Hypothalamic Phosphodiesterase 3B Pathway Mediates Anorectic and Body Weight-Reducing Effects of Insulin in Male Mice.
Hypothalamic Phosphodiesterase 3B Pathway Mediates Anorectic and Body Weight-Reducing Effects of Insulin in Male Mice.
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DOI：
10.1159/000445523
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发表时间：
2017
影响因子：
4.1
通讯作者：
Sahu A
中科院分区：
文献类型：
--
作者：
Sahu M;Anamthathmakula P;Sahu A
胰岛素在下丘脑中的作用在能量平衡的调节中起着关键作用，然而，介导胰岛素作用的细胞内信号机制还不完全清楚。虽然磷酸二酯酶-3B(PDE3B)在脂肪组织中介导胰岛素作用，并且在与能量平衡有关的下丘脑区高表达，但它在下丘脑中介导胰岛素作用的作用(如果有的话)尚不清楚。我们测试了下丘脑中胰岛素的作用是由PDE3B介导的假设。用酶法检测了外周和中枢给予胰岛素对成年小鼠下丘脑PDE3B活性的影响。Western blotting和免疫组织化学还检测了下丘脑中p-Akt和p-STAT3的水平。并比较瘦素对上述指标的影响。我们在中心注射胰岛素之前注射PDE3抑制剂西洛他胺，并检测12-24小时的食物摄入量和24小时的体重。最后，我们用定量聚合酶链式反应检测了西洛胺对胰岛素诱导的下丘脑前阿片黑素皮质素(POMC)、神经降压素(NT)、神经肽Y(NPY)和刺鼠相关肽(AgRP)基因表达的影响。外周或中心注射胰岛素显着增加下丘脑PDE3B活性，与p-Akt水平增加有关，但对p-STAT3水平没有任何影响。然而，瘦素诱导的PDE3B活性增加与下丘脑中p-Akt和p-STAT3水平的增加有关。预先给予西洛胺可逆转胰岛素对下丘脑Pomc基因表达的刺激作用和厌食和体重减轻作用。胰岛素不改变NT、NPY和AgRP的mRNA水平。胰岛素对下丘脑PDE3B活性的诱导，以及西洛胺逆转厌食和减肥效应以及胰岛素对下丘脑POMC基因表达的刺激作用，提示PDE3B的激活是下丘脑胰岛素信号转导的一种新机制。
Insulin action in the hypothalamus plays a critical role in the regulation of energy homeostasis, yet the intracellular signaling mechanisms mediating insulin action are incompletely understood. Although phosphodiesterase-3B (PDE3B) mediates insulin action in the adipose tissue and it is highly expressed in the hypothalamic areas implicated in energy homeostasis, its role, if any, in mediating insulin action in the hypothalamus is unknown. We tested the hypothesis that insulin action in the hypothalamus is mediated by PDE3B. Using enzymatic assay, we examined the effects of peripheral or central administration of insulin on hypothalamic PDE3B activity in adult mice. Western blotting and immunohistochemistry also examined p-Akt and p-STAT3 levels in the hypothalamus. Effects of leptin on these parameters were also compared. We injected cilostamide, a PDE3 inhibitor, prior to central injection of insulin and examined 12–24 hr food intake and 24 hr body weight. Finally, we examined the effect of cilostamide on insulin-induced proopiomelanocortin (Pomc), neurotensin (Nt), neuropeptide Y (Npy) and agouti-related peptide (Agrp) gene expression in the hypothalamus by qPCR. peripheral or central injection of insulin significantly increased PDE3B activity in the hypothalamus in association with increased p-Akt levels but without any change in p-STAT3 levels. However, leptin–induced increase in PDE3B activity was associated with an increase in both p-Akt and p-STAT3 levels in the hypothalamus. Prior administration of cilostamide reversed the anorectic and body weight reducing effects as well as stimulatory effect of insulin on hypothalamic Pomc mRNA levels. Insulin did not alter Nt, Npy and Agrp mRNA levels. Insulin induction of hypothalamic PDE3B activity, and the reversal of anorectic and body weight-reducing effects and stimulatory effect of insulin on hypothalamic Pomc gene expression by cilostamide suggest that activation of PDE3B is a novel mechanism of insulin signaling in the hypothalamus.
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影响因子：
15.9
作者：
Choi, Young Hun;Park, Sunhee;Manganiello, Vincent C.
通讯作者：
Manganiello, Vincent C.
影响因子：
7.7
作者：
Hallschmid M;Higgs S;Thienel M;Ott V;Lehnert H
通讯作者：
Lehnert H
影响因子：
4.8
作者：
Kelly, Michy P.;Adamowicz, Wendy;Kleiman, Robin J.
通讯作者：
Kleiman, Robin J.
影响因子：
5
作者：
LUTTINGER, D;KING, RA;PRANGE, AJ
通讯作者：
PRANGE, AJ
影响因子：
5.3
作者：
Cui, H;Cai, F;Belsham, DD
通讯作者：
Belsham, DD