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

Autor:	Bentsen MA; UW Medicine Diabetes Institute, University of Washington, Seattle, WA, USA.; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Rausch DM; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Mirzadeh Z; Barrow Neurological Institute, Phoenix, AZ, USA., Muta K; UW Medicine Diabetes Institute, University of Washington, Seattle, WA, USA.; Chakri Naruebodindra Medical Institute, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand., Scarlett JM; UW Medicine Diabetes Institute, University of Washington, Seattle, WA, USA.; Department of Pediatric Gastroenterology and Hepatology, Seattle Children's Hospital, Seattle, WA, USA., Brown JM; UW Medicine Diabetes Institute, University of Washington, Seattle, WA, USA., Herranz-Pérez V; Cavanilles Institute of Biodiversity and Evolutionary Biology, University of Valencia, Valencia, Spain.; Predepartamental Unit of Medicine, Jaume I University, Castelló de la Plana, Spain., Baquero AF; Obesity Research Unit, Novo Nordisk Research Center Seattle, Inc., Seattle, WA, USA., Thompson J; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Alonge KM; UW Medicine Diabetes Institute, University of Washington, Seattle, WA, USA., Faber CL; UW Medicine Diabetes Institute, University of Washington, Seattle, WA, USA., Kaiyala KJ; Department of Oral Health Sciences, School of Dentistry, University of Washington, Seattle, WA, USA., Bennett C; Obesity Research Unit, Novo Nordisk Research Center Seattle, Inc., Seattle, WA, USA., Pyke C; Pathology & Imaging, Global Discovery and Development Sciences, Novo Nordisk A/S, Maaloev, Denmark., Ratner C; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Egerod KL; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Holst B; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Meek TH; Obesity Research Unit, Novo Nordisk Research Center Seattle, Inc., Seattle, WA, USA., Kutlu B; Obesity Research Unit, Novo Nordisk Research Center Seattle, Inc., Seattle, WA, USA., Zhang Y; Obesity Research Unit, Novo Nordisk Research Center Seattle, Inc., Seattle, WA, USA., Sparso T; Bioinformatics and Data Mining, Global Research Technologies, Novo Nordisk A/S, Maaloev, Denmark., Grove KL; Obesity Research Unit, Novo Nordisk Research Center Seattle, Inc., Seattle, WA, USA., Morton GJ; UW Medicine Diabetes Institute, University of Washington, Seattle, WA, USA., Kornum BR; Department of Neuroscience, University of Copenhagen, Copenhagen, Denmark., García-Verdugo JM; Cavanilles Institute of Biodiversity and Evolutionary Biology, University of Valencia, Valencia, Spain., Secher A; Diabetes Research, Global Drug Discovery, Novo Nordisk A/S, Maaloev, Denmark., Jorgensen R; Diabetes Research, Global Drug Discovery, Novo Nordisk A/S, Maaloev, Denmark.; Cytoki Pharma, Copenhagen, Denmark., Schwartz MW; UW Medicine Diabetes Institute, University of Washington, Seattle, WA, USA. mschwart@uw.edu., Pers TH; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. tune.pers@sund.ku.dk.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2020 Sep 07; Vol. 11 (1), pp. 4458. Date of Electronic Publication: 2020 Sep 07.
DOI:	10.1038/s41467-020-17720-5
Abstrakt:	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.
Databáze:	MEDLINE
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