Regulation of adipose tissue remodeling by the CCNC-Mediator

Project Summary/Abstract: Obesity has become a major health problem. In contrast to pathologic obesity, “metabolically healthy obesity” features less insulin resistance with more small adipocytes in subcutaneous adipose tissues. The inability to increase the adipocyte number has been proposed as a cause of insulin resistance and type 2 diabetes in obesity. However, the regulatory mechanisms that control the number of adipocytes remain enigmatic. Through functional screens, we have previously identified Cyclin C (CCNC) as a critical regulator in brown adipogenesis. CCNC protein in mouse liver and brown fat is robustly downregulated in obesity or aging. Relevant to human diseases, CCNC is significantly associated with body mass index (BMI) and type 2 diabetes in GWAS data, and the amino acid sequences of human, mouse, and rat CCNC are identical. Using mouse models, we found that CCNC deletion at the whole-body level, or specifically in Ucp1+ cells or hepatocytes enhanced cold-induced white adipose tissue (WAT) browning. Moreover, CCNC deletion in hepatocytes resulted in a “metabolically healthy obesity” -like phenotype. These preliminary studies support the role of CCNC in WAT remodeling and metabolic disease. Although CCNC was historically named a “cyclin”, it does not directly regulate the cell cycle. Instead, CCNC is the most conserved subunit of the Mediator complex, which is a multi-protein cofactor in gene transcription. During transcription, the Mediator complex is recruited by activated transcription factors to interact with the basal transcription machinery. As a result, the Mediator complex regulates transcription highly depending on the gene of interest, cell type, and microenvironment of the cell. The central hypothesis of this project is that in the context of the Mediator complex, CCNC regulates nutritional or environmental cues-induced WAT remodeling through both WAT cell-autonomous and liver-WAT crosstalk mechanisms, and the liver secretome can modulate the abundance of adipocyte progenitor cells (APCs). In addition to our previous work, our hypothesis is supported by preliminary data from studying liver-specific knockout of CCNC in mouse models, including reduced insulin resistance and increased subcutaneous adipocyte number under high-fat diet, increased cell proliferation in subcutaneous WAT, and upregulation of hepatic Pdgfa gene and elevation of PDGF-AA in blood. To test the hypothesis, we will pursue two Specific Aims. Aim 1 will study the WAT cell-autonomous mechanisms and metabolic functions of enhanced WAT browning upon CCNC deficiency. Aim 2 will study the cellular and molecular mechanisms for liver CCNC regulation of WAT remodeling in mouse models of diet-induced obesity and cold exposure with a focus on the role of liver-derived PDGF-AA. A combined genetic and gene delivery approaches together with physiological, metabolic, histological, biochemical, and molecular analyses will be used to carry out the proposed studies. All key animal models, reagents, and techniques have been established, and key supporting data have been obtained. Successful completion of these studies will yield novel insight into the role of the human BMI-associated CCNC surface of the Mediator complex in regulating metabolism. Moreover, the experimental and conceptual models will become a foundation of future studies on obesity. In the long run, we hope to identify new targets and/or strategies for the prevention, diagnosis, and treatment of obesity and type 2 diabetes.