FGF19, FGF21, and an FGFR1/β-Klotho-Activating Antibody Act on the Nervous System to Regulate Body Weight and Glycemia
Open accessAbstract
Despite the different physiologic functions of FGF19 and FGF21 as hormonal regulators of fed and fasted metabolism, their pharmacologic administration causes similar increases in energy expenditure, weight loss, and enhanced insulin sensitivity in obese animals. Here, in genetic loss-of-function studies of the shared co-receptor β-Klotho, we show that these pharmacologic effects are mediated through a common, tissue-specific pathway. Surprisingly, FGF19 and FGF21 actions in liver and adipose tissue are not required for their longer-term weight loss and glycemic effects. In contrast, β-Klotho in neurons is essential for both FGF19 and FGF21 to cause weight loss and lower glucose and insulin levels. We further show an FGF21 mimetic antibody that activates the FGF receptor 1/β-Klotho complex also requires neuronal β-Klotho for its metabolic effects. These studies highlight the importance of the nervous system in mediating the beneficial weight loss and glycemic effects of endocrine FGF drugs.
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Loss of KLB from hepatocytes is dispensable for the insulin-sensitizing effects of FGF21.
“loss of KLB from hepatocytes is dispensable for the insulin-sensitizing effects of FGF21 (ref. 67).”
From Metabolic messengers: FGF21 (2021) · cites this paper as [67]
FGF21 acutely enhances insulin sensitivity through direct actions on adipose tissues.
“FGF21 acutely enhances insulin sensitivity through direct actions on adipose tissues65,67.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [67]
Loss of FGF21 signalling to adipose tissues abolishes the insulin-sensitizing effects of FGF21 in both lean and DIO mice.
“loss of FGF21 signalling to adipose tissues, as accomplished by crossing Klbfl/fl mice with adiponectin-Cre mice65,67, abolishes the insulin-sensitizing effects of FGF21 in both lean and diet-induced obese (DIO) mice”
From Metabolic messengers: FGF21 (2021) · cites this paper as [67]
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 [67]
Loss of KLB in hepatocytes does not alter FGF21-mediated decreases in body weight, improvements in insulin sensitivity, and glucose and lipid homeostasis in DIO mice.
“loss of KLB in hepatocytes does not alter the FGF21-mediated decreases in body weight, and the improvements in both insulin sensitivity and glucose and lipid homeostasis in DIO mice67.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [67]
FGF21 directly signals adipose tissue to improve insulin sensitivity.
“FGF21 directly signals adipose tissue to improve insulin sensitivity [169,170]”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [170]
The chronic effects of FGF21 on body weight and improved insulin sensitivity are retained in adipose-specific Klb knockout mice (Klbfl/fl;Adiponectin-Cre).
“Although FGF21 signals directly to adipose tissues to acutely enhance insulin sensitivity, the chronic effects of FGF21 on body weight and improved insulin sensitivity are retained in adipose-specific Klb knockout mice (Klbfl/fl;Adiponectin-Cre) (11, 74), demonstrating that direct signaling to adipose tissues is not required for the chronic effects of FGF21 (Figure 4).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [74]
Administration of a bispecific FGFR1-β-klotho agonist to diet-induced obese wild-type mice promotes weight loss and improves glucose homeostasis, effects that are lost when β-klotho is removed from the CNS.
“Consistent with recombinant FGF21 administration, the administration of a bispecific FGFR1–β-klotho agonist to diet-induced obese wild-type mice promotes weight loss and improves glucose homeostasis, effects that are lost when β-klotho is removed from the CNS (74).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [74]
The loss of β-klotho in hepatocytes or adipocytes does not impair FGF21-mediated effects on body weight.
“In contrast, the loss of β-klotho in hepatocytes (74) or adipocytes (11, 74) does not impair FGF21-mediated effects on body weight.”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [74]
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References 54 · Cited by 261
- Authors
- Lan, T., Morgan, D. A., Rahmouni, K., Sonoda, J., Fu, X., Burgess, S. C., Holland, W. L., Kliewer, S. A., & Mangelsdorf, D. J.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- University of Iowa (US)
- Genentech (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Kliewer, Steven A.
- Mangelsdorf, David J.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2017-11
- Volume
- 26
- Issue
- 5
- Pages
- 709-718.e3
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC5679468
- OpenAlex
- W2762869502
- Cited by
- 261
- References
- 54
- Citations by year
- 2026: 19 · 2025: 32 · 2024: 25 · 2023: 25 · 2022: 39 · 2021: 27 · 2020: 39 · 2019: 32 · 2018: 21 · 2017: 2
- FWCI
- 10.50
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (1P01AG051459, R01DK067158)
- Howard Hughes Medical Institute
- Welch Foundation (I-1275, I-1558, I-1804)
- 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 › Nephrology › Parathyroid Disorders and Treatments
- Keywords
- FGF19, FGF21, β-Klotho, FGFR1, weight loss, glycemia, insulin sensitivity, energy expenditure, obesity
- MeSH terms
- Klotho Proteins, Adipose Tissue, Animals, Antibodies, Monoclonal, Blood Glucose, Fibroblast Growth Factors, Insulin Resistance, Liver, Membrane Proteins, Mice, Inbred C57BL, Mice, Obese, Nervous System, Neurons, Weight Loss, Mice, Knockout, Mice, Receptor, Fibroblast Growth Factor, Type 1
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