Gómez-Hernández Almudena, Beneit Nuria, Escribano Óscar, Díaz-Castroverde Sabela, García-Gómez Gema, Fernández Silvia, Benito Manuel
Biochemistry and Molecular Biology II Department, School of Pharmacy, Complutense University of Madrid; Health Research Institute of San Carlos Clinic Hospital; and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas 28020 Madrid, Spain.
Endocrinology. 2016 Sep;157(9):3517-28. doi: 10.1210/en.2016-1148. Epub 2016 Jul 14.
Obesity is one of the major risk factors for the development of cardiovascular diseases and is characterized by abnormal accumulation of adipose tissue, including perivascular adipose tissue (PVAT). However, brown adipose tissue (BAT) activation reduces visceral adiposity. To demonstrate that severe brown fat lipoatrophy might accelerate atherosclerotic process, we generated a new mouse model without insulin receptor (IR) in BAT and without apolipoprotein (Apo)E (BAT-specific IR knockout [BATIRKO];ApoE(-/-) mice) and assessed vascular and metabolic alterations associated to obesity. In addition, we analyzed the contribution of the adipose organ to vascular inflammation. Brown fat lipoatrophy induces visceral adiposity, mainly in gonadal depot (gonadal white adipose tissue [gWAT]), severe glucose intolerance, high postprandial glucose levels, and a severe defect in acute insulin secretion. BATIRKO;ApoE(-/-) mice showed greater hypertriglyceridemia than the obtained in ApoE(-/-) and hypercholesterolemia similar to ApoE(-/-) mice. BATIRKO;ApoE(-/-) mice, in addition to primary insulin resistance in BAT, also showed a significant decrease in insulin signaling in liver, gWAT, heart, aorta artery, and thoracic PVAT. More importantly, our results suggest that severe brown fat lipoatrophy aggravates the atherosclerotic process, characterized by a significant increase of lipid depots, atherosclerotic coverage, lesion size and complexity, increased macrophage infiltration, and proinflammatory markers expression. Finally, an increase of TNF-α and leptin as well as a decrease of adiponectin by BAT, gWAT, and thoracic PVAT might also be responsible of vascular damage. Our results suggest that severe brown lipoatrophy aggravates atherosclerotic process. Thus, BAT activation might protect against obesity and its associated metabolic alterations.
肥胖是心血管疾病发生的主要危险因素之一，其特征是脂肪组织异常蓄积，包括血管周围脂肪组织（PVAT）。然而，棕色脂肪组织（BAT）的激活可减少内脏脂肪。为了证明严重的棕色脂肪萎缩可能加速动脉粥样硬化进程，我们构建了一种新的小鼠模型，该模型在BAT中无胰岛素受体（IR）且无载脂蛋白（Apo）E（BAT特异性IR基因敲除[BATIRKO]；ApoE(-/-)小鼠），并评估了与肥胖相关的血管和代谢改变。此外，我们分析了脂肪器官对血管炎症的作用。棕色脂肪萎缩会导致内脏脂肪增加，主要是在性腺部位（性腺白色脂肪组织[gWAT]），出现严重的葡萄糖不耐受、餐后高血糖水平以及急性胰岛素分泌严重缺陷。BATIRKO；ApoE(-/-)小鼠表现出比ApoE(-/-)小鼠更严重的高甘油三酯血症，且高胆固醇血症与ApoE(-/-)小鼠相似。BATIRKO；ApoE(-/-)小鼠除了BAT存在原发性胰岛素抵抗外，在肝脏、gWAT、心脏、主动脉和胸段PVAT中胰岛素信号也显著降低。更重要的是，我们的结果表明严重的棕色脂肪萎缩会加剧动脉粥样硬化进程，其特征是脂质蓄积、动脉粥样硬化覆盖范围、病变大小和复杂性显著增加，巨噬细胞浸润增加以及促炎标志物表达增加。最后，BAT、gWAT和胸段PVAT中肿瘤坏死因子-α和瘦素增加以及脂联素减少也可能是血管损伤的原因。我们的结果表明严重的棕色脂肪萎缩会加剧动脉粥样硬化进程。因此，激活BAT可能预防肥胖及其相关的代谢改变。
