Sustained diabetes remission induced by FGF1 involves a shift in transcriptionally distinct AgRP neuron subpopulations

Authors

• Nadia Aalling, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
• Petar V. Todorov, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
• Shad Hassan, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
• Dylan M. Belmont-Rausch, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
• Oliver Pugerup Christensen, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
• Claes Ottzen Laurentiussen, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
• Anja M. Jørgensen, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
• Kimberly M. Alonge, UW Medicine Diabetes Institute, Department of Medicine, University of Washington, Seattle, WA, USA; McKnight Brain Institute, Department of Neuroscience, University of Florida, Gainesville, FL, USA.
• Jarrad M. Scarlett, UW Medicine Diabetes Institute, Department of Medicine, University of Washington, Seattle, WA, USA.
• Zaman Mirzadeh, Department of Neurosurgery, Barrow Neurological Institute, Phoenix, AZ, USA.
• Jenny M. Brown, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
• Michael W. Schwartz, UW Medicine Diabetes Institute, Department of Medicine, University of Washington, Seattle, WA, USA.
• Tune H. Pers, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark. Electronic address: tune.pers@sund.ku.dk.

Document Type

Article

Abstract

In rodent models of type 2 diabetes, a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1) induces sustained remission of hyperglycemia. Overactive agouti-related peptide (AgRP) neurons, located in the hypothalamic arcuate nucleus, are a hallmark of diabetic states, and their long-term inhibition has been linked to FGF1's antidiabetic effects. To investigate the underlying mechanism(s), we performed single-nucleus RNA sequencing of the mediobasal hypothalamus at Days 5 and 14 post-injection in wild-type and diabetic (Lep) mice treated with FGF1 or vehicle. We found that AgRP neurons from Lep mice form a transcriptionally distinct, hyperactive subpopulation. By Day 5, icv FGF1 induced a subset of these neurons to shift toward a less active, wild-type-like state, characterized by reduced activity-linked gene expression that persisted through Day 14. Spatial transcriptomics revealed that this FGF1-responsive AgRP subset is positioned dorsally within the arcuate nucleus. The transcriptional shift was accompanied by increased transcriptional processes indicative of GABAergic signaling, axonogenesis, and astrocyte-AgRP and oligodendrocyte-AgRP interactions. These glial inputs involve astrocytic neurexins and the perineuronal net (PNN) component phosphacan, suggesting both intrinsic and extrinsic mechanisms underlie FGF1-induced AgRP silencing. Combined with evidence that FGF1 increases assembly in the arcuate nucleus, our findings reveal a cell-type-specific model for how FGF1 elicits long-term reprogramming of hypothalamic circuits to achieve diabetes remission.

Publication Date

12-9-2025

Publication Title

Molecular metabolism

E-ISSN

2212-8778

First Page

102300

PubMed ID

41371441

Digital Object Identifier (DOI)

10.1016/j.molmet.2025.102300

Recommended Citation

Aalling, Nadia; Todorov, Petar V.; Hassan, Shad; Belmont-Rausch, Dylan M.; Christensen, Oliver Pugerup; Laurentiussen, Claes Ottzen; Jørgensen, Anja M.; Alonge, Kimberly M.; Scarlett, Jarrad M.; Mirzadeh, Zaman; Brown, Jenny M.; Schwartz, Michael W.; and Pers, Tune H., "Sustained diabetes remission induced by FGF1 involves a shift in transcriptionally distinct AgRP neuron subpopulations" (2025). Translational Neuroscience. 2487.
https://scholar.barrowneuro.org/neurobiology/2487