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Published on: May 19, 2023
FGF21 resistance is not mediated by downregulation of beta-klotho expression in white adipose tissue
Kathleen R Markan1,2, Meghan C Naber1,2, Sarah M Small1,2
1Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
Objective:
Fibroblast growth factor 21 (FGF21) is an endocrine hormone that regulates metabolic homeostasis. Previous work has suggested that impairment of FGF21 signaling in adipose tissue may occur through downregulation of the obligate FGF21 co-receptor, β-klotho, which leads to "FGF21 resistance" during the onset of diet-induced obesity. Here, we sought to determine whether maintenance of β-klotho expression in adipose tissue prevents FGF21 resistance and whether other mechanisms also contribute to FGF21 resistance in vivo.
Methods:
We generated adipose-specific β-klotho transgenic mice to determine whether maintenance of β-klotho expression in adipose tissue prevents FGF21 resistance in vivo.
Results:
β-klotho protein levels are markedly decreased in white adipose tissue, but not liver or brown adipose tissue, during diet-induced obesity. Maintenance of β-klotho protein expression in adipose tissue does not alleviate impaired FGF21 signaling in white adipose or increase FGF21 sensitivity in vivo.
Conclusions:
In white adipose tissue, downregulation of β-klotho expression is not the major mechanism contributing to impaired FGF21 signaling in white adipose tissue.
Insights
Fibroblast growth factor 21 (FGF21) resistance in obesity is not primarily caused by reduced β-klotho in white adipose tissue. Maintaining β-klotho levels did not restore FGF21 sensitivity in vivo.
Area of Science:
- Metabolic homeostasis and endocrine signaling
Background:
- Fibroblast growth factor 21 (FGF21) regulates metabolic homeostasis.
- Diet-induced obesity can lead to FGF21 resistance, potentially due to decreased co-receptor β-klotho in adipose tissue.
Purpose of the Study:
- To investigate if maintaining β-klotho expression in adipose tissue prevents FGF21 resistance.
- To explore other mechanisms contributing to FGF21 resistance in vivo.
Main Methods:
- Generation of adipose-specific β-klotho transgenic mice.
- Assessment of FGF21 signaling and sensitivity in vivo.
Main Results:
- White adipose tissue showed decreased β-klotho protein during diet-induced obesity, unlike liver or brown adipose tissue.
- Maintaining adipose β-klotho did not improve FGF21 signaling or sensitivity in white adipose tissue.
Conclusions:
- Reduced β-klotho expression is not the primary driver of impaired FGF21 signaling in white adipose tissue during obesity.
- Other mechanisms contribute to FGF21 resistance.
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