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

ABSTRACT: 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.

SUBMITTER: Larsson SC

PROVIDER: S-EPMC8146158 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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

Larsson Susanna C SC Gill Dipender D

Nutrients 20210429 5

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 <i>FGF21</i> gene region was leveraged to investigate the potential clinical effects of targeting FGF21. The <i>FGF21</i> G allele was associated wi ...[more]

PMID: 33946944

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Project description:BackgroundSkeletal muscle is a plastic tissue that adapts to changes in exercise, nutrition, and stress by secreting myokines and myometabolites. These muscle-secreted factors have autocrine, paracrine, and endocrine effects, contributing to whole body homeostasis. Muscle dysfunction in aging sarcopenia, cancer cachexia, and diabetes is tightly correlated with the disruption of the physiological homeostasis at the whole body level. The expression levels of the myokine fibroblast growth factor 21 (FGF21) are very low in normal healthy muscles. However, fasting, ER stress, mitochondrial myopathies, and metabolic disorders induce its release from muscles. Although our understanding of the systemic effects of muscle-derived FGF21 is exponentially increasing, the direct contribution of FGF21 to muscle function has not been investigated yet.MethodsMuscle-specific FGF21 knockout mice were generated to investigate the consequences of FGF21 deletion concerning skeletal muscle mass and force. To identify the mechanisms underlying FGF21-dependent adaptations in skeletal muscle during starvation, the study was performed on muscles collected from both fed and fasted adult mice. In vivo overexpression of FGF21 was performed in skeletal muscle to assess whether FGF21 is sufficient per se to induce muscle atrophy.ResultsWe show that FGF21 does not contribute to muscle homeostasis in basal conditions in terms of fibre type distribution, fibre size, and muscle force. In contrast, FGF21 is required for fasting-induced muscle atrophy and weakness. The mass of isolated muscles from control-fasted mice was reduced by 15-25% (P < 0.05) compared with fed control mice. FGF21-null muscles, however, were significantly protected from muscle loss and weakness during fasting. Such important protection is due to the maintenance of protein synthesis rate in knockout muscles during fasting compared with a 70% reduction in control-fasted muscles (P < 0.01), together with a significant reduction of the mitophagy flux via the regulation of the mitochondrial protein Bnip3. The contribution of FGF21 to the atrophy programme was supported by in vivo FGF21 overexpression in muscles, which was sufficient to induce autophagy and muscle loss by 15% (P < 0.05). Bnip3 inhibition protected against FGF21-dependent muscle wasting in adult animals (P < 0.05).ConclusionsFGF21 is a novel player in the regulation of muscle mass that requires the mitophagy protein Bnip3.

Dataset Information

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

Publications

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

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