The rise in the incidence of obesity and the subsequent increase in the prevalence of nonalcoholic fatty liver disease, insulin resistance, and Type II Diabetes (T2DM) have led to a need to understand the mechanisms that control energy metabolism. The sponsor's laboratory and others have contributed significantly to understanding insulin signaling and the onset of insulin resistance in the liver, muscle, and adipose tissue. Metabolic signaling in fat cells is critical to our understanding of T2DM. Adipose tissue is an organ devoted not only to nutrient storage, but also has an endocrine function important to the control of systemic glucose and lipid homeostasis. A current attractive model for the development of insulin resistance is that it first begins in adipose tissue and is then propagated to other insulin sensitive organs. This proposal will ask: what are the effects of defective signaling in adipose tissue on insulin resistance in other key organs? To ask this question, we will use model systems with adipose- specific deletion of Akt2 and Akt1 deleted concurrently with Akt2. We will first probe the local consequences of disrupting Akt-dependent insulin signaling and what actions of insulin are Akt- independent in adipocytes. By enhancing our understanding of the cell-autonomous effects of Akt2 and Akt1/Akt2 deletion in adipocytes in vivo, we will be able to better interpret the non- autonomous effects of insulin resistance in adipose tissue and ascertain whether there is a compensatory role for Akt1 when cells are deficient for Akt2. Data have suggested that insulin resistance can be propagated from adipocyte-specific to the whole body;however, much controversy remains in the literature. Our models with adipocyte-specific Akt2 and Akt1/Akt2 deletion will address this question. We hypothesize that loss of Akt in adipocytes will affect other metabolic organs, conferring a phenotype of decreased insulin sensitivity and glucose intolerance. The experiments in this proposal are highly relevant to understanding the mechanisms by which obesity frequently leads to insulin resistance in adipose tissue, liver and muscle.
In the last several decades, the rate of obesity and Type II Diabetes mellitus has become an epidemic in the United States. Understanding how insulin resistance propagates in individuals from one metabolic organ to others is critical for the development of effective therapeutics aimed at treating the many health effects of obesity.