Obesity is an epidemic in the USA and is a leading cause of morbidity. The rise in obesity is associated with the onset of Metabolic Syndrome (MS). Contributing to this epidemic is a lifestyle that disrupts the daily circadian rhythm (lack of regular sleep). The goal of this project is to define the molecular networks regulating energy storage and utilization as a requisite for understanding MS and as a first step in developing effective ways to counter MS-associated morbidities. SRC-2 is a critical regulator of energy homeostasis and is an attractive potential target for treating MS. Over the last funding period, we demonstrated that SRC-2 is a critical regulator of energy homeostasis in the mouse liver, regulating glucose mobilization and fat absorption by regulating the activities of Nuclear Receptors, NRs. Since the last submission, we have conducted genome-wide in vivo chromatin immuno-precipitation and next generation sequencing (ChlP-Seq) for SRC-2 in mouse liver. Preliminary analysis of the SRC-2 chromatin binding sites revealed motif sequences that indicate that SRC-2 interacts with a variety of NRs bound to DNA, as expected, but it also co-occupies El box motifs, known binding sites for the core circadian regulators BMAL1 and CLOCK. We now have preliminary data to demonstrate that circadian homeostasis is significantly disrupted in SRC-2 null mice and that SRC-2 regulates the expression of a cassette of Core Circadian Genes (CCGs). Thus, we hypothesize that SRC-2 plays a critical role in regulating metabolism by controlling the circadian rhythm in the liver- and in other metabolically important tissues, such as adipose tissue. In this renewal, we will investigate how disrupting the expression of SRC-2 alters the circadian regulation of liver and adipose energy metabolism. This will be accomplished in three specific aims: 1: The physiologic role of SRC-2 in the circadian regulation of liver metabolism and the overall impact on MS in the mouse will be determined; 2: The interactions of SRC-2 and BMAL1 and CLOCK will be defined; 3:
This aim will determine the role of adipocyte expression of SRC-2 in the regulation of weight homeostasis, glucose mobilization, and adipocyte circadian rhythm.
Obesity is an epidemic in the United States and is a leading cause of morbidity. This epidemic can be associated with changes in diet and disruptions of our daily routine. The goal of this project is to investigate the role of transcriptional coregulator SRC-2 in this process. SRC-2 is a key regulator of the body's ability to control caloric intake and a regulator of our daily metabolic rhythms.
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