Diabetes Center and Department of Anatomy, University of California, San Francisco, California, USA.
Center for Hypothalamic Research, Department of Internal Medicine, the University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA.
Mol Metab. 2024 Feb;80:101886. doi: 10.1016/j.molmet.2024.101886. Epub 2024 Jan 19.
The central melanocortin system is essential for the regulation of food intake and body weight. Agouti-related protein (AgRP) is the sole orexigenic component of the central melanocortin system and is conserved across mammalian species. AgRP is currently known to be expressed exclusively in the mediobasal hypothalamus, and hypothalamic AgRP-expressing neurons are essential for feeding. Here we characterized a previously unknown population of AgRP cells in the mouse hindbrain.
Expression of AgRP in the hindbrain was investigated using gene expression analysis, single-cell RNA sequencing, immunofluorescent analysis and multiple transgenic mice with reporter expressions. Activation of AgRP neurons was achieved by Designer Receptors Exclusively Activated by Designer Drugs (DREADD) and by transcranial focal photo-stimulation using a step-function opsin with ultra-high light sensitivity (SOUL).
AgRP expressing cells were present in the area postrema (AP) and the adjacent subpostrema area (SubP) and commissural nucleus of the solitary tract (cNTS) of the mouse hindbrain (termed AgRP herein). AgRP cells consisted of locally projecting neurons as well as tanycyte-like cells. Food deprivation stimulated hindbrain Agrp expression as well as neuronal activity of subsets of AgRP cells. In adult mice that lacked hypothalamic AgRP neurons, chemogenetic activation of AgRP neurons resulted in hyperphagia and weight gain. In addition, transcranial focal photo-stimulation of hindbrain AgRP cells increased food intake in adult mice with or without hypothalamic AgRP neurons.
Our study indicates that the central melanocortin system in the hindbrain possesses an orexigenic component, and that AgRP neurons stimulate feeding independently of hypothalamic AgRP neurons.
中枢黑皮质素系统对食物摄入和体重调节至关重要。Agouti 相关蛋白（AgRP）是中枢黑皮质素系统中唯一的致食欲成分，在哺乳动物中保守。AgRP 目前已知仅在中脑基底下丘脑表达，下丘脑 AgRP 表达神经元是进食所必需的。在这里，我们描述了小鼠后脑中以前未知的 AgRP 细胞群体。
使用基因表达分析、单细胞 RNA 测序、免疫荧光分析和具有报告基因表达的多种转基因小鼠，研究后脑中 AgRP 的表达。通过 Designer Receptors Exclusively Activated by Designer Drugs (DREADD) 和具有超高光敏感性的阶跃功能视蛋白（SOUL）的经颅焦点光刺激来激活 AgRP 神经元。
AgRP 表达细胞存在于小鼠后脑的后极（AP）和相邻的后极下区（SubP）和孤束核的连合核（cNTS）（称为 AgRP）。AgRP 细胞由局部投射神经元和 tanycyte 样细胞组成。禁食刺激后脑 Agrp 表达以及亚群 AgRP 细胞的神经元活性。在缺乏下丘脑 AgRP 神经元的成年小鼠中，化学遗传激活 AgRP 神经元导致摄食过度和体重增加。此外，经颅焦点光刺激后脑 AgRP 细胞增加了具有或不具有下丘脑 AgRP 神经元的成年小鼠的食物摄入。
我们的研究表明，后脑中的中枢黑皮质素系统具有致食欲成分，并且 AgRP 神经元刺激进食独立于下丘脑 AgRP 神经元。
