LRP1 regulates food intake and energy balance in GABAergic neurons independently of leptin action.
LRP1 regulates food intake and energy balance in GABAergic neurons independently of leptin action.
复制标题
DOI：
10.1152/ajpendo.00399.2020
复制
发表时间：
2020-12
期刊：
影响因子：
--
通讯作者：
M. Kang;J. Seo;Hyon Lee;Aykut Uner;Won-Mo Yang;Kellen Cristina da Cruz Rodrigues;Hyun Jeong Kim;Wendy Li;John N. Campbell;Y. Dagon;Young-Bum Kim
中科院分区：
文献类型：
--
作者：
M. Kang;J. Seo;Hyon Lee;Aykut Uner;Won-Mo Yang;Kellen Cristina da Cruz Rodrigues;Hyun Jeong Kim;Wendy Li;John N. Campbell;Y. Dagon;Young-Bum Kim
低密度脂蛋白受体相关蛋白 1 (LRP1) 是 LDL 受体家族的成员，在全身葡萄糖和脂质稳态中发挥关键作用。 LRP1 还通过介导瘦素的厌食作用来调节下丘脑的能量平衡，尽管所涉及的潜在神经回路仍不清楚。由于 GABA 能神经元是下丘脑瘦素作用的主要介质，因此我们使用表达 Vgat 或 AgRP 的神经元（Vgat-Cre；LRP1loxP/loxP 或 AgRP-Cre；LRP1loxP/loxP）中缺乏 LRP1 的小鼠研究了 GABA 能 LRP1 在能量平衡和瘦素作用中的作用。在这里，我们发现 GABA 能神经元中的 LRP1 缺陷会导致正常饮食的雄性和雌性小鼠严重肥胖。这种效应很可能是由于食物摄入量增加、能量消耗和运动活动减少所致。 GABA能神经元特异性LRP1缺陷小鼠的肥胖增加伴随着高瘦素血症和高胰岛素血症。这些小鼠的胰岛素抵抗和葡萄糖耐受不良是在体重没有变化的情况下发生的。重要的是，GABA 能神经元中的 LRP1 并不是瘦素作用所必需的，正常瘦素的厌食作用和瘦素诱导的下丘脑 Stat3 磷酸化证明了这一点。相比之下，AgRP 神经元中的 LRP1 缺乏对肥胖和热量摄入没有影响。总之，我们的数据确定 GABA 能神经元是支撑 LRP1 依赖性全身能量平衡和体重稳态调节的关键神经回路。我们进一步发现 GABAergic LRP1 信号通路独立于瘦素信号和 AgRP 神经元调节食物摄入和能量消耗。
Low-density lipoprotein receptor-related protein 1 (LRP1) is a member of LDL receptor family that plays a key role in systemic glucose and lipid homeostasis. LRP1 also regulates energy balance in the hypothalamus by mediating leptin's anorexigenic action, although the underlying neurocircuitry involved is still unclear. Because GABAergic neurons are a major mediator of hypothalamic leptin action, we studied the role of GABAergic LRP1 in energy balance and leptin action using mice lacking LRP1 in Vgat- or AgRP-expressing neurons (Vgat-Cre; LRP1loxP/loxP or AgRP-Cre; LRP1loxP/loxP). Here we show that LRP1 deficiency in GABAergic neurons results in severe obesity in male and female mice fed a normal chow diet. This effect is most likely due to increased food intake and decreased energy expenditure and locomotor activity. Increased adiposity in GABAergic neuron-specific LRP1-deficient mice is accompanied by hyperleptinemia and hyperinsulinemia. Insulin resistance and glucose intolerance in these mice are occurred without change in body weight. Importantly, LRP1 in GABAergic neurons is not required for leptin action, as evidenced by normal leptin's anorexigenic action and leptin-induced hypothalamic Stat3 phosphorylation. In contrast, LRP1 deficiency in AgRP neurons has no effect on adiposity and caloric intake. In conclusion, our data identify GABAergic neurons as a key neurocircuitry that underpins LRP1-dependent regulation of systemic energy balance and body-weight homeostasis. We further find that the GABAergic LRP1 signaling pathway modulates food intake and energy expenditure independently of leptin signaling and AgRP neurons.