FGF21 Signals to Glutamatergic Neurons in the Ventromedial Hypothalamus to Suppress Carbohydrate Intake

Sharon O Jensen-Cody; Kyle H Flippo; Kristin E Claflin; Yavuz Yavuz; Sarah A Sapouckey; Grant C Walters; Yuriy M Usachev; Deniz Atasoy; Matthew P Gillum; Matthew J Potthoff

doi:10.1016/j.cmet.2020.06.008

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FGF21 Signals to Glutamatergic Neurons in the Ventromedial Hypothalamus to Suppress Carbohydrate Intake

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FGF21 Signals to Glutamatergic Neurons in the Ventromedial Hypothalamus to Suppress Carbohydrate Intake

Sharon O Jensen-Cody, Kyle H Flippo, Kristin E Claflin, Yavuz Yavuz, Sarah A Sapouckey, Grant C Walters, Yuriy M Usachev, Deniz Atasoy, Matthew P Gillum and Matthew J Potthoff

Cell metabolism, Vol.32(2), pp.273-286.e6

08/04/2020

DOI: 10.1016/j.cmet.2020.06.008

PMID: 32640184

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Abstract

Fibroblast growth factor 21 (FGF21) is an endocrine hormone produced by the liver that regulates nutrient and metabolic homeostasis. FGF21 production is increased in response to macronutrient imbalance and signals to the brain to suppress sugar intake and sweet-taste preference. However, the central targets mediating these effects have been unclear. Here, we identify FGF21 target cells in the hypothalamus and reveal that FGF21 signaling to glutamatergic neurons is both necessary and sufficient to mediate FGF21-induced sugar suppression and sweet-taste preference. Moreover, we show that FGF21 acts directly in the ventromedial hypothalamus (VMH) to specifically regulate sucrose intake, but not non-nutritive sweet-taste preference, body weight, or energy expenditure. Finally, our data demonstrate that FGF21 affects neuronal activity by increasing activation and excitability of neurons in the VMH. Thus, FGF21 signaling to glutamatergic neurons in the VMH is an important component of the neurocircuitry that functions to regulate sucrose intake. [Display omitted] •Hypothalamic scRNA-seq analyses in Klb-CRE mice identified central targets of FGF21•FGF21 signals to Vglut2+ neurons to reduce sugar intake and sweet-taste preference•FGF21 signals to VMH neurons to suppress sugar intake•FGF21 markedly enhances glucose sensitivity of β-klotho neurons in the VMH FGF21 is a liver-derived hormone that signals to the brain to regulate macronutrient intake and energy homeostasis. Here, it is shown that FGF21 administration signals to glutamatergic neurons in the ventromedial hypothalamus (VMH) to suppress sugar intake, but not to increase energy expenditure, while enhancing glucose responsiveness of VMH glucose-sensitive neurons to elevated glucose levels.

Brain

VMH

liver

hepatokine

PVN

sugar intake

sweet-taste preference

macronutrient

glucose sensing

hypothalamus

FGF21

Details

Title: Subtitle: FGF21 Signals to Glutamatergic Neurons in the Ventromedial Hypothalamus to Suppress Carbohydrate Intake
Creators: Sharon O Jensen-Cody - Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
Kyle H Flippo - Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
Kristin E Claflin - Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
Yavuz Yavuz - Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
Sarah A Sapouckey - Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
Grant C Walters - Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
Yuriy M Usachev - Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
Deniz Atasoy - Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
Matthew P Gillum - Section for Nutrient and Metabolite Sensing, the Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, 2200 Copenhagen, Denmark
Matthew J Potthoff - Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
Resource Type: Journal article
Publication Details: Cell metabolism, Vol.32(2), pp.273-286.e6
Publisher: Elsevier Inc
DOI: 10.1016/j.cmet.2020.06.008
PMID: 32640184
ISSN: 1550-4131
eISSN: 1932-7420
Grant note: DOI: 10.13039/100000738, name: U.S. Department of Veterans Affairs; DOI: 10.13039/100000002, name: National Institutes of Health; DOI: 10.13039/100000968, name: American Heart Association
Language: English
Date published: 08/04/2020
Academic Unit: Neurology; Iowa Neuroscience Institute; Anesthesia; UI Research Foundation; Neuroscience and Pharmacology
Record Identifier: 9984065887702771

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