Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931, Cologne, Germany.
Policlinic for Endocrinology, Diabetes and Preventive Medicine (PEDP), University Hospital Cologne, Kerpener Strasse 26, 50924, Cologne, Germany.
Nat Commun. 2023 Nov 29;14(1):7824. doi: 10.1038/s41467-023-42595-7.
Dysregulation of hypothalamic ceramides has been associated with disrupted neuronal pathways in control of energy and glucose homeostasis. However, the specific ceramide species promoting neuronal lipotoxicity in obesity have remained obscure. Here, we find increased expression of the C ceramide-producing ceramide synthase (CerS)6 in cultured hypothalamic neurons exposed to palmitate in vitro and in the hypothalamus of obese mice. Conditional deletion of CerS6 in hypothalamic neurons attenuates high-fat diet (HFD)-dependent weight gain and improves glucose metabolism. Specifically, CerS6 deficiency in neurons expressing pro-opiomelanocortin (POMC) or steroidogenic factor 1 (SF-1) alters feeding behavior and alleviates the adverse metabolic effects of HFD feeding on insulin sensitivity and glucose tolerance. POMC-expressing cell-selective deletion of CerS6 prevents the diet-induced alterations of mitochondrial morphology and improves cellular leptin sensitivity. Our experiments reveal functions of CerS6-derived ceramides in hypothalamic lipotoxicity, altered mitochondrial dynamics, and ER/mitochondrial stress in the deregulation of food intake and glucose metabolism in obesity.
下丘脑神经酰胺的失调与能量和葡萄糖稳态控制中神经元途径的破坏有关。然而，在肥胖症中促进神经元脂肪毒性的特定神经酰胺种类仍不清楚。在这里，我们发现培养的下丘脑神经元在体外暴露于棕榈酸和肥胖小鼠的下丘脑中有增加的 C 神经酰胺产生神经酰胺合酶（CerS）6 的表达。条件性敲除下丘脑神经元中的 CerS6 可减轻高脂肪饮食（HFD）引起的体重增加并改善葡萄糖代谢。具体而言，表达促黑激素原（POMC）或类固醇生成因子 1（SF-1）的神经元中 CerS6 的缺失改变了进食行为，并减轻了 HFD 喂养对胰岛素敏感性和葡萄糖耐量的不良代谢影响。POMC 表达细胞选择性敲除 CerS6 可防止饮食引起的线粒体形态改变，并提高细胞瘦素敏感性。我们的实验揭示了 CerS6 衍生的神经酰胺在肥胖症中下丘脑脂肪毒性、线粒体动力学改变以及内质网/线粒体应激中对摄食和葡萄糖代谢失调的作用。
