A Single-Cell Transcriptomics Roadmap to Investigate Diabetes Remission Induced by the Central Action of Fibroblast Growth Factor-1 (FGF-1)

Abstract

Recently, lasting remission of hyperglycemia was achieved in rodent models of type 2 diabetes (T2D) by a single intracerebroventricular (icv) injection of FGF-1. While the mechanism underlying this effect is unknown, the lack of association with changes of body fat mass or risk of hypoglycaemia raises the possibility that icv FGF-1 normalizes the defended level of glycemia, rather than simply lowering blood glucose levels. Recent work from our lab has identified gluco-regulatory neurocircuits in the mediobasal hypothalamus (MBH) as targets for this FGF-1 effect. To investigate the mechanism underlying FGF-1 action in this brain area, we used large-scale single cell RNA-sequencing to identify and characterize FGF-1-responsive cells in mouse MBH. Based on >70,000 single cell MBH transcriptomes from diabetic ob/ob mice harvested 5d after a single icv injection of either FGF-1 or vehicle, we identified >20 cell clusters and >900 cell type-specific differentially expressed genes (p<0.01). Among these potential targets of the MBH response to FGF-1 in diabetic mice, we found that FGF-1 treatment robustly increased the proportion of newly formed oligodendrocytes, a response that can be predicted to yield new mature oligodendrocytes and associated myelination of axons. These preliminary results demonstrate that transcriptional identification and characterisation of icv FGF-1-responsive cell clusters may both advance our understanding of brain control of glucose homeostasis and identify novel targets for diabetes prevention and treatment. Disclosure M.A. Bentsen: None. D. Rausch: None. J. Scarlett: None. K.M. Alonge: None. P.N. Timshel: None. Z. Mirzadeh: None. A. Secher: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. Employee; Spouse/Partner; Gubra. R. Jorgensen: Employee; Self; Novo Nordisk Inc.. T. Pers: None. M.W. Schwartz: Consultant; Self; Novo Nordisk A/S. Research Support; Self; Novo Nordisk A/S.