Inhibitory Regulation of FOXO1 in PPARδ Expression Drives Mitochondrial Dysfunction and Insulin Resistance
Soyoung Park1,2, Hye-Na Cha1,2, Min-Gyeong Shin1
1Department of Physiology, College of Medicine, Yeungnam University, Daegu, Republic of Korea.
Diabetes
|April 24, 2024
Summary
Forkhead box O1 (FOXO1) deficiency improves skeletal muscle metabolism and exercise capacity by enhancing mitochondrial function. FOXO1 links insulin resistance and mitochondrial dysfunction via PPARδ signaling.
Area of Science:
- Metabolic regulation in skeletal muscle
- Mitochondrial function and dysfunction
- Insulin resistance mechanisms
Background:
- Forkhead box O1 (FOXO1) is known to regulate muscle growth, but its specific metabolic roles and underlying mechanisms in skeletal muscle are not fully understood.
- Obesity and diabetes are often associated with impaired skeletal muscle metabolism and insulin resistance.
Purpose of the Study:
- To investigate the metabolic role of FOXO1 in skeletal muscle.
- To elucidate the mechanisms by which FOXO1 influences insulin sensitivity, fatty acid oxidation, mitochondrial function, and exercise capacity.
Main Methods:
- Generation of skeletal muscle-specific Foxo1 inducible knockout (mFOXO1 iKO) mice.
- High-fat diet feeding to induce obesity in mice.
- Assessment of insulin sensitivity, fatty acid oxidation, mitochondrial respiration, and exercise performance.
- Analysis of peroxisome proliferator-activated receptor δ (PPARδ) expression and its role.
- Correlation analysis of FOXO1, PPARδ, and mitochondrial proteins in human skeletal muscle samples from diabetic patients.
Main Results:
- Obese mFOXO1 iKO mice demonstrated improved mitochondrial respiratory capacity, reduced insulin resistance, enhanced fatty acid oxidation, and better exercise capacity.
- FOXO1 deficiency led to transcriptional inhibition of PPARδ in skeletal muscle; PPARδ deletion abrogated the beneficial effects.
- Skeletal muscle from diabetic patients showed elevated FOXO1 levels, negatively correlated with PPARδ and electron transport chain proteins.
Conclusions:
- FOXO1 acts as a repressor of PPARδ gene expression in skeletal muscle.
- FOXO1 deficiency confers metabolic benefits in skeletal muscle, including improved mitochondrial function and insulin sensitivity.
- FOXO1 represents a potential therapeutic target linking insulin resistance and mitochondrial dysfunction in skeletal muscle via the PPARδ pathway.
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