Key Takeaways & Executive Findings
- •• Mitochondrial dysfunction impairs adipocyte browning by suppressing UCP1 expression and disrupting key signaling pathways (PPAR-γ/PGC-1α and AMPK/mTOR), leading to reduced energy expenditure and insulin resistance. • The review highlights the intersection of mitochondrial dysfunction with neurodegenerative disorders via oxidative stress, suggesting a systemic link between metabolic and neurological diseases. • Structural mitochondrial anomalies and mtDNA-nuclear DNA crosstalk complicate therapeutic targeting, emphasizing the need for advanced research approaches. • Future precision therapies, such as gene editing and single-cell omics, hold promise for restoring mitochondrial function and enhancing adipocyte browning to combat obesity and related metabolic syndromes.
Abstract
Mitochondrial dysfunction critically disrupts adipocyte remodeling by impairing the thermogenic browning process essential for combating obesity through the upregulation of uncoupling protein 1 (UCP1) and mitochondrial biogenesis. Deficiencies in mitochondrial metabolism, dynamics (including fusion/fission), and autophagy suppress adipocyte plasticity, directly inhibiting UCP1 expression and destabilizing the PPAR-γ/PGC-1α and adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) signaling pathways. These disruptions reduce energy expenditure, exacerbate insulin resistance, and promote metabolic syndrome. Moreover, mitochondrial inactivation intersects with neurodegenerative disorders via oxidative stress induced by β-amyloid and α-synuclein aggregation, amplifying systemic metabolic dysregulation. Structural mitochondrial anomalies further impede lipid utilization and adipose tissue adaptation, but unresolved crosstalk between mtDNA and nuclear DNA complicates therapeutic targeting. Future research must prioritize spatiotemporal mapping of mitochondrial dynamics in adipocyte differentiation via single-cell omics to identify key regulatory nodes. Addressing these mechanisms could unlock precision therapies, such as gene editing, to restore mitochondrial function, enhance adipocyte browning, and mitigate obesity, related pathologies alongside neurodegenerative and age-associated diseases.
1. Introduction
The global prevalence of obesity has reached alarming levels, escalating into a major public health crisis that now affects over two billion people worldwide [1]. Most epidemiological data on obesity rely on body mass index (BMI). The World Health Organization defines overweight as a BMI between 25.0 and 29.9 kg/m2, whereas obesity is classified as a BMI ≥ 30.0 kg/m2. Severe obesity, associated with heightened health risks, is characterized by a BMI ≥ 40 kg/m2 [2]. Notably, a BMI > 30 kg/m2 serves as the standard threshold for adult obesity, and when the BMI exceeds 40 kg/m2, the risk of obesity-related mortality increases by 100% compared with individuals with a normal weight [3].
Regional analyses highlight significant global trends in obesity prevalence. In China, the standardized mean BMI increased from 22.7 kg/m2 in 2004 to 24.4 kg/m2 in 2018, whereas the prevalence of obesity increased sharply from 3.1% to 8.1% [4]. This trend is not isolated: globally, both men and women exhibit parallel increases in obesity rates. Gender disparities persist across all regions, with the prevalence of obesity being higher among women (18%) than among men (14%). The global age-standardized obesity rate climbed from 8.8% in 1990 to 18.5% in 2022, with the incidence in males increasing from 4.8% to 14.0% over the same period. Between 1990 and 2022, obesity rates rose by more than 20% among women in 49 regions and among men in 24 regions [5]. These escalating trends underscore the profound public health impact of obesity and the urgent need for targeted interventions.
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Yunwen Xu, Shiqin Xie, Luoyang Han, Liang Xu, Yuqin Zhu (2026). Mitochondrial dysfunction in adipocyte differentiation: implications for obesity and metabolic syndrome intervention. Acta Biochimica et Biophysica Sinica. https://doi.org/10.3724/abbs.2025153
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Frequently Asked Questions
What is the role of mitochondrial dysfunction in adipocyte differentiation?
Mitochondrial dysfunction impairs the thermogenic browning process of adipocytes by suppressing UCP1 expression and disrupting key signaling pathways such as PPAR-γ/PGC-1α and AMPK/mTOR, leading to reduced energy expenditure and increased insulin resistance.
How does mitochondrial dysfunction contribute to obesity and metabolic syndrome?
Mitochondrial dysfunction reduces energy expenditure and promotes insulin resistance, exacerbating obesity and metabolic syndrome. It also intersects with neurodegenerative disorders via oxidative stress, amplifying systemic metabolic dysregulation.
What are the potential therapeutic strategies for restoring mitochondrial function in adipocytes?
Future precision therapies, such as gene editing and single-cell omics, aim to restore mitochondrial function, enhance adipocyte browning, and mitigate obesity and related pathologies.
What is the significance of the crosstalk between mtDNA and nuclear DNA in mitochondrial dysfunction?
The unresolved crosstalk between mtDNA and nuclear DNA complicates therapeutic targeting, as it affects mitochondrial dynamics and function, and understanding this interaction is crucial for developing effective interventions.
What research approaches are recommended for future studies on mitochondrial dynamics in adipocyte differentiation?
Future research should prioritize spatiotemporal mapping of mitochondrial dynamics using single-cell omics to identify key regulatory nodes and develop targeted therapies.
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