Adipocytes play a crucial role in the maintenance of global energy homeostasis through the regulated storage and mobilization of triglyceride and secretion of a variety of adipokines. However, the molecular mechanisms by which adipocytic lipid metabolism is controlled are not completely understood. In particular, the potential role of glucose storage as glycogen in the modulation of lipid metabolism has not been investigated, largely due to the low absolute levels of glycogen in adipose tissue. However, we have provided preliminary data from a novel transgenic model demonstrating that murine adipocytes are capable of stably storing 100-400-fold more glycogen than control littermates. These results were obtained by overexpression of the endogenous adipocytic protein PTG, which targets protein phosphatase-1 to glycogen. Our central hypothesis is that adipocytic glycogen levels are actively established and defended rather than result from a residual default mechanism. Further, we will test the supposition that the transcriptional regulation of PTG expression is a critical determinant of glycogen levels in adipose tissue, which in turn modulates rates of lipogenesis and lipolysis. To test these hypotheses, we propose three specific Aims.
In Aim 1, we will define the specific promoter elements and transcription factors that induce PTG expression during adipogenesis and mediate the hormonal modulation of PTG levels in mature adipocytes.
In Aim 2, we will generate and characterize an inducible, adipose-tissue specific PTG knockout mouse line to determine the impact of disrupting adipocytic glycogen storage on lipid metabolism and cell function. Finally, in Aim 3, we will fully investigate the metabolic impact of bi-directional modulation of glycogen metabolism on global energy utilization. We will utilize an integrated set of approaches, including in vitro assays of energy storage and mobilization in primary adipocytes coupled with in vivo measurement of energy mobilization and usage. Cumulatively, these experiments define the role of PTG in the control of adipocytic glycogen storage and will investigate the underappreciated but potentially fundamental metabolic connections between glycogen and lipid metabolism is adipose tissue.
Obesity and the resulting metabolic complications such as type 2 diabetes are increasing at an alarming rate in this country. We will test the hypothesis that glucose and lipid storage work coordinately to regulate energy metabolism in the adipocyte. We will also determine the impact of altering glycogen storage in fat cells on their function in vitro and in vivo.
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