FNDC5 Human
Description
Metabolic Regulation
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Adipose Tissue Browning: Irisin promotes white adipose tissue (WAT) conversion to brown adipose tissue (BAT) by upregulating uncoupling protein 1 (UCP1), enhancing energy expenditure .
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Insulin Sensitivity: FNDC5 genetic variants correlate with prediabetic traits, suggesting a role in glucose metabolism .
Bone Remodeling
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Cortical Bone Density: Irisin increases bone cortical thickness and mineral density in mice, influencing osteoblast activity .
Cognitive Effects
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BDNF Regulation: Irisin enhances brain-derived neurotrophic factor (BDNF) expression, potentially mitigating cognitive decline in conditions like Alzheimer’s disease .
Tissue-Specific Expression
FNDC5 mRNA is predominantly expressed in skeletal muscle, with lower levels in heart, liver, and adipose tissue .
| Tissue | FNDC5 mRNA Expression | Key Observations |
|---|---|---|
| Skeletal muscle | High | Primary source of irisin |
| Heart | Moderate | Potential role in cardiac metabolism |
| Liver | Low | Limited contribution to systemic irisin |
Predictors of Circulating Irisin
Cross-sectional studies in humans reveal:
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Positive Correlations: Biceps circumference (muscle mass), BMI, glucose, IGF-1.
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Negative Correlations: Age, insulin, cholesterol, adiponectin .
Exercise and Weight Loss Effects
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Acute Exercise: Irisin levels rise within 30 minutes, linked to ATP, glycolysis, and lipolysis .
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Bariatric Surgery: Muscle FNDC5 mRNA and irisin levels decline post-weight loss, paralleling reduced body mass .
Human-Specific Challenges
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ATA Start Codon Mutation: The non-canonical start codon in the human FNDC5 gene may limit irisin production, though mass spectrometry confirms detectable plasma irisin (~3 ng/ml) .
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Assay Reliability: Early studies relied on antibody-based irisin detection, which has been criticized for cross-reactivity. Knockout models and recombinant irisin administration are now preferred .
Genetic Variants
A 2013 study identified FNDC5 SNPs associated with insulin resistance and glucose intolerance. For example, rs16837905 (T/A) correlated with reduced insulin sensitivity in prediabetic cohorts .
Exercise Mimetics
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Irisin Supplementation: Preclinical studies suggest irisin may improve cognitive function and obesity-related metabolic dysfunction, though human trials are lacking .
Genetic Interventions
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FNDC5 Overexpression: Strategies to enhance FNDC5 translation (e.g., correcting the ATA start codon) could improve metabolic outcomes in obesity and diabetes .
References
Product Specs
Q&A
Basic Research Questions
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What is FNDC5 and how is it related to irisin in humans?
FNDC5 is a transmembrane protein expressed primarily in skeletal muscle, heart, and brain. The fibronectin type III domain and part of the linker region (amino acids 29-140) was proposed to be proteolytically cleaved to produce a circulating peptide called irisin. This 112-amino acid peptide has a theoretical molecular weight of 12,600 Da without glycosylation. The irisin peptide is 100% conserved between humans and multiple other mammalian species, suggesting important biological functions . Scientific debate continues regarding the exact mechanism of FNDC5 cleavage, as experimental evidence for this process remains limited, with only a few studies demonstrating bands near the expected size range for deglycosylated irisin (~13,000 Da) in human plasma .
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What is the molecular structure of human FNDC5?
Human FNDC5 protein comprises several structural domains: a 28-amino acid signal peptide, a 93-amino acid fibronectin type III domain (FNIII), a 30-amino acid linker region, a 19-amino acid transmembrane segment, and a 39-amino acid intracellular domain . The proposed irisin peptide corresponds to the FNIII domain plus 19 amino acids of the linker region. Unlike mouse FNDC5, human FNDC5 contains a non-canonical ATA start codon rather than the standard ATG, which has implications for translation efficiency and has generated controversy regarding the physiological relevance of FNDC5/irisin in humans .
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How is FNDC5 expression regulated in human tissues?
FNDC5 expression shows tissue-specific regulation patterns in humans. In muscle tissue, FNDC5 mRNA expression positively correlates with PGC-1α (peroxisome proliferator-activated receptor γ coactivator 1α) expression , which increases with exercise. BMI also shows positive correlation with muscle FNDC5 mRNA expression. Additionally, PPARγ mRNA levels moderately correlate with FNDC5 mRNA levels . During embryonic development, FNDC5 is involved in cardiogenesis, with overexpression affecting cardiac differentiation processes . Alternative splicing of the FNDC5 gene results in at least four different isoforms with varying amino acid sequences .
Product Science Overview
FNDC5 was first characterized in 2002 as a transmembrane protein expressed in various tissues, including skeletal muscle, heart, and brain . The protein contains a fibronectin type III domain, which is a common structural motif involved in cell adhesion and receptor binding. The human FNDC5 gene is located on chromosome 1 and is known to produce multiple transcript variants through alternative splicing .
The most intriguing aspect of FNDC5 is its role as the precursor to irisin. During physical exercise, the ectodomain of FNDC5 is cleaved to release irisin, a 112-amino acid hormone . Irisin was named after the Greek messenger goddess Iris, reflecting its role in conveying signals within the body . This hormone has been shown to induce the browning of white adipose tissue, a process that increases energy expenditure and has potential implications for combating obesity and metabolic disorders .
Research on FNDC5 and irisin has expanded rapidly since the discovery of irisin in 2012. Studies have explored the hormone’s effects on various physiological processes:
- Metabolism: Irisin has been linked to improved glucose homeostasis and lipid metabolism. It is believed to play a role in the beneficial effects of exercise on metabolic health .
- Bone Remodeling: Recent studies suggest that irisin may influence bone density and strength, potentially offering new avenues for treating osteoporosis .
- Cognitive Function: There is emerging evidence that irisin may have neuroprotective effects and could be involved in brain health, including the regulation of brain-derived neurotrophic factor (BDNF) and neurogenesis .
Despite the promising findings, the study of FNDC5 and irisin is not without challenges. Some researchers have questioned the accuracy of assays used to measure irisin levels in plasma, leading to discrepancies in reported data . Additionally, while animal studies have shown significant effects of irisin on adipose tissue and metabolism, similar results in humans have been less consistent .
Human recombinant FNDC5 is produced through recombinant DNA technology, allowing for the study of this protein in various experimental settings. This recombinant form is crucial for investigating the detailed mechanisms of FNDC5 and irisin, as well as their potential therapeutic applications.
