Type 2 diabetes (T2D) is largely influenced by lifestyle factors, particularly nutrition and physical activity. A sedentary lifestyle combined with a hypercaloric diet leads to weight gain, increased body fat, and reduced cardiorespiratory fitness, increasing T2D risk. Regular physical activity mitigates these risks, even without dietary changes, by improving insulin sensitivity. While the benefits of exercise on skeletal muscle (SM) are well-documented, including increased muscle mass, capillarization, and mitochondrial content, the role of other tissues, such as SCAT, in metabolic homeostasis remains less clear. SCAT serves as a physiological buffer for energy imbalance, but its dysregulation is linked to insulin resistance and T2D. Studies have shown that long-term endurance training can improve SCAT insulin sensitivity and alter the abundance of enzymes involved in lipolysis, glyceroneogenesis, and oxidative phosphorylation. However, less is known about the acute and repeated transcriptomic responses of SCAT to exercise. This study hypothesized that SCAT, even though not directly utilized during exercise, would acutely respond to exercise, paving the way for long-term effects on lipid metabolism and potentially mitochondrial function. The study aimed to characterize SCAT transcript levels in response to acute and repeated bouts of exercise compared to SM changes in matched human donors.

Extensive research has characterized the molecular adaptations in skeletal muscle in response to exercise, including increased muscle mass, capillarization, and mitochondrial content, which enhances glucose disposal. However, the understanding of the molecular adaptations in adipose tissue in response to exercise is less complete. While some studies have indicated improvements in SCAT insulin sensitivity and changes in enzymes related to lipid metabolism and mitochondrial function after long-term endurance training, more comprehensive investigation, particularly at the transcriptomic level, is needed. There is conflicting evidence regarding the potential for beigeing or browning of white adipose tissue in response to exercise. This study aimed to address these gaps in knowledge by employing a matched transcriptomics approach to compare the responses of SCAT and skeletal muscle to both acute and chronic exercise.

This study involved 14 sedentary participants (overweight or obese, 27 ± 4 years old) who underwent an 8-week supervised endurance training program (3 times/week, 1 hour/session at 80% VO₂peak). Muscle and SCAT biopsies were collected at four time points: baseline, 60 minutes after the first exercise bout (untrained acute), 60 minutes after the last exercise bout (trained acute), and 5 days post-intervention (trained). Transcriptomic analysis using Human Clariom S arrays was performed, and high-resolution respirometry assessed mitochondrial respiration. Data were analyzed using R software. The study also integrated transcriptomic data from the CLOCK study (NCT02487576) to assess the relationship between lipid metabolism and circadian rhythms. Statistical analyses included limma t-tests and BH correction for multiple testing.

In SCAT, 37 transcripts were acutely regulated (FC ≥ 1.2, FDR < 10%) after the first exercise bout, compared to 394 in skeletal muscle. Only 5 transcripts showed overlapping regulation between the two tissues. In SCAT, the acute exercise response was enriched in pathways associated with lipogenesis and lipid metabolism, with downregulation of transcripts related to lipid uptake, storage, and lipogenesis. Upstream regulator analysis suggested β-adrenergic regulation as a potential major driver. Circadian clock modulation was also observed in SCAT after acute exercise. After 8 weeks of training, only one transcript (SMAD7) was significantly downregulated in SCAT, suggesting a less dramatic long-term transcriptomic response. However, at a less stringent statistical threshold (p < 0.01), 209 transcripts were found to be differentially expressed after training in SCAT, and circadian rhythm was a significantly enriched pathway. Skeletal muscle showed a far more extensive acute response (394 transcripts), with a majority being upregulated. Only 5 transcripts showed overlapping regulation with SCAT after acute exercise. Following 8 weeks of training, at a less stringent threshold (p < 0.01), 365 transcripts were differentially expressed in skeletal muscle. Mitochondrial respiration was significantly increased in skeletal muscle post-training, but not in SCAT. No evidence for beigeing/browning was found in SCAT.

This study provides novel insights into the distinct molecular adaptations of SCAT and skeletal muscle to exercise. The acute downregulation of lipogenesis and lipid storage transcripts in SCAT, coupled with the modulation of the circadian rhythm, suggests a mechanism for counteracting metabolic syndrome progression. The lack of overlap in transcriptomic changes between SCAT and skeletal muscle emphasizes their independent responses to exercise. The activation of β-adrenergic signaling may be a key mediator of SCAT's acute response. The absence of significant changes in mitochondrial respiration and beigeing/browning in SCAT contrasts with the robust changes observed in skeletal muscle, highlighting the different roles of these tissues in metabolic adaptation to exercise. The difference in response between this study and previous work studying lean individuals may be due to differences in study design, phenotype, or length of training intervention.

This study demonstrates distinct and largely independent adaptations of SCAT and skeletal muscle to exercise. SCAT's acute downregulation of lipid metabolism genes and its potential circadian rhythm modulation may contribute to the metabolic benefits of exercise. The lack of browning/beigeing or changes in mitochondrial respiration in SCAT suggests a different mechanism of adaptation compared to skeletal muscle. Future research should focus on validating findings at the protein level and investigating the specific roles of β-adrenergic signaling and circadian rhythms in mediating SCAT's response to exercise.

The study's limitations include the lack of proteomic validation, the limited number of biopsies and time points, and the absence of an untrained control group. The focus on overweight or obese individuals may limit the generalizability of findings to lean individuals. Additionally, the chosen time point for analyzing long-term effects might not capture all training-induced changes. Future studies would benefit from addressing these limitations to further clarify the mechanisms and implications of SCAT adaptation to exercise.