Transcriptomic analysis links diverse hypothalamic cell types to fibroblast growth factor 1-induced sustained diabetes remission.

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.

• Authors: Marie A Bentsen, Dylan M Rausch, Zaman Mirzadeh, Kenjiro Muta, Jarrad M Scarlett, Jenny M Brown, Vicente Herranz-Pérez, Arian F Baquero, Jonatan Thompson, Kimberly M Alonge, Chelsea L Faber, Karl J Kaiyala, Camdin Bennett, Charles Pyke, Cecilia Ratner, Kristoffer L Egerod, Birgitte Holst, Thomas H Meek, Burak Kutlu, Yu Zhang, Thomas Sparso, Kevin L Grove, Gregory J Morton, Birgitte R Kornum, José-Manuel García-Verdugo, Anna Secher, Rasmus Jorgensen, Michael W Schwartz, Tune H Pers
• Journal: Nature communications (Nat Commun) Vol. 11 Issue 1 Pg. 4458 (09 07 2020) ISSN: 2041-1723 [Electronic] England
• PMID: 32895383 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Agouti-Related Protein
• Agrp protein, mouse
• Blood Glucose
• Dietary Sucrose
• Hypoglycemic Agents
• Leptin
• MC4R protein, mouse
• Melanocortins
• Receptor, Melanocortin, Type 4
• Receptors, Melanocortin
• Recombinant Proteins
• Fibroblast Growth Factor 1
• SHU 9119
• Melanocyte-Stimulating Hormones

Topics

• Agouti-Related Protein (metabolism)
• Animals
• Astrocytes (drug effects, metabolism)
• Blood Glucose (analysis)
• Cell Communication
• Cell Nucleus (drug effects, metabolism)
• Diabetes Mellitus, Experimental (blood, diet therapy, etiology, pathology)
• Diabetes Mellitus, Type 2 (blood, drug therapy, etiology, pathology)
• Diet, High-Fat (adverse effects)
• Dietary Sucrose (administration & dosage, adverse effects)
• Fibroblast Growth Factor 1 (administration & dosage)
• Humans
• Hypoglycemic Agents (administration & dosage)
• Hypothalamus (cytology, drug effects, pathology)
• Injections, Intraventricular
• Leptin (genetics)
• Male
• Melanocortins (metabolism)
• Melanocyte-Stimulating Hormones (administration & dosage)
• Mice
• Mice, Knockout
• Neurons (drug effects, metabolism)
• Oligodendroglia (drug effects, metabolism)
• RNA-Seq
• Receptor, Melanocortin, Type 4 (genetics)
• Receptors, Melanocortin (antagonists & inhibitors, metabolism)
• Recombinant Proteins (administration & dosage)
• Remission Induction (methods)
• Signal Transduction (drug effects)
• Single-Cell Analysis
• Stereotaxic Techniques
• Transcriptome (drug effects)