The Role of Amp-Activated Protein Kinase in the Regulation of Fatty Acid Synthesis in Adipocytes

Background and Rationale: Obesity-associated dysfunctions in adipose tissue underlie the development of insulin resistance and diabetes. Many studies have observed a close correlation between systemic insulin sensitivity and the level of fatty acid (FA) synthesis in adipose tissue. FA derivatives produced by this pathway act as lipokines that are secreted to the circulation and promote systemic insulin sensitivity. These lipokines are commonly reduced in individuals with obesity and insulin resistance. In spite of its important role in maintaining insulin sensitivity, the regulation of FA synthesis in adipocytes is not fully understood. Here we will specifically study the role of AMP-activated protein kinase (AMPK), which is known to regulate the activity of acetyl-CoA carboxylase, the rate-limiting enzyme in FA synthesis. AMPK activators are being developed for the treatment of insulin resistance, due to their beneficial effects in muscle and liver, but the role of AMPK in adipocytes is far less studied.
Aims: We aim to determine the role of AMPK in the control of FA synthesis in adipocytes and whether AMPK mediates the stimulatory effect of insulin on this pathway. We will also explore potential dysregulation of adipocyte AMPK in obesity and insulin resistance.
Approach: We will use a novel generation of AMPK activators, primary adipocytes from humans, as well as transgenic animal models.
Significance: Ultimately, the results from this study will increase our knowledge about how obesity-associated insulin resistance develops.