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.
Development of effective new strategies to promote adipose tissue health will reduce the incidence of diabetes and positively impact public health in the United States and around the world. ATP-citrate lyase (ACLY) is an enzyme that generates acetyl-CoA for de novo lipogenesis within the cytosol and histone acetylation within the nucleus. Here 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 thermogenesis.
