Modulation of Adipocyte Function by Protein Kinase D, Histone Deacetylase, and Protein Acetylation

Obesity has been linked to many chronic diseases, including insulin resistance, diabetes mellitus, cardiovascular diseases, and cancer. Therefore, it has been a major health issue in modern society including Taiwan. Obesity is primarily due to hypertrophy of adipocytes with excess fat storage, leading to malfunction of adipocytes. Thus, understanding the functions of adipocytes and how they are regulated are important. Protein kinase D (PKD) isoforms belong to the members of calmodulin-dependent protein kinase (CaMK) serine/threonine kinase family. They regulate many cellular and physiological functions. However, the role of PKD in adipocytes remains largely unknown. Using 3T3-L1 adipocytes and isolated primary adipocytes as the model system, we found that PKDs regulates lipid storage and expression of genes involved in lipogenesis. Interestingly, we also found that class IIa histone deacetylases (HDACs) may mediate some PKD actions in regulating adipocyte functions. Moreover, PKD may also regulate ATP citrate lyase (ACLY), the enzyme catalyzing the glucose-derived acetyl CoA, suggesting that PKD may also affect protein acetylation in adipocytes. Therefore, we aim to use 3T3-L1 adipocytes, primary adipocytes, and mouse model to address the following important questions: (1) What are the molecular mechanisms by which PKDs via modulating class IIa HDACs to regulate adipocyte functions? (2) How do PKDs modulate protein acetylation in adipocytes, and what is the physiological importance following this regulation? (3) How does obesity dis-regulate the PKD/HDAC/protein acetylation in adipocytes? These studies not only will give us insight on the molecular mechanism controlling adipocyte functions, but also provide potential therapeutic targets in treating diseases in the future.

Project ID:PC10907-1524
External Project ID:MOST109-2320-B182-007