Journal Article

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

Bennett, Camdin, Thompson, Jonatan, Egerod, Kristoffer L., Zhang, Yu, Scarlett, Jarrad M., Kaiyala, Karl J., Herranz-Pérez, Vicente, Jorgensen, Rasmus, Holst, Birgitte, Pers, Tune H., Alonge, Kimberly M., Bentsen, Marie A., Baquero, Arian F., Faber, Chelsea L., Secher, Anna, Muta, Kenjiro, Kutlu, Burak, Pyke, Charles, Morton, Gregory J., García-Verdugo, José-Manuel, Mirzadeh, Zaman, Meek, Thomas H., Ratner, Cecilia, Sparso, Thomas, Schwartz, Michael W., Grove, Kevin L., Rausch, Dylan M., Brown, Jenny M., Kornum, Birgitte R.

2020

Overview

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 ob/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. In rodent models of type 2 diabetes, sustained remission of hyperglycemia can be induced by FGF1 action in the mediobasal hypothalamus. Here, the authors show that FGF1-injection is followed by marked changes in glial cell populations and that the sustained glycemic response is dependent on intact melanocortin signaling.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/51 / 14/28 / 14/32 / 38/39 / 38/91 / 631/114/2397 / 631/1647/2017 / 631/378 / 692/163/2743/137/773 / Agouti-Related Protein - metabolism / Animal models / Animals / Antidiabetics / Astrocytes / Astrocytes - drug effects / Astrocytes - metabolism / Blood Glucose - analysis / Cell Communication / Cell interactions / Cell Nucleus - drug effects / Cell Nucleus - metabolism / Diabetes / Diabetes mellitus (non-insulin dependent) / Diabetes Mellitus, Experimental - blood / Diabetes Mellitus, Experimental - diet therapy / Diabetes Mellitus, Experimental - etiology / Diabetes Mellitus, Experimental - pathology / Diabetes Mellitus, Type 2 - blood / Diabetes Mellitus, Type 2 - drug therapy / Diabetes Mellitus, Type 2 - etiology / Diabetes Mellitus, Type 2 - pathology / Diet, High-Fat - adverse effects / Dietary Sucrose - administration & dosage / Dietary Sucrose - adverse effects / Ependymal cells / Fibroblast growth factor 1 / Fibroblast Growth Factor 1 - administration & dosage / Fibroblasts / Glial cells / Growth factors / Humanities and Social Sciences / Humans / Hyperglycemia / Hypoglycemic Agents - administration & dosage / Hypothalamus / Hypothalamus - cytology / Hypothalamus - drug effects / Hypothalamus - pathology / Injection / Injections, Intraventricular / Leptin - genetics / Male / Melanocortin / Melanocortins - metabolism / Melanocyte-Stimulating Hormones - administration & dosage / Mice / Mice, Knockout / multidisciplinary / Neuronal-glial interactions / Neurons / Neurons - drug effects / Neurons - metabolism / Oligodendroglia - drug effects / Oligodendroglia - metabolism / Receptor, Melanocortin, Type 4 - genetics / Receptors, Melanocortin - antagonists & inhibitors / Receptors, Melanocortin - metabolism / Recombinant Proteins - administration & dosage / Remission / Remission (Medicine) / Remission Induction - methods / RNA-Seq / Rodents / Science / Science (multidisciplinary) / Signal Transduction - drug effects / Signaling / Single-Cell Analysis / Stereotaxic Techniques / Tanycytes / Transcription / Transcriptome - drug effects