Lasting remission of hyperglycemia can be achieved in rodent models of type 2 diabetes by a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF-1), and the mediobasal hypothalamus (MBH) was recently identified as a target for this effect. To investigate the cellular basis of FGF-1 action in the MBH, we combined whole tissue RNA-sequencing with large-scale single cell and single nuclei RNA-sequencing to generate >60,000 single cell transcriptomes from diabetic ob/ob mice harvested 5d after a single icv injection of either FGF-1 or vehicle. Of the 4 known FGF receptor genes, 3 were expressed in the MBH, primarily by glial cells rather than neurons. Employing weighted gene co-expression network analysis, distinct modules that correlated with icv FGF-1 treatment were identified, again primarily in glial cells. In astrocytes, the response to FGF-1 closely paralleled the neuroprotective “A2” transcriptional phenotype induced by stroke, and both the proportion of differentiating oligodendrocytes and genes involved in extracellular matrix remodeling of the perivascular space were also upregulated by FGF-1. By comparison, the neuronal response to icv FGF-1 was one of generalized inhibition, including decreased expression of Agrp and Pmch (encoding agouti-related peptide and pro-melanin-concentrating hormone (MCH), respectively). Since Agrp and MCH neurons are activated in ob/ob mice, and since this effect predisposes to hyperglycemia, these findings support a model in which sustained inhibition of these and perhaps other neuronal subsets underlies diabetes remission induced by icv FGF-1. Moreover, this neuronal inhibition appears to be driven by neuroprotective glial responses elicited by FGF-1. These data add to growing evidence of a crucial role for neuron-glia interactions in hypothalamic control of glucose homeostasis.
M.A. Bentsen: None. D. Rausch: None. Z. Mirzadeh: Consultant; Self; Novo Nordisk A/S. J. Scarlett: None. J.M. Brown: None. K.M. Alonge: Research Support; Self; Novo Nordisk Inc. T.H. Meek: Employee; Self; Novo Nordisk Inc. A. Secher: Employee; Spouse/Partner; Gubra. Employee; Self; Novo Nordisk A/S. Speaker's Bureau; Spouse/Partner; Gubra. Stock/Shareholder; Self; Novo Nordisk A/S. R. Jorgensen: Employee; Self; Novo Nordisk A/S. T. Pers: None. M.W. Schwartz: Consultant; Self; Novo Nordisk A/S. Research Support; Self; Novo Nordisk A/S.
National Institutes of Health; Novo Nordisk Foundation; Lundbeck Foundation; Novo Nordisk A/S