The study by Petersen et al. (1) provides valuable insights into the relationship between weight loss, skeletal muscle lipids, and insulin sensitivity in individuals with obesity and type 2 diabetes (T2D). The authors demonstrate that an ∼20% decrease in mitochondrial-endoplasmic reticulum (ER) C18:0 ceramide content accompanies improved insulin sensitivity after weight loss while sarcolemmal sn-1,2-DAG and C18:0 ceramide remain unchanged. These findings emphasize the compartment-specific role of ceramides in metabolic health. However, several critical questions remain unaddressed, limiting the mechanistic understanding of these observations.
First, while the reduction in mitochondrial-ER C18:0 ceramide is compelling, the study does not elucidate how this decrease directly enhances insulin signaling. Recent work by Chaurasia et al. (2) highlights that mitochondrial ceramides impair electron transport chain activity by displacing coenzyme Q, increasing reactive oxygen species. Measuring mitochondrial respiration or reactive oxygen species in future studies could clarify whether the observed ceramide reduction alleviates oxidative stress, thereby improving insulin sensitivity.
Second, the paradoxical increase in C24:1 ceramide postintervention warrants exploration. Unlike saturated ceramides, C24:1 species may exert protective effects. Raichur et al. (3) identified that CerS2-generated C24:1 ceramides counteract lipotoxicity by promoting lipid droplet formation, suggesting a compensatory mechanism. The interplay between CerS1 (C18:0) and CerS2 (C24:1) activities could explain the reciprocal changes in ceramide species, a hypothesis not tested here.
Third, the study design excluded exercise, yet physical activity independently modulates muscle lipids. Thyfault et al. (4) demonstrated that exercise reduces C18:0 ceramide while increasing C24:1, mirroring the current findings. This raises the possibility that inadvertent increases in physical activity during the intervention confounded results. Future trials should objectively monitor activity levels to isolate weight loss effects.
Additionally, participants retained obesity (post-BMI 35 kg/m2) postintervention. Whether further weight loss or metabolic normalization would amplify ceramide reductions remains unclear. A study by Hinte et al. (5) found the presence of obesogenic memory after weight loss and metabolic stimuli, suggesting dynamic lipid adaptations beyond initial interventions that lead to the potential yo-yo effect (weight gain rebound).
Finally, the role of residual insulin resistance (HbA1c 5.9%) and statin use in 71% of participants was unexplored. Statins alter ceramide metabolism, potentially masking true effects of weight loss (6). Stratifying analyses by statin use could refine interpretations.
In conclusion, while Petersen et al. advance our understanding of mitochondrial ceramides, mechanistic and contextual gaps persist. Future work integrating multiomics, mitochondrial functional assays, and controlled lifestyle interventions will clarify how lipid subspecies and compartments orchestrate metabolic improvements.
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Acknowledgments. The author acknowledges the use of artificial intelligence (AI) in the drafting process of the manuscript. The AI was employed to assist in generating initial text, refining language, and enhancing clarity and coherence. All content developed using AI was carefully reviewed, revised, and approved by the authors to ensure accuracy, scientific integrity, and alignment with the study’s objectives.
Funding. This study was funded by the Indonesian Ministry of Research, Technology, and Higher Education (Kemenristek DIKTI). The authors express their gratitude for the financial support that made this research and publication possible.
Duality of Interest. No potential conflicts of interest relevant to this article were reported.
