TNFα-Induced Oxidative Stress and Mitochondrial Dysfunction Alter Hypothalamic Neurogenesis and Promote Appetite Versus Satiety Neuropeptide Expression in Mice.
TNFα-Induced Oxidative Stress and Mitochondrial Dysfunction Alter Hypothalamic Neurogenesis and Promote Appetite Versus Satiety Neuropeptide Expression in Mice.
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DOI：
10.3390/brainsci12070900
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发表时间：
2022-07-09
期刊：
影响因子：
3.3
通讯作者：
Ross, Michael G.
中科院分区：
文献类型：
--
作者：
Desai, Mina;Stiles, Linsey;Torsoni, Adriana S.;Torsoni, Marcio A.;Shirihai, Orian S.;Ross, Michael G.
关键词：
母体肥胖导致子代程序性摄食过多和肥胖。后代食物摄入量的增加部分是由于下丘脑神经祖细胞（NPC）优先分化为食欲（AgRP）与食欲（POMC）神经元。改变的神经发生可能涉及下丘脑bHLH（碱性螺旋-环-螺旋）神经调节因子（Hes 1，Mash 1和Ngn 3）。虽然潜在机制尚不清楚，但已知线粒体功能对神经发生至关重要，并受到促炎细胞因子（如TNFα）的影响。肥胖与炎症和氧化应激途径的激活有关。在肥胖妊娠中，在母体和脐带血中观察到TNFα水平升高，表明胎儿暴露增加。由于TNFα影响神经发生和线粒体功能，我们检测了TNFα和活性氧化物质（ROS）过氧化氢（H2 O2）对新生小鼠下丘脑NPC培养物的影响。TNFα处理损害NPC线粒体功能，增加ROS产生和NPC增殖，并降低前神经原性Mash 1/Ngn 3蛋白表达。与此一致，AgRP蛋白表达增加，POMC减少。值得注意的是，用H2 O2处理产生了与TNFα相似的效果，并且还降低了抗氧化剂SIRT 1的蛋白表达。STAT 3/NFκB的抑制阻止了TNFα的作用，表明TNFα通过涉及两种信号通路的脑组织诱导的氧化应激介导其对NPC的作用。
Maternal obesity results in programmed offspring hyperphagia and obesity. The increased offspring food intake is due in part to the preferential differentiation of hypothalamic neuroprogenitor cells (NPCs) to orexigenic (AgRP) vs. anorexigenic (POMC) neurons. The altered neurogenesis may involve hypothalamic bHLH (basic helix–loop–helix) neuroregulatory factors (Hes1, Mash1, and Ngn3). Whilst the underlying mechanism remains unclear, it is known that mitochondrial function is critical for neurogenesis and is impacted by proinflammatory cytokines such as TNFα. Obesity is associated with the activation of inflammation and oxidative stress pathways. In obese pregnancies, increased levels of TNFα are seen in maternal and cord blood, indicating increased fetal exposure. As TNFα influences neurogenesis and mitochondrial function, we tested the effects of TNFα and reactive oxidative species (ROS) hydrogen peroxide (H2O2) on hypothalamic NPC cultures from newborn mice. TNFα treatment impaired NPC mitochondrial function, increased ROS production and NPC proliferation, and decreased the protein expression of proneurogenic Mash1/Ngn3. Consistent with this, AgRP protein expression was increased and POMC was decreased. Notably, treatment with H2O2 produced similar effects as TNFα and also reduced the protein expression of antioxidant SIRT1. The inhibition of STAT3/NFκB prevented the effects of TNFα, suggesting that TNFα mediates its effects on NPCs via mitochondrial-induced oxidative stress that involves both signaling pathways.
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DOI：
10.1038/ijo.2015.15
发表时间：
2015-04
期刊：
International journal of obesity (2005)
影响因子：
--
作者：
Catalano P;deMouzon SH
通讯作者：
deMouzon SH
影响因子：
2.9
作者：
Desai M;Li T;Ross MG
通讯作者：
Ross MG
影响因子：
4.6
作者：
Bigarella, Carolina L.;Liang, Raymond;Ghaffari, Saghi
通讯作者：
Ghaffari, Saghi
影响因子：
4.3
作者：
Bubici, C;Papa, S;Franzoso, G
通讯作者：
Franzoso, G
影响因子：
2.2
作者：
de Toledo Baldi, E.;Dias Bobbo, V. C.;Pereira de Araujo, E.
通讯作者：
Pereira de Araujo, E.