Mitochondrial remodeling in obesity: mechanistic links to impaired energy metabolism and therapeutic perspectives

Obesity is characterized not only by excessive adiposity but also by profound disturbances in cellular and systemic energy homeostasis. Metabolic inflexibility, defined as the impaired ability to adapt substrate utilization in response to nutrient availability and energetic demands, has emerged as a central feature of obesity-associated metabolic dysfunction. Increasing evidence suggests that mitochondrial remodeling represents an important mechanism linking obesity to tissue-specific metabolic alterations, systemic metabolic dysfunction, and insulin resistance. Across adipose tissue, skeletal muscle, and liver, obesity induces tissue-specific alterations in mitochondrial biogenesis, dynamics, oxidative metabolism, quality-control pathways, and redox signaling, ultimately disrupting substrate utilization and insulin signaling. Importantly, mitochondrial adaptations appear highly dynamic and context dependent, suggesting that certain responses may initially arise as compensatory mechanisms before becoming maladaptive during disease progression. In addition, translational differences between experimental models and humans contribute to the heterogeneity observed in obesity-associated mitochondrial phenotypes. Here, we integrate preclinical and clinical evidence to examine the molecular mechanisms underlying tissue-specific mitochondrial remodeling and its contribution to metabolic inflexibility. We further discuss how lifestyle, pharmacological, and surgical interventions modulate mitochondrial pathways involved in restoring metabolic flexibility and improving metabolic health. Collectively, this review highlights tissue-specific mitochondrial remodeling as a dynamic and context-dependent process linking obesity to metabolic inflexibility and impaired metabolic adaptability, while identifying mitochondrial plasticity as a promising therapeutic target.