Genetic Evidence Supporting Fibroblast Growth Factor 21 Signalling as a Pharmacological Target for Cardiometabolic Outcomes and Alzheimer’s Disease

Fibroblast growth factor 21 (FGF21) is a human metabolic hormone whose effects include modification of macronutrient preference and energy homeostasis. In animal models, FGF21 has been shown to have beneficial effects on cardiometabolic outcomes, Alzheimer’s disease risk and lifespan. In this study, the single-nucleotide polymorphism rs838133 in the FGF21 gene region was leveraged to investigate the potential clinical effects of targeting FGF21. The FGF21 G allele was associated with lower intakes of total sugars and alcohol, and higher intakes of protein and fat as well as favourable with lipid levels, blood pressure traits, waist-to-hip ratio, systemic inflammation, cardiovascular outcomes, Alzheimer’s disease risk and lifespan. These findings may be used to anticipate the effects of pharmacologically increasing FGF21 signalling.

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Genetic evidence supporting fibroblast growth factor 21 signalling as a pharmacological target for cardiometabolic outcomes and Alzheimer's disease

10.22541/au.161375114.48745725/v1 ◽

2021 ◽

Author(s):

Susanna Larsson ◽

Dipender Gill

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Clinical Trials ◽

Growth Factor ◽

Fibroblast Growth Factor ◽

Disease Risk ◽

Fibroblast Growth Factor 21 ◽

Clinical Effects ◽

Fibroblast Growth ◽

Pharmacological Target

Fibroblast growth factor 21 (FGF21) is a human metabolic hormone that is being pursued in early stage clinical trials as pharmacological target to treat a range of metabolic diseases. In animal models, increased FGF21 signalling has been shown to have beneficial effects on cardiometabolic outcomes, Alzheimer’s disease risk and lifespan. However, studies investigating the effect of FGF21 signalling on these clinical outcomes in humans have been inconclusive. In this study, a genetic variant associated with higher circulating FGF21 levels was leveraged to investigate its clinical effects in humans. Higher genetically proxied circulating FGF21 levels were associated favourably with lipid levels, blood pressure traits, waist-to-hip ratio, chronic inflammation, cardiovascular outcomes, Alzheimer’s disease risk and lifespan. These findings may be used to anticipate the effects of pharmacologically increasing FGF21 signalling and inform the design of further clinical trials.

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Fibroblast growth factor 21 ameliorates neurodegeneration in rat and cellular models of Alzheimer’s disease

Redox Biology ◽

10.1016/j.redox.2019.101133 ◽

2019 ◽

Vol 22 ◽

pp. 101133 ◽

Cited By ~ 10

Author(s):

Song Chen ◽

Su-Ting Chen ◽

Yan Sun ◽

Zheng Xu ◽

Ying Wang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Growth Factor ◽

Fibroblast Growth Factor ◽

Fibroblast Growth Factor 21 ◽

Fibroblast Growth ◽

Cellular Models

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Resistance to the Beneficial Metabolic Effects and Hepatic Antioxidant Defense Actions of Fibroblast Growth Factor 21 Treatment in Growth Hormone-Overexpressing Transgenic Mice

International Journal of Endocrinology ◽

10.1155/2015/282375 ◽

2015 ◽

Vol 2015 ◽

pp. 1-11 ◽

Cited By ~ 1

Author(s):

Ravneet K. Boparai ◽

Oge Arum ◽

Johanna G. Miquet ◽

Michal M. Masternak ◽

Andrzej Bartke ◽

...

Keyword(s):

Growth Hormone ◽

Lipid Metabolism ◽

Growth Factor ◽

Transgenic Mice ◽

Fibroblast Growth Factor ◽

Energy Homeostasis ◽

Antioxidant Defense ◽

Fibroblast Growth Factor 21 ◽

Fibroblast Growth ◽

Beneficial Effects

Fibroblast growth factor 21 (FGF21) modulates a diverse range of biological functions, including glucose and lipid metabolism, adaptive starvation response, and energy homeostasis, but with limited mechanistic insight. FGF21 treatment has been shown to inhibit hepatic growth hormone (GH) intracellular signaling. To evaluate GH axis involvement in FGF21 actions, transgenic mice overexpressing bovine GH were used. Expectedly, in response to FGF21 treatment control littermates showed metabolic improvements whereas GH transgenic mice resisted most of the beneficial effects of FGF21, except an attenuation of the innate hyperinsulinemia. Since FGF21 is believed to exert its effects mostly at the transcriptional level, we analyzed and observed significant upregulation in expression of various genes involved in carbohydrate and lipid metabolism, energy homeostasis, and antioxidant defense in FGF21-treated controls, but not in GH transgenics. The resistance of GH transgenic mice to FGF21-induced changes underlines the necessity of normal GH signaling for the beneficial effects of FGF21.

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