Paeger Lars, Pippow Andreas, Hess Simon, Paehler Moritz, Klein Andreas C, Husch Andreas, Pouzat Christophe, Brüning Jens C, Kloppenburg Peter
Biocenter, Institute for Zoology, University of Cologne, Cologne, Germany.
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany.
Elife. 2017 Aug 1;6:e25641. doi: 10.7554/eLife.25641.
Satiety-signaling, pro-opiomelanocortin (POMC)-expressing neurons in the arcuate nucleus of the hypothalamus play a pivotal role in the regulation of energy homeostasis. Recent studies reported altered mitochondrial dynamics and decreased mitochondria- endoplasmic reticulum contacts in POMC neurons during diet-induced obesity. Since mitochondria play a crucial role in Ca signaling, we investigated whether obesity alters Ca handling of these neurons in mice. In diet-induced obesity, cellular Ca handling properties including mitochondrial Ca uptake capacity are impaired, and an increased resting level of free intracellular Ca is accompanied by a marked decrease in neuronal excitability. Experimentally increasing or decreasing intracellular Ca concentrations reproduced electrophysiological properties observed in diet-induced obesity. Taken together, we provide the first direct evidence for a diet-dependent deterioration of Ca homeostasis in POMC neurons during obesity development resulting in impaired function of these critical energy homeostasis-regulating neurons.
在下丘脑弓状核中表达促阿片黑素皮质素（POMC）的饱足信号神经元在能量平衡调节中起关键作用。最近的研究报道，在饮食诱导的肥胖过程中，POMC神经元的线粒体动力学发生改变，线粒体与内质网的接触减少。由于线粒体在钙信号传导中起关键作用，我们研究了肥胖是否会改变小鼠这些神经元的钙处理。在饮食诱导的肥胖中，包括线粒体钙摄取能力在内的细胞钙处理特性受损，细胞内游离钙的静息水平升高，同时神经元兴奋性显著降低。通过实验增加或降低细胞内钙浓度，再现了饮食诱导肥胖中观察到的电生理特性。综上所述，我们提供了首个直接证据，证明在肥胖发展过程中，POMC神经元的钙稳态会因饮食而恶化，导致这些关键的能量平衡调节神经元功能受损。
