Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Boston, Massachusetts, USA; Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA;
Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA; Cardiovascular Division, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA; and.
FASEB J. 2014 Oct;28(10):4408-19. doi: 10.1096/fj.14-253971. Epub 2014 Jul 8.
Mitochondrial dysfunction in adipose tissue occurs in obesity, type 2 diabetes, and some forms of lipodystrophy, but whether this dysfunction contributes to or is the result of these disorders is unknown. To investigate the physiological consequences of severe mitochondrial impairment in adipose tissue, we generated mice deficient in mitochondrial transcription factor A (TFAM) in adipocytes by using mice carrying adiponectin-Cre and TFAM floxed alleles. These adiponectin TFAM-knockout (adipo-TFAM-KO) mice had a 75-81% reduction in TFAM in the subcutaneous and intra-abdominal white adipose tissue (WAT) and interscapular brown adipose tissue (BAT), causing decreased expression and enzymatic activity of proteins in complexes I, III, and IV of the electron transport chain (ETC). This mitochondrial dysfunction led to adipocyte death and inflammation in WAT and a whitening of BAT. As a result, adipo-TFAM-KO mice were resistant to weight gain, but exhibited insulin resistance on both normal chow and high-fat diets. These lipodystrophic mice also developed hypertension, cardiac hypertrophy, and cardiac dysfunction. Thus, isolated mitochondrial dysfunction in adipose tissue can lead a syndrome of lipodystrophy with metabolic syndrome and cardiovascular complications.
脂肪组织中的线粒体功能障碍发生在肥胖、2 型糖尿病和某些形式的脂肪营养不良中，但这种功能障碍是这些疾病的原因还是结果尚不清楚。为了研究脂肪组织中严重线粒体损伤的生理后果，我们利用携带脂联素-Cre 和 TFAM 基因敲除等位基因的小鼠，在脂肪细胞中生成了线粒体转录因子 A（TFAM）缺陷型小鼠。这些脂联素 TFAM 敲除（adipo-TFAM-KO）小鼠的皮下和腹腔白色脂肪组织（WAT）和肩胛间棕色脂肪组织（BAT）中的 TFAM 减少了 75-81%，导致电子传递链（ETC）复合物 I、III 和 IV 的蛋白表达和酶活性降低。这种线粒体功能障碍导致 WAT 中的脂肪细胞死亡和炎症，以及 BAT 的白化。结果，adipo-TFAM-KO 小鼠对体重增加有抵抗力，但在正常饲料和高脂肪饮食中均表现出胰岛素抵抗。这些脂肪营养不良小鼠还发展出高血压、心脏肥大和心脏功能障碍。因此，脂肪组织中孤立的线粒体功能障碍可导致伴有代谢综合征和心血管并发症的脂肪营养不良综合征。
