Molecular Transducers of Physical Activity: Liver Adaptations Drive Brain Benefits

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PROJECT SUMMARY/ABSTRACT Physical inactivity is linked to at least 40 chronic disease conditions including insulin resistance, type 2 diabetes, nonalcoholic fatty liver disease, advanced brain aging, loss of cognition, and neurodegeneration. In contrast, regular exercise and maintenance of higher cardiorespiratory fitness expands health-span by maintaining each of these factors and reducing risk for a myriad of chronic conditions. While the beneficial effects of exercise are extensively recognized, the molecular mechanism(s) underpinning these benefits are less well understood. Existing literature and data recently released by MoTrPAC indicate that liver-derived factors may play a central role in the systemic benefit of exercise. Studies in this proposal will profile known and unknown factors released from the liver after exercise that may serve as molecular transducers of exercise and drive positive adaptations in liver, skeletal muscle, and brain health. We have focused on MoTrPAC data revealing a robust ~200-fold acute exercise induced upregulation in hepatic mRNA expression of orphan nuclear receptor neuro-derived clone 77 (Nur77 or NR4A1) that occurred in conjunction with an elevation in hepatic fibroblast growth factor 21 (FGF21) mRNA and elevated plasma ketone levels. Nur77 and FGF21 are intimately linked, as Nur77 transcriptionally regulates FGF21 and both are known to regulate hepatic ketogenesis. In addition, both FGF21 and ketone bodies are primarily liver-derived and both are known to have strong systemic and neuroprotective properties. However, little is known about the role of these factors in exercise-mediated changes in brain and cognitive health. Here we will test our central hypothesis that exercise-induced hepatic adaptations are central to the molecular adaptations that occur in the skeletal muscle and brain with acute and chronic exercise. We will mechanistically interrogate if hepatic Nur77 (via a liver-specific AAV-shRNA knockdown approach) is a critical exercise-induced factor driving both hepatic FGF21 and ketone production in male and female Fischer 344 rats (Aim 1). Similarly, we will target ketogenesis directly by knocking down liver HMG-CoA synthase 2 (HMGCS2, the key regulatory enzyme in hepatic ketogenesis) (Aim 1). In addition, we will perform an unbiased screen of extracellular vesicles and miRNAs released by the liver in response to acute and chronic exercise training and test whether there are novel secreted factors originating in the liver regulate carbohydrate and lipid metabolism in neuronal and skeletal muscle cells (Aim 2). Collectively, our proposed approaches will establish the critical mechanistic importance of Nur77 and HMGCS2 in the regulation of hepatic FGF21 and ketone-mediated benefits in liver, skeletal muscle, and brain health. In addition, these studies will also potentially identify other novel exercise-induced molecular transducers originating from the liver.