Circadian-metabolic crosstalk in tanycyte endocrine signaling and neurogenesis

About This Grant

Project Summary/Abstract Circadian clocks are ubiquitous in tissues, regulate many metabolic functions, and their misalignment or disruption contributes to deleterious health consequences. Although molecular underpinning of the circadian clock is well-studied, the role of the clock in tissue-specific metabolic functions, such as that of tanycytes, is poorly understood. Tanycytes, specialized hypothalamic glial cells, gate the entrance of nutrients and hormones to the brain, signal to hypothalamic neurons, and generate new neurons relevant for feeding and sleep. Circadian rhythms in peripheral signaling to the brain are necessary to maintain whole-body energy homeostasis, but the contribution of cell-autonomous circadian rhythms in tanycytes to this process is completely unexplored. My recent work has identified the presence of these rhythms in tanycytes and found that the core circadian clock gene Bmal1 in tanycytes regulates leptin signaling, diet-induced weight gain, and adult neurogenesis in female mice. This proposal examines the mechanisms of circadian regulation of tanycyte endocrine signaling and neurogenesis, their relevance to feeding behavior, and the contribution of diet and sex differences to these processes. I hypothesize that there is an autonomous circadian rhythm in tanycyte leptin signaling to the arcuate nucleus of the hypothalamus, the brain's feeding control center (Aim 1). Based on published and preliminary data, I propose that tanycyte circadian rhythms influence feeding behavior through endocrine signaling and neurogenesis (Aim 2). I further hypothesize that tanycyte neurogenesis is controlled by circadian rhythms both at the level of initial cell division and differentiation (Aim 3). Finally, I will interrogate the effects of sex hormone signaling on tanycyte circadian-metabolic function (Aim 4). To pursue these aims, I will use a combination of cellular and molecular assays (immunolabeling, single-cell RNA sequencing), functional bioassays (BrdU cell division labeling, stem cell lineage tracing, metabolic phenotyping) and behavioral assays. Successful completion of this project will offer important advances in understanding both circadian rhythms in tanycyte metabolic function and behavior. First, understanding molecular mechanisms of the tanycyte rhythms will further define the role of the clock in gating periphery to brain communication. Second, it will provide new insights into the regulation of food intake. Third, it will identify novel pathways through which diet and sex differences influence the circadian transcriptome. Understanding the temporal gating of tanycyte function under pathophysiologic conditions is important for developing interventions to improve human health. Plan for Career Development: My training plan leverages a highly complementary co-mentorship arrangement between Dr. Amita Sehgal and Dr. Stewart Anderson who possess deep expertise in circadian rhythms/metabolism and stem cell metabolism/neurogenesis respectively. I will receive significant consultative support from Dr. Ron Anafi of the University of Pennsylvania Center for Subcellular Genomics and Drs. Joseph Baur and Corey Holman, directors of the Rodent Metabolic Phenotyping Center at Penn. My research and transition to independence will benefit from this strong mentorship team, state-of-the-art facilities/equipment, and professional development resources offered through the Penn office of Biomedical Postdoctoral Programs.