Molecular Control of Brown Adipose Cell Fate and Energy Metabolism

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DESCRIPTION (provided by applicant): Obesity develops when energy intake chronically exceeds total energy expenditure. Currently, most anti- obesity medications act to repress energy intake, either by suppressing appetite or by inhibiting intestinal fat absorption. However, due to side effects including depression, oily bowel movements and steatorrhea, there is an urgent need for alternative approaches. Because brown adipose tissue (BAT) dissipates energy to produce heat as a defense against cold and obesity, altering the molecular pathway to increase the amount or thermogenic activity of BAT may lead to an alternative and effective therapeutic intervention to counteract human obesity and metabolic disorders. Our long-term goals are to understand the molecular circuits that regulate the fate specification of brown adipose cells and to investigate their physiological roles in energy homeostasis. We have previously shown that brown adipocytes arise from a subset of dermomytomal precursors through the action of a transcription factor, PRDM16; however, it remains unclear how the PRDM16 action in the myoblast-to-brown fat switch is regulated. We identified a lysine methyltransferase, EHMT1 as a critical component of the PRDM16 transcriptional complex. EHMT1 is expressed at its highest in BAT and is highly induced by PRDM16. Notably, EHMT1 appears to act as a developmental switch of brown adipocytes versus myocytes. Importantly, loss of the EHMT1 gene is associated with obesity in mice and in humans; however, its underlying mechanism remains completely unknown. Our current objective is thus to investigate the physiological function and mechanism of EHMT1 that controls brown adipose cell fate in vivo. Based on our preliminary data, we will test the hypothesis that EHMT1 plays a pivotal role in energy homeostasis as a developmental switch that controls brown adipose cell fate through modulating the function of the PRDM16 complex. To test this hypothesis, we will pursue the following specific aims: In Aim1, we will determine the genetic requirement of EHMT1 in the fate specification and maintenance of brown adipose cells in vitro and in vivo. In Aim2, we will analyze the metabolic phenotypes of adipose-specific EHMT1 knockout mice and EHMT1 heterozygous null mice and critically characterize EHMT1's physiological role in controlling energy expenditure and glucose homeostasis in vivo. In Aim3, we will conduct biochemical analyses and use cultured cells to elucidate the mechanism by which EHMT1 acts as a developmental switch of brown fat lineage. The expected outcome of these studies is to characterize a completely novel upstream regulatory pathway of brown adipose cell fate specification. Our findings will have a significant impact, because, to our knowledge, this study will characterize the first enzyme that controls the cell fate switch between brown adipose versus skeletal muscle. The identified mechanism will allow us to manipulate this developmental pathway by pharmacological approaches, which may provide a possible therapeutic target.