Central injection of fibroblast growth factor 1 induces sustained remission of diabetic hyperglycemia in rodents

Abstract In rodent models of type 2 diabetes (T2D), sustained remission of hyperglycemia can be induced by a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1), and the mediobasal hypothalamus (MBH) was recently implicated as the brain area responsible for this effect. To better understand the cellular response to FGF1 in the MBH, we sequenced >79,000 single-cell transcriptomes from the hypothalamus of diabetic Lepob/ob mice obtained on Days 1 and 5 after icv injection of either FGF1 or vehicle. A wide range of transcriptional responses to FGF1 was observed across diverse hypothalamic cell types, with glial cell types responding much more robustly than neurons at both time points. Tanycytes and ependymal cells were the most FGF1-responsive cell type at Day 1, but astrocytes and oligodendrocyte lineage cells subsequently became more responsive. Based on histochemical and ultrastructural evidence of enhanced cell-cell interactions between astrocytes and Agrp neurons (key components of the melanocortin system), we performed a series of studies showing that intact melanocortin signaling is required for the sustained antidiabetic action of FGF1. These data collectively suggest that hypothalamic glial cells are leading targets for the effects of FGF1 and that sustained diabetes remission is dependent on intact melanocortin signaling.

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An Action in the Hypothalamic Arcuate Nucleus Is Sufficient to Explain the Sustained Remission of Diabetes Induced by Central Administration of Fibroblast Growth Factor-1 (FGF-1)

Diabetes ◽

10.2337/db18-372-or ◽

2018 ◽

Vol 67 (Supplement 1) ◽

pp. 372-OR

Author(s):

JENNY M. BROWN ◽

JARRAD SCARLETT ◽

MILES E. MATSEN ◽

ANNA SECHER ◽

RASMUS JORGENSEN ◽

...

Keyword(s):

Growth Factor ◽

Fibroblast Growth Factor ◽

Arcuate Nucleus ◽

Sustained Remission ◽

Fibroblast Growth ◽

Central Administration ◽

Remission Of Diabetes ◽

Hypothalamic Arcuate Nucleus

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

10.1101/2020.12.24.424313 ◽

2020 ◽

Author(s):

Jenny M. Brown ◽

Marie A. Bentsen ◽

Dylan M. Rausch ◽

Bao Anh Phan ◽

Danielle Wieck ◽

...

Keyword(s):

Growth Factor ◽

Fibroblast Growth Factor ◽

Diabetes Remission ◽

Mitogen Activated Protein Kinase ◽

Erk Signaling ◽

Sustained Remission ◽

Fibroblast Growth ◽

Extracellular Signal ◽

Mitogen Activated Protein

SummaryThe capacity of the brain to elicit sustained remission of hyperglycemia in rodent models of type 2 diabetes following intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1) is well established. Here, we show that following icv FGF1 injection, hypothalamic signaling by extracellular signal-regulated kinases 1 and 2 (ERK1/2), members of the mitogen-activated protein kinase (MAPK) family is induced 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, fails to mimic the sustained glucose lowering induced by FGF1. These data identify sustained activation of hypothalamic MAPK/ERK signaling as playing an essential role in the mechanism underlying diabetes remission induced by icv FGF1 administration.

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