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FGF21 Signals to Glutamatergic Neurons in the Ventromedial Hypothalamus to Suppress Carbohydrate Intake
Open accessAbstract
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.
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In the citing paper
“KLB expression is primarily restricted to specific metabolic tissues (for example, the liver, pancreas and adipose tissue)5, and lower expression is observed in the brain22,48–50. Despite some reports to the contrary51,52, KLB is not expressed in muscle5,41.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [48]
In the citing paper
“In contrast to the reported restriction of KLB expression to the suprachiasmatic nucleus49, KLB is expressed in numerous cell types and regions throughout the hypothalamus48 (and CNS).”
From Metabolic messengers: FGF21 (2021) · cites this paper as [48]
In the citing paper
“FGF21 accomplishes this action by increasing the excitability of KLB+ neurons in the VMH48.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [48]
In the citing paper
“While physiological FGF21 signalling to glutamatergic neurons in the paraventricular nucleus regulates basal sucrose intake22,48, FGF21 signalling to glutamatergic neurons in the ventromedial hypothalamus (VMH) is required for FGF21-mediated suppression of simple-sugar intake48.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [48]
In the citing paper
“FGF21 increases the sensitivity of both glucose-excited and glucose-inhibited neurons in the VMH in response to increased, but not decreased, glucose concentrations48.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [48]
In the citing paper
“Recent work has demonstrated that FGF21 signals directly to glutamatergic, but not GABAergic or dopaminergic, neurons in regulating simple-sugar intake and sweet-taste preference48.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [48]
In the citing paper
“these same neurons are dispensable in FGF21-mediated increases in energy expenditure.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [48]
In the citing paper
“These findings indicate that FGF21 signals through distinct populations of neurons, thereby mediating effects on macronutrient intake and energy expenditure48.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [48]
In the citing paper
“FGF21 signaling to the ventromedial hypothalamus (VMH) is required for its effects on lowering carbohydrate intake but not non-nutritive sweet-taste preference or body weight.”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [173]
In the citing paper
“Recent research demonstrated that FGF21 signaling to glutamatergic neurons lowers carbohydrate intake and non-nutritive sweet-taste preference in mice [173].”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [173]
In the citing paper
“FGF21 enhances the activity of VMH glucose-sensing neurons in response to glucose presumably to regulate carbohydrate intake [173].”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [173]
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Citations
Cites
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A robust and high-throughput Cre reporting and characterization system for the whole mouse brain
Madisen, L., Zwingman, T. A., Sunkin, S. M., Oh, S. W., Zariwala, H. A., Gu, H., Ng, L. L., Palmiter, R. D., Hawrylycz, M. J., Jones, A. R., et al. (2010) · Nature Neuroscience · doi:10.1038/nn.2467 · Cited by 6,907
A resource of Cre driver lines for genetic targeting of GABAergic neurons in cerebral cortex
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Chan, K. Y., Jang, M. J., Yoo, B. B., Greenbaum, A., Ravi, N., Wu, W.-L., Sánchez-Guardado, L., Lois, C., Mazmanian, S. K., Deverman, B. E., et al. (2017) · Nature Neuroscience · doi:10.1038/nn.4593 · Cited by 1,578
Leptin Action on GABAergic Neurons Prevents Obesity and Reduces Inhibitory Tone to POMC Neurons
Vong, L., Ye, C., Yang, Z., Choi, B. J., Chua, S. C., & Lowell, B. B. (2011) · Neuron · doi:10.1016/j.neuron.2011.05.028 · Cited by 1,237
Divergence of Melanocortin Pathways in the Control of Food Intake and Energy Expenditure
Balthasar, N., Dalgaard, L. T., Lee, C. E., Yu, J. H., Funahashi, H., Williams, T. B., Ferreira, M. A. R., Tang, V., McGovern, R. A., Kenny, C. D., et al. (2005) · Cell · doi:10.1016/j.cell.2005.08.035 · Cited by 1,107
Solon-Biet, S. M., McMahon, A. C., Ballard, J. W. O., Ruohonen, K., Wu, L. E., Cogger, V. C., Warren, A., Huang, X., Pichaud, N., Melvin, R. G., et al. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.02.009 · Cited by 904
The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes
Gaich, G., Chien, J. Y., Fu, H., Glass, L. C., Deeg, M. A., Holland, W. L., Kharitonenkov, A., Bumol, T., Schilske, H. K., & Moller, D. E. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.08.005 · Cited by 885
Hypothalamic circuits regulating appetite and energy homeostasis: pathways to obesity
Timper, K., & Brüning, J. C. (2017) · Disease Models & Mechanisms · doi:10.1242/dmm.026609 · Cited by 851
Cited by
Sorted by citations
Flippo, K. H., & Potthoff, M. J. (2021) · Nature Metabolism · doi:10.1038/s42255-021-00354-2 · Cited by 311
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Hepatokines and metabolism: Deciphering communication from the liver
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Metadata
- Authors
- Jensen-Cody, S. O., Flippo, K. H., Claflin, K. E., Yavuz, Y., Sapouckey, S. A., Walters, G. C., Usachev, Y. M., Atasoy, D., Gillum, M. P., & Potthoff, M. J.
- Affiliations
- University of Iowa (US)
- University of Copenhagen (DK)
- Corresponding author
- Gillum, Matthew P.
- Potthoff, Matthew J.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2020-08
- Volume
- 32
- Issue
- 2
- Pages
- 273-286.e6
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC7734879
- OpenAlex
- W3039069992
- Cited by
- 166
- References
- 71
- Citations by year
- 2026: 26 · 2025: 38 · 2024: 18 · 2023: 24 · 2022: 32 · 2021: 21 · 2020: 7
- FWCI
- 6.81
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Veterans Affairs
- National Institutes of Health
- American Heart Association
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Nursing › Nutrition and Dietetics › Biochemical Analysis and Sensing Techniques
- Keywords
- FGF21, ventromedial hypothalamus, glutamatergic neurons, sucrose intake, carbohydrate intake, sweet taste preference, neuronal excitability
- MeSH terms
- Animals, Energy Intake, Carbohydrates, Female, Fibroblast Growth Factors, Male, Mice, Inbred C57BL, Mice, Transgenic, Neurons, Signal Transduction, Mice
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