Role of hypothalamic MAPK/ERK signaling in diabetes remission induced by the central action of fibroblast growth factor 1

The capacity of the brain to elicit sustained remission of hyperglycemia in rodent models of type 2 diabetes (T2D) following intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1) is well established. Here, we show that icv FGF1 injection induces signaling by extracellular signal-regulated kinases 1 and 2 (ERK1/2), members of the mitogen-activated protein kinase (MAPK) family in the hypothalamus, and that this activation persists for at least 24h. Further, we show that in diabetic Lepob/ob mice, this prolonged response is required for the sustained antidiabetic action of FGF1, since it is abolished by sustained (but not acute) pharmacologic blockade of hypothalamic MAPK/ERK signaling. We also demonstrate that FGF1 R50E, a FGF1 mutant that activates FGF receptors but induces only transient hypothalamic MAPK/ERK signaling, elicits transient but not sustained glucose lowering. These data implicate sustained hypothalamic MAPK/ERK signaling in the mechanism underlying diabetes remission induced by icv FGF1. single-cell RNA sequencing (10X genomics Chromium system) and bulk RNA-sequencing