Pozo Macarena, Rodríguez-Rodríguez Rosalía, Ramírez Sara, Seoane-Collazo Patricia, López Miguel, Serra Dolors, Herrero Laura, Casals Núria
Basic Sciences Department, Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya, 08195 Sant Cugat del Vallès, Barcelona, Spain.
NeurObesity Group, Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, 15782 Santiago de Compostela, Spain.
Endocrinology. 2017 Jul 1;158(7):2226-2238. doi: 10.1210/en.2017-00151.
Carnitine palmitoyltransferase (CPT) 1C, a brain-specific protein localized in the endoplasmic reticulum of neurons, is expressed in almost all brain regions. Based on global knockout (KO) models, CPT1C has demonstrated relevance in hippocampus-dependent spatial learning and in hypothalamic regulation of energy balance. Specifically, it has been shown that CPT1C is protective against high-fat diet-induced obesity (DIO), and that CPT1C KO mice show reduced peripheral fatty acid oxidation (FAO) during both fasting and DIO. However, the mechanisms mediating CPT1C-dependent regulation of energy homeostasis remain unclear. Here, we focus on the mechanistic understanding of hypothalamic CPT1C on the regulation of fuel selection in liver and muscle of male mice during energy deprivation situations, such as fasting. In CPT1C-deficient mice, modulation of the main hypothalamic energy sensors (5' adenosine monophosphate-activated protein kinase, Sirtuin 1, and mammalian target of rapamycin) was impaired and plasma catecholamine levels were decreased. Consequently, CPT1C-deficient mice presented defective fasting-induced FAO in liver, leading to higher triacylglycerol accumulation and lower glycogen levels. Moreover, muscle pyruvate dehydrogenase activity was increased, which was indicative of glycolysis enhancement. The respiratory quotient did not decrease in CPT1C KO mice after 48 hours of fasting, confirming a defective switch on fuel substrate selection under hypoglycemia. Phenotype reversion studies identified the mediobasal hypothalamus (MBH) as the main area mediating CPT1C effects on fuel selection. Overall, our data demonstrate that CPT1C in the MBH is necessary for proper hypothalamic sensing of a negative energy balance and fuel partitioning in liver and muscle.
肉碱棕榈酰转移酶（CPT）1C是一种定位于神经元内质网的脑特异性蛋白，几乎在所有脑区均有表达。基于全基因敲除（KO）模型，CPT1C已被证明与海马体依赖的空间学习以及下丘脑对能量平衡的调节有关。具体而言，研究表明CPT1C对高脂饮食诱导的肥胖（DIO）具有保护作用，并且CPT1C基因敲除小鼠在禁食和DIO期间外周脂肪酸氧化（FAO）均减少。然而，介导CPT1C依赖性能量稳态调节的机制仍不清楚。在此，我们着重从机制上理解下丘脑CPT1C在能量剥夺情况下（如禁食）对雄性小鼠肝脏和肌肉中燃料选择的调节作用。在CPT1C缺陷小鼠中，主要下丘脑能量传感器（5' 单磷酸腺苷激活的蛋白激酶、沉默调节蛋白1和雷帕霉素哺乳动物靶标）的调节受到损害，血浆儿茶酚胺水平降低。因此，CPT1C缺陷小鼠肝脏中禁食诱导的FAO存在缺陷，导致三酰甘油积累增加和糖原水平降低。此外，肌肉丙酮酸脱氢酶活性增加，这表明糖酵解增强。禁食48小时后，CPT1C基因敲除小鼠的呼吸商并未降低，这证实了在低血糖情况下燃料底物选择的转换存在缺陷。表型逆转研究确定中基底下丘脑（MBH）是介导CPT1C对燃料选择影响的主要区域。总体而言，我们的数据表明，MBH中的CPT1C对于下丘脑正确感知负能量平衡以及肝脏和肌肉中的燃料分配是必需的。
