FGF21 signaling in glutamatergic neurons is required for weight loss associated with dietary protein dilution
Open accessAbstract
Alterations in macronutrient intake can have profound effects on energy intake and whole-body metabolism. For example, reducing protein intake increases energy expenditure, increases insulin sensitivity and decreases body weight in rodents. Fibroblast growth factor 21 (FGF21) signaling in the brain is necessary for the metabolic effects of dietary protein restriction and has more recently been proposed to promote protein preference. However, the neuron populations through which FGF21 elicits these effects are unknown. Here, we demonstrate that deletion of β-klotho in glutamatergic, but not GABAergic, neurons abrogated the effects of dietary protein restriction on reducing body weight, but not on improving insulin sensitivity in both diet-induced obese and lean mice. Specifically, FGF21 signaling in glutamatergic neurons is necessary for protection against body weight gain and induction of UCP1 in adipose tissues associated with dietary protein restriction. However, β-klotho expression in glutamatergic neurons was dispensable for the effects of dietary protein restriction to increase insulin sensitivity. In addition, we report that FGF21 administration does not alter protein preference, but instead promotes the foraging of other macronutrients primarily by suppressing simple sugar consumption. This work provides important new insights into the neural substrates and mechanisms behind the endocrine control of metabolism during dietary protein dilution.
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Effects of extended FGF21 signalling in promoting weight loss through increased energy expenditure are mediated through direct actions on the CNS, not adipose tissues.
“These effects of extended FGF21 signalling in promoting weight loss through increased energy expenditure are mediated through direct actions on the central nervous system67,80–84, not adipose tissues65,67,85”
From Metabolic messengers: FGF21 (2021) · cites this paper as [84]
FGF21 signals to the CNS and suppresses simple-sugar intake and sweet-taste preference, but not protein or lipid intake.
“FGF21 signals to the CNS and consequently suppresses simple-sugar intake and sweet-taste preference22,122, but not protein or lipid intake22,84.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [84]
FGF21 signalling to the CNS is required for the weight loss associated with a low-protein diet.
“In addition, as expected according to the mechanism of FGF21’s action in increasing energy expenditure, FGF21 signalling to the CNS is required for the weight loss associated with a low-protein diet83,84.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [84]
FGF21 signalling to glutamatergic, but not GABAergic, neurons is required for the weight loss associated with dietary-protein dilution.
“Interestingly, similarly to its effects in suppressing simple-sugar intake and sweet-taste preference, FGF21 signalling to glutamatergic, but not GABAergic, neurons is required for the weight loss associated with dietary-protein dilution84.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [84]
The increase in FGF21 in response to low protein results in increased energy expenditure and lower body weight gain.
“This robust increase in FGF21 results in increased energy expenditure and lower body weight gain [155,156,160,163] (Figure 2)”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [163]
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Self-citation
- Authors
- Flippo, K. H., Jensen-Cody, S. O., Claflin, K. E., & Potthoff, M. J.
- Affiliations
- University of Iowa (US)
- Corresponding author
- Potthoff, Matthew J.
- Venue
- Scientific Reports
- Published
- 2020-11-11
- Volume
- 10
- Issue
- 1
- Pages
- 19521-19521
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC7658965
- OpenAlex
- W3098645453
- Cited by
- 49
- References
- 44
- Citations by year
- 2026: 5 · 2025: 11 · 2024: 2 · 2023: 13 · 2022: 11 · 2021: 6 · 2020: 1
- FWCI
- 2.51
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (T32 DK112751, DK117515, DK117510, R01DK106104)
- 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 › Medicine › Physiology › Dietary Effects on Health
- Keywords
- β-Klotho, glutamatergic neurons, protein restriction, protein dilution, weight loss, insulin sensitivity, diet-induced obesity, UCP1, adipose tissue thermogenesis, macronutrient preference, sugar consumption
- MeSH terms
- Klotho Proteins, Animals, Diet, Reducing, Dietary Proteins, Fibroblast Growth Factors, Insulin Resistance, Male, Membrane Proteins, Mice, Inbred C57BL, Neurons, Obesity, Sucrose, Signal Transduction, Weight Loss, Mice, Knockout, Diet, Protein-Restricted, Vesicular Inhibitory Amino Acid Transport Proteins, Vesicular Glutamate Transport Protein 2, GABAergic Neurons
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