High fat diet remodels the gene regulatory networks in the preoptic area

Abstract

Diabetes is characterized by widespread dysfunction throughout the body due to chronic hyperglycemia. To offset the beta cell failure and insulin resistance through potentially intact mechanisms in the individual, the central nervous system is an intriguing target for restoring glycemic control. While the current generation of diabetes therapeutics operate, at least in part, by re-tuning the function of dynamic neural circuits that maintain energy balance, neurological markers for remission have not been established for metabolic disease in many parts of the brain that are involved in energy balance and glucose homeostasis. These remission modules could be then applied to lesser established brain regions and expedite the discovery of diabetes-related functions in additional regions. To meet this goal, we used a previously published hypothalamic single cell sequencing dataset from ob/ob mice in remission from diabetes due to FGF1 treatment and identified remission modules (i.e. clusters of genes) that can be used to locate the networks that are corrected with successful treatment. We applied the remission modules to a dataset using C57 mice from the preoptic area of the hypothalamus, a region with links to metabolic disease but little characterization. We identified markers in both excitatory and inhibitory neurons in the preoptic area and validated their expression in the preoptic area using RNA scope. Together, these studies establish a remission module in hypothalamic neurons that can be used to define key cell types and markers in the brain that are responsive to correction of glucose homeostasis.