The Role of Akt2 in Hepatic Lipid Metabolism

Insulin drives the global anabolic response to nutrient ingestion, regulating both carbohydrate and lipid metabolism. When insulin resistance occurs in Type 2 Diabetes Mellitus, dysregulation of both of these processes ensues, resulting in hyperglycemia and lipid abnormalities. One of the most prevalent morbidities associated with insulin resistance is the abnormal accumulation of triglycerides in the liver, called hepatic steatosis, though the underlying pathogenesis of this accumulation remains unclear. There is certainly an inappropriate increase in de novo lipogenesis in the livers of individuals with hepatic steatosis, but the insulin signaling pathway involved in the control of normal, and therefore abnormal, lipogenesis remain undefined. Previous studies have demonstrated that Akt2 is critical to insulin’s control of glucose metabolism, but its role in lipid metabolism has remained controversial. Here we show that Akt2 is required for hepatic lipid accumulation in obese, insulin-resistant states induced by either leptin-deficiency or high fat diet feeding. Leptin-deficient ob/ob mice lacking hepatic Akt2 failed to amass triglycerides in their livers, associated with and most likely due to a decrease in lipogenic gene expression and de novo lipogenesis. However, Akt2 is also required for steatotic pathways unrelated to fatty acid synthesis, as mice fed high fat diet had reduced liver triglycerides in the absence of hepatic Akt2 but did not exhibit changes in lipogenesis. In addition, we show that Akt2 is a requisite component of the normal insulin signaling pathway that controls de novo lipogenesis in lean non-steatotic livers. Following high-carbohydrate feeding, influx of glucose and secretion of insulin induce hepatic de novo lipogenesis in normal animals. However, liver-specific Akt2 null mice failed to induce de novo lipogenesis in response to high-carbohydrate feeding. These data demonstrate that Akt2 is required for the insulin-dependent regulation of hepatic lipid metabolism both in normal livers and during insulin resistance. These studies contribute to our understanding of insulin’s control of metabolism, and may potentially aid in the development of therapeutics for diseases that are increasing in prevalence around the world. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Cell & Molecular Biology First Advisor Morris J. Birnbaum