The Role of CREBRF on Hypothalamic Function

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Obesity is escalating at an alarming rate and is a major contributor to associated to multiple serious health problems such as Type 2 diabetes. Interesting, a missense variant in humans was identified in the poorly understood gene CREBRF to increase BMI while protecting from developing diabetes. CREBRF is a transcriptional co-regulator that is expressed centrally and within the hypothalamus, whose neurons integrate information from other brain regions as well as the periphery to control many homeostatic functions such as food intake and stress responses. Furthermore, loss of CREBRF in mice impacts hypothalamic output observed by a reduction in body weight, glucocorticoid levels after an acute stressor, and anxiety-like behaviors. Therefore, the overall objective of this proposal is to determine how CREBRF impacts hypothalamic function by determining its localization and recruitment to the genome in a brain region critical for stress responses. Our central hypothesis is that CREBRF functions as a transcriptional co-regulator to regulate gene expression, ultimately influencing metabolic and behavioral outcomes. The central hypothesis will be tested using the novel CREBRF3xFLAG mouse model and our expertise in neuroanatomy, genome-wide analysis, and behavioral phenotyping to achieve the following sub-aims: 1.) to determine the impact of CREBRF on the transcriptional response to acute stress within the hypothalamus, 2.) to systematically characterize hypothalamic CREBRF by determining its regulation and localization during acute stress, and 3.) to perform baseline phenotyping for this novel CREBRF3xFLAG global mouse model. Using antibodies to detect the 3x-FLAG tag, we expect to gain a substantial amount of information about CREBRF while ensuring this small tag does not impact CREBRF function and interpretation of our results. This research will provide deep understanding for a relatively unknown gene and advance our understanding for how CREBRF impacts physiology and behavior. These Sub-Aims will complement ongoing K01 research and expand our research capabilities to further understand the role of CREBRF on hypothalamic function, ultimately impacting output. Support provided by this R03 Award will allow Dr. Frahm to continue to build her independent research program by generating preliminary data for a competitive R01 grant submission.