Brain insulin signaling suppresses lipolysis in the absence of peripheral insulin receptors and requires the MAPK pathway.
Brain insulin signaling suppresses lipolysis in the absence of peripheral insulin receptors and requires the MAPK pathway.
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DOI：
10.1016/j.molmet.2023.101723
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发表时间：
2023-07
影响因子：
8.1
通讯作者：
Scherer, Thomas
中科院分区：
文献类型：
--
作者：
Metz, Matthaeus;O'Hare, James;Cheng, Bob;Puchowicz, Michelle;Buettner, Christoph;Scherer, Thomas
关键词：
胰岛素平衡儿茶酚胺诱导的脂解作用的能力决定了胰岛素在脂肪组织中的作用。胰岛素直接在脂肪细胞水平抑制脂解，并通过大脑中的信号传导间接抑制脂解。在这里，我们进一步表征了脑胰岛素信号在调节脂解中的作用，并定义了脑胰岛素抑制脂解所需的细胞内胰岛素信号通路。我们使用高胰岛素钳夹研究结合示踪稀释技术，在两种不同的小鼠模型中评估胰岛素抑制脂解的能力，这两种小鼠模型在所有组织中具有诱导型胰岛素受体耗竭（IRΔWB）或仅限于除脑外的外周组织（IRΔPER）。为了确定脑胰岛素抑制脂解所需的潜在信号通路，我们连续向雄性Sprague道利大鼠的下丘脑内侧基底部注入胰岛素+/− a PI 3 K或MAPK抑制剂，并评估钳夹期间的脂解。IRΔPER和IRΔWB小鼠的胰岛素受体基因缺失均导致明显的高血糖和胰岛素抵抗。然而，胰岛素抑制脂解的能力在IRΔPER中大部分保留，但在IRΔWB小鼠中完全消失，表明只要脑胰岛素受体存在，胰岛素仍然能够抑制脂解。阻断MAPK而非PI 3 K通路会损害脑胰岛素信号对脂解的抑制作用。脑胰岛素是胰岛素抑制脂肪组织脂解所必需的，并且依赖于完整的下丘脑MAPK信号传导。大脑中的胰岛素信号足以抑制脂肪分解。胰岛素的抗脂肪分解作用需要下丘脑MAPK。MAPK抑制损害脂解和葡萄糖产生的抑制。
Insulin's ability to counterbalance catecholamine-induced lipolysis defines insulin action in adipose tissue. Insulin suppresses lipolysis directly at the level of the adipocyte and indirectly through signaling in the brain. Here, we further characterized the role of brain insulin signaling in regulating lipolysis and defined the intracellular insulin signaling pathway required for brain insulin to suppress lipolysis. We used hyperinsulinemic clamp studies coupled with tracer dilution techniques to assess insulin's ability to suppress lipolysis in two different mouse models with inducible insulin receptor depletion in all tissues (IRΔWB) or restricted to peripheral tissues excluding the brain (IRΔPER). To identify the underlying signaling pathway required for brain insulin to inhibit lipolysis, we continuously infused insulin +/− a PI3K or MAPK inhibitor into the mediobasal hypothalamus of male Sprague Dawley rats and assessed lipolysis during clamps. Genetic insulin receptor deletion induced marked hyperglycemia and insulin resistance in both IRΔPER and IRΔWB mice. However, the ability of insulin to suppress lipolysis was largely preserved in IRΔPER, but completely obliterated in IRΔWB mice indicating that insulin is still able to suppress lipolysis as long as brain insulin receptors are present. Blocking the MAPK, but not the PI3K pathway impaired the inhibition of lipolysis by brain insulin signaling. Brain insulin is required for insulin to suppress adipose tissue lipolysis and depends on intact hypothalamic MAPK signaling. Insulin signaling in the brain is sufficient for suppression of lipolysis. Hypothalamic MAPK is required for insulin's anti-lipolytic actions. MAPK inhibition impairs suppression of lipolysis and glucose production.
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调节健康和疾病中肝葡萄糖代谢。
DOI：
10.1038/nrendo.2017.80
发表时间：
2017-10
期刊：
Nature reviews. Endocrinology
影响因子：
--
作者：
Petersen MC;Vatner DF;Shulman GI
通讯作者：
Shulman GI
影响因子：
29
作者：
Balland E;Dam J;Langlet F;Caron E;Steculorum S;Messina A;Rasika S;Falluel-Morel A;Anouar Y;Dehouck B;Trinquet E;Jockers R;Bouret SG;Prévot V
通讯作者：
Prévot V
影响因子：
15.9
作者：
FRIED, SK;RUSSELL, CD;BROLIN, RE
通讯作者：
BROLIN, RE
影响因子：
5.8
作者：
Brown JM;Bentsen MA;Rausch DM;Phan BA;Wieck D;Wasanwala H;Matsen ME;Acharya N;Richardson NE;Zhao X;Zhai P;Secher A;Morton GJ;Pers TH;Schwartz MW;Scarlett JM
通讯作者：
Scarlett JM
影响因子：
29
作者：
Gelling, RW;Morton, GJ;Schwartz, MW
通讯作者：
Schwartz, MW