脑乳酸状态的控制。后脑代谢感觉对低血糖相关一氧化氮或 GABA 释放的调节可能涉及 AMPK 依赖机制，在每个性别 VMN 的特定头尾部。需要进一步努力研究后脑乳糖敏感的 VMN 神经递质在雄性和雌性大鼠中乳酸介导的低血糖性高胰高血糖素血症和高皮质酮血症中的作用。
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