PROJECT ABSTRACT The prevalence of obesity is on the rise and a better understanding of the drivers of this epidemic is crucial. As novel insights implicate bone in regulating energy metabolism, it is crucial to understand how diseases of positive energy balance, like obesity, affect the different functions of bone. While obesity is known to impact the structural function of bone causing increased fragility, it is unclear how the metabolic function of bone is compromised in obesity. Filling this gap in our knowledge is critical for developing therapeutics that can reestablish energy metabolism while maintaining musculoskeletal health in obesity. In this proposal, we explore the effects of obesity on bone regulated energy metabolism and focus particularly on osteocytes, that constitute 95% of cells in bone. Our compelling preliminary data puts forth the premise that TGFβ signaling is a key modulator of osteocyte-intrinsic energy metabolism (cellular). Thus, we test the hypothesis that obesity impacts osteocytic TGFβ signaling that in turn contributes to deregulated systemic energy metabolism. Furthermore, our data suggest that osteocytic TGFβ signaling also coordinates the activities of epigenetic factors to shape the transcriptome of osteocytes. These epigenetic factors have previously been implicated in obesity; however, their relation to TGFβ signaling and cellular energy metabolism of osteocytes remains unexplored. Together, these findings motivate my central hypothesis, that osteocytic TGFβ signaling drives metabolic dysfunction in obesity through an epigenetic mechanism. My aims to test this hypothesis are to: 1) determine if obesity induces metabolic reprogramming in osteocytes in a TGFβ- dependent manner, 2) determine if ablation of osteocytic TGFβ rescues metabolic dysfunction in obesity, and 3) identify the function of TGFβ responsive epigenetic factors in regulating osteocyte driven energy metabolism during obesity. Using hyperglycemia and hyperlipidemia (in vitro) and DIO (diet-induced obesity, in vivo) to model obesity, we will monitor the link between osteocytic TGFβ signaling, cellular- and systemic- energy metabolism, and study its role in regulating the obesity-induced metabolic dysfunction. For combining ChIP- Seq, ATAC-Seq, and RNA-Seq approaches, we will generate a network landscape connecting epigenetic marks, modifiers, chromatin accessibility patterns, and corresponding molecular pathways that are impacted by obesity in osteocytes. In the future, this landscape of molecular and epigenetic networks will serve as a blueprint that can be used to interpret osteocyte function in metabolism in response to distinct nutrient cues. Such a blueprint will be particularly informative in devising or predicting outcomes of pharmacologic interventions and will lay the foundation for my independent research that dissects the intricacies behind the crosstalk between bone function and energy metabolism. Project Abstract