Obesity, which is caused by chronic imbalance between energy intake and energy expenditure, is a leading risk factor for the development of type 2 diabetes and cardiovascular disease. Recent studies have demonstrated that adult humans harbor brown/beige adipocytes, whose thermogenic activity can be induced by cold exposure or adrenergic agonists. Since activation of brown/beige adipocytes in mice and humans promotes negative energy balance and weight loss, there is great clinical interest in therapeutically targeting brown fat to treat obesity, type 2 diabetes, and cardiovascular disease. Although the transcriptional and signaling pathways that regulate development of brown adipose tissue are known, our understanding of how brown fat is maintained in its inactive state is limited. This is an important question to address because humans primarily live in their thermal comfort or neutral zone, which causes their brown adipose to become inactive. To fill this fundamental gap in our knowledge, we analyzed transcriptomes of active and inactive brown adipose tissue using RNA-seq. These studies revealed the transcriptional signatures of inactive brown adipose tissue in adult mice and led to the identification of novel transcriptional regulators of brown fat thermogenesis. In this grant application, we will utilize techniques from mouse genetics, metabolism, adipocyte biology, and genomics to dissect the underlying mechanisms that maintain thermogenic competence in inactive brown adipose tissue. The two major questions we will address are: 1) What transcription factors maintain thermogenic competence of inactive brown adipose tissue in thermoneutral mice? and 2) What are the genetic and metabolic mechanisms by which these transcription factors maintain brown fat in its inactive state? The successful completion of these aims will provide novel insights into how brown adipose tissue is maintained at thermoneutrality, thus advancing our understanding of how to therapeutically target this tissue for the treatment of human obesity and metabolic diseases.
Obesity is a global epidemic that results from chronic imbalance between energy intake and energy expenditure, and a potential way of treating obesity is to increase energy expenditure via the heat producing actions of brown fat, which is found in mice and humans. Although many factors have been identified that regulate differentiation and activation of brown adipocytes, little is known about how brown adipose tissue is maintained in its inactive state. In this application, we will identify the factors and mechanisms that maintain brown adipose tissue when it is inactive.
