Novel transcription factor for UCP-1 expression in brown fat

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DESCRIPTION (provided by applicant): Obesity is a global health epidemic that is associated with decreased life span and increased incidence of metabolic diseases like type 2 diabetes and heart disease. Two types of fat exist. White fat stores energy in the form of fatty acids, and brown fat is the mammalian thermogenic organ. Brown fat has recently proven to be present in adult humans-a finding which has drawn considerable interest because increases in brown fat- specific gene expression appear to protect again obesity and metabolic syndrome. While it is known that brown fat thermogenesis can tip the energy balance in favor of use rather than storage, how and why this occurs is unclear at the molecular level. Furthermore, anti-obesity strategies could include increasing expression of brown-fat specific thermogenic genes including uncoupling protein-1 (UCP1) as well as brown fat formation. Since not much is known about the brown fat transcriptional network, a better understanding of this fnetwork is the immediate goal for the research project. Our lab has identified a novel zinc finger transcription factor that is preferentially expressed in brown fat at a high level, and our preliminary data indicate one target of this transcription factor (designated as B2) is UCP1, the most important known thermogenic gene, which is found exclusively in brown fat and critical for brown fat thermogenesis. The goal of the work to be undertaken in this NRSA fellowship is to understand the biology of B2 and its role in brown fat. Aim 1 seeks to define the DNA binding site for B2 in the UCP1 promoter using biochemical and molecular approaches. Aim 2 is to identify the protein interaction partners of B2 by tandem affinity purification and mass spectrometry. Finally, Aim 3 is to assess the role of B2 in vivo by developing and analyzing B2 knockout mice. These studies will make an important contribution to the newly resurgent field of brown fat biology by characterizing the novel transcription factor B2 and may provide new directions for the study of brown fat in obesity. PUBLIC HEALTH RELEVANCE: The prevalence of obesity in our society is unmistakable, and people with the disease have a shorter lifespan and an increased chance of diabetes and heart disease. This study seeks to understand the genetic regulation of brown fat, which burns fat as heat. By understanding more about brown fat, we may find new treatment targets that would activate this type of fat, burn more fat, and therefore reduce obesity.