Acetyl-CoA metabolism and nutrient sensing in adipocytes

近几十年来，肥胖症和相关代谢性疾病，如2型糖尿病和脂肪肝的发病率稳步上升。脂肪组织内的营养代谢对全身代谢健康至关重要。虽然最近的研究指出了信号和代谢途径之间的双向关系，但营养代谢在调节脂肪细胞信号和基因表达方面的作用尚不清楚。对这种关系的新见解可能会指向肥胖症和糖尿病的治疗策略。乙酰辅酶A的核质池对于脂类的从头合成和蛋白质赖氨酸乙酰化是至关重要的。最近的研究表明，组蛋白和其他细胞蛋白的乙酰化对乙酰辅酶A的可用性很敏感，因此乙酰化可能是一种以营养敏感的方式调节基因表达的机制。三磷酸腺苷-柠檬酸裂解酶(ACLY)是葡萄糖合成核质乙酰辅酶A的主要酶。在肥胖或高脂肪喂养时，脂肪组织中的ACLY被抑制，而碳水化合物则相反地诱导。我们以前的研究表明，ACLY以一种营养依赖的方式调节组蛋白乙酰化和脂肪细胞中葡萄糖代谢基因的表达。我们已经培育出在所有脂肪组织(Aclyf/f；adiponectin-Cre)中缺乏Acly的小鼠，特别是棕色脂肪组织(Aclyf/f；Ucp1-Cre)。ACLY缺乏会导致白色和棕色脂肪组织中基因表达模式和脂肪代谢的改变。基于大量的初步数据，我们建议检验这一假说，即ACLY产生的葡萄糖依赖的乙酰-辅酶A使脂肪细胞中的营养依赖的基因调控，作为碳水化合物处理和胰岛素反应以及产热的关键控制机制。具体地说，我们将测试ACLY在脂肪特异性和全身性碳水化合物代谢中的作用，并确定ACLY调节白色脂肪细胞基因表达的机制。我们将确定ACLY在冷诱导的BAT重塑中的作用，并阐明乙酰辅酶A代谢促进产热的机制。我们认为，乙酰辅酶A代谢紊乱是代谢性疾病的一个特征，通过确定关键的乙酰辅酶A产生者ACLY在脂肪细胞中的作用，这些研究将指向改善有代谢性疾病风险的个体的代谢健康的新策略。

Rates of obesity and associated metabolic diseases such as type 2-diabetes and fatty liver disease have risen steadily in recent decades. Nutrient metabolism within adipose tissue is essential for whole body metabolic health. While recent studies have pointed towards a bidirectional relationship between signaling and metabolic pathways, the role of nutrient metabolism in modulating signaling and gene expression in adipocytes is poorly understood. Novel insights into this relationship could point towards therapeutic strategies for obesity and diabetes. Nuclear-cytoplasmic pools of acetyl-CoA are crucial for de novo synthesis of lipids and for protein lysine acetylation. Recent studies have revealed that acetylation of histones and other cellular proteins is sensitive to acetyl-CoA availability, and that acetylation may thus serve as a mechanism to modulate gene expression in a nutrient-sensitive manner. ATP-citrate lyase (ACLY) is the major enzyme responsible for generating nuclear-cytoplasmic acetyl-CoA from glucose. ACLY is suppressed in adipose tissue in obesity or upon high fat feeding and is conversely induced by carbohydrates. Our previous studies implicated ACLY in regulating histone acetylation and expression of glucose metabolism genes in adipocytes, in a nutrient-dependent manner. We have generated mice lacking Acly in all adipose tissues (Aclyf/f; Adiponectin-Cre) and specifically in brown adipose tissue (Aclyf/f; Ucp1-Cre). ACLY deficiency results in altered gene expression patterns and lipid metabolism in both white and brown adipose tissue. Based on extensive preliminary data, we propose to test the hypothesis that glucose-dependent acetyl-CoA production by ACLY enables nutrient-dependent gene regulation in adipocytes, serving as a key control mechanism for carbohydrate handling and insulin response, as well as for thermogenesis. Specifically, we will test ACLY’s role in fat-specific and systemic carbohydrate metabolism and define the mechanisms through which ACLY regulates gene expression in white adipocytes. We will define the role of ACLY in cold-induced BAT remodeling and elucidate the mechanisms by which acetyl-CoA metabolism promotes thermogenesis. We propose that disruption of acetyl-CoA metabolism is a feature of metabolic disease, and that by defining the roles of the key acetyl-CoA producer ACLY in adipocytes, these studies will point to new strategies to improve the metabolic health of individuals with or at risk for metabolic diseases.