Title

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

Authors

Marie A. Bentsen, UW Medicine Diabetes Institute, University of Washington, Seattle, WA, USA.
Dylan M. Rausch, Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Zaman Mirzadeh, Barrow Neurological Institute, Phoenix, AZ, USA.
Kenjiro Muta, UW Medicine Diabetes Institute, University of Washington, Seattle, WA, USA.
Jarrad M. Scarlett, UW Medicine Diabetes Institute, University of Washington, Seattle, WA, USA.
Jenny M. Brown, UW Medicine Diabetes Institute, University of Washington, Seattle, WA, USA.
Vicente Herranz-Pérez, Cavanilles Institute of Biodiversity and Evolutionary Biology, University of Valencia, Valencia, Spain.
Arian F. Baquero, Obesity Research Unit, Novo Nordisk Research Center Seattle, Inc., Seattle, WA, USA.
Jonatan Thompson, Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Kimberly M. Alonge, UW Medicine Diabetes Institute, University of Washington, Seattle, WA, USA.
Chelsea L. Faber, UW Medicine Diabetes Institute, University of Washington, Seattle, WA, USA.
Karl J. Kaiyala, Department of Oral Health Sciences, School of Dentistry, University of Washington, Seattle, WA, USA.
Camdin Bennett, Obesity Research Unit, Novo Nordisk Research Center Seattle, Inc., Seattle, WA, USA.
Charles Pyke, Pathology & Imaging, Global Discovery and Development Sciences, Novo Nordisk A/S, Maaloev, Denmark.
Cecilia Ratner, Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Kristoffer L. Egerod, Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Birgitte Holst, Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Thomas H. Meek, Obesity Research Unit, Novo Nordisk Research Center Seattle, Inc., Seattle, WA, USA.
Burak Kutlu, Obesity Research Unit, Novo Nordisk Research Center Seattle, Inc., Seattle, WA, USA.
Yu Zhang, Obesity Research Unit, Novo Nordisk Research Center Seattle, Inc., Seattle, WA, USA.
Thomas Sparso, Bioinformatics and Data Mining, Global Research Technologies, Novo Nordisk A/S, Maaloev, Denmark.
Kevin L. Grove, Obesity Research Unit, Novo Nordisk Research Center Seattle, Inc., Seattle, WA, USA.
Gregory J. Morton, UW Medicine Diabetes Institute, University of Washington, Seattle, WA, USA.
Birgitte R. Kornum, Department of Neuroscience, University of Copenhagen, Copenhagen, Denmark.
José-Manuel García-Verdugo, Cavanilles Institute of Biodiversity and Evolutionary Biology, University of Valencia, Valencia, Spain.
Anna Secher, Diabetes Research, Global Drug Discovery, Novo Nordisk A/S, Maaloev, Denmark.
Rasmus Jorgensen, Diabetes Research, Global Drug Discovery, Novo Nordisk A/S, Maaloev, Denmark.
Michael W. Schwartz, UW Medicine Diabetes Institute, University of Washington, Seattle, WA, USA. mschwart@uw.edu.
Tune H. Pers, Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. tune.pers@sund.ku.dk.

Document Type

Article

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 Lep 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.

Medical Subject Headings

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)

Publication Date

9-7-2020

Publication Title

Nature communications

E-ISSN

2041-1723

Volume

11

Issue

1

First Page

4458

PubMed ID

32895383

Digital Object Identifier (DOI)

10.1038/s41467-020-17720-5

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