Abstract
[Purpose] Impaired insulin-mediated suppression of adipocyte lipolysis, adipose tissue insulin resistance (ATIR), may influence lipolysis and substrate utilization during exercise. This pilot study aimed to investigate the effects of ATIR on metabolic responses and substrate utilization during exercise in young men. [Participants and Methods] Twenty-four young men were divided into two groups based on their ATIR index (Adipo-IR): low Adipo-IR (LA) and high Adipo-IR (HA). The participants performed 40 min of aerobic exercise at an intensity corresponding to 40% peak oxygen uptake. Venous blood samples were collected at baseline and immediately after exercise to measure hormones and metabolite levels. Expired gas was collected during the exercise to estimate substrate oxidation. [Results] After adjusting for whole-body insulin resistance, circulating free fatty acid (FFA) levels at baseline and immediately after exercise were significantly higher in the HA group than in the LA group. The HA group demonstrated significantly lower carbohydrate oxidation and significantly higher fat oxidation than the LA group. Adipo-IR and FFA levels were significantly correlated with parameters of substrate utilization during exercise. [Conclusion] ATIR was associated with substrate utilization during exercise, independent of whole-body insulin resistance. ATIR may play a distinct role in the regulation of substrate utilization during exercise.
Key words: Lipolysis, Substrate utilization, Respiratory exchange ratio
INTRODUCTION
Adipose tissue insulin resistance (ATIR) is a type of adipose tissue dysfunction characterized by decreased insulin sensitivity in adipose tissue. ATIR impairs the ability of insulin to suppress adipocyte lipolysis and to promote lipogenesis1). Consequently, the release of fatty acids (FA) from adipocytes into the circulation is enhanced. Excess FA in the circulation leads to ectopic lipid accumulation in various tissues, such as the liver, heart, and skeletal muscle, thereby contributing to metabolic dysfunction2).
Because exercise promotes lipolysis and fat oxidation3), ATIR may influence the response of metabolites and substrate oxidation to exercise. Impairment of the anti-lipolytic action of insulin caused by ATIR may lead to a greater increase in lipolysis during exercise. Moreover, excessive release of FA from adipose tissue can elevate the availability of circulating free FA (FFA), potentially leading to increased fat oxidation during exercise4, 5). However, to date, no studies have investigated the effects of ATIR on metabolic response and substrate oxidation during exercise. Although no studies have specifically investigated the effects of ATIR, previous studies have reported that whole-body insulin resistance (IR) influences substrate utilization during exercise5, 6). Because ATIR is closely associated with whole-body IR1), these findings provide valuable insights into the potential role of ATIR in regulating substrate utilization during exercise. During exercise, FFA availability did not differ between insulin-sensitive and insulin-resistant women; however, carbohydrate (CHO) oxidation6) or fat oxidation7) is lower in individuals with insulin resistance than in insulin-sensitive individuals. In addition, obese men with elevated FFA and insulin levels have higher FFA levels and fat oxidation during exercise than lean men8). Collectively, these findings imply that ATIR plays a role in the regulation of metabolic responses during exercise.
Therefore, this pilot study aimed to explore the effects of ATIR on hormone and metabolite responses and substrate utilization during exercise in young men. We hypothesized that individuals with higher ATIR would exhibit greater lipolysis and fat oxidation during exercise due to increased circulating FFA availability.
PARTICIPANTS AND METHODS
This study was a secondary analysis of data obtained from our previous studies9, 10). The dataset was originally collected to investigate the response of fatty acid binding protein 4 during acute exercise. In the present study, we reanalyzed these data to examine the effect of ATIR on substrate utilization during acute exercise. All original studies were conducted in accordance with the principles of the Declaration of Helsinki and were approved by the Ethics Committee of the National Institute of Fitness and Sports in Kanoya (approval numbers: 4-1, and 22-1-5). The present secondary analysis was also approved by the same ethics commitee (approval numbers: 25-1-41). After receiving a detailed explanation of the purpose, design, protocol, and potential risks of the study, each of the 24 healthy young men (age: 23.6 ± 3.6 years, weight: 68.3 ± 6.9 kg, height: 171.5 ± 6.6 cm) provided written informed consent. The exclusion criteria were as follows: female sex, age <18 or >40 years, regular exercise habits (spontaneous exercise ≥2 times/week), taking medications known to affect lipid and CHO metabolism, and current smoking. Since no established cutoff value for ATIR is currently available, the participants were classified into low ATIR (LA) and high ATIR (HA) groups based on the median value (13.8) of the ATIR index (Adipo-IR).
Anthropometry and preliminary tests were conducted as described previously9,10,11). Briefly, height and body composition (body weight, fat mass, and fat-free mass) were measured using a stadiometer and a dual-frequency body composition monitor (RD-804L; Tanita Corp., Tokyo, Japan), respectively. Body mass index was calculated as weight in kilograms divided by the square of height in meters.
Resting systolic and diastolic blood pressures were measured using an automatic sphygmomanometer (HEM-1040; Omron Corp., Kyoto, Japan). Peak oxygen uptake (VO2peak) was estimated using an incremental protocol on a cycle ergometer (Aerobike 75XLII, Konami Sports Life, Kanagawa, Japan). During the test, VO2, carbon dioxide output [VCO2], and respiratory exchange ratio [RER] were measured using a gas analyzer (K4b2; COSMED, Rome, Italy). The criteria by Colakoglu et al.12) for reaching the VO2peak were used.
The participants arrived at our laboratory after fasting overnight for at least 12 h. Each participant rested in the supine position for 15 min. Thereafter, a fasting venous blood sample (baseline) was collected. Blood pressure and body composition were measured using the aforementioned devices.
After approximately a 5-min rest, the participants completed a 40-min cycle exercise at 40% VO2peak. VO2, VCO2, and RER were measured during aerobic exercise at 9–10, 19–20, 29–30, and 39–40 min using a gas analyzer (K4b2; COSMED, Rome, Italy). Heart rate (HR) was continuously monitored during the exercise using a wrist-worn HR monitor (Polar A370; Polar Japan, Tokyo, Japan). Venous blood samples were withdrawn from each participant immediately after the exercise. The participants were instructed to consume meals individually adjusted for energy and nutrient content the day before the main experiment, and refrain from strenuous exercise and physical activity 24 h before the experiment. The lead investigator verbally confirmed their compliance with the conditions before each trial.
Blood was sampled and analyzed as described previously9,10,11). Plasma adrenaline, noradrenaline, serum insulin, glucose, FFA, glycerol, total cholesterol, high-density lipoprotein cholesterol, and triglyceride concentrations were measured at baseline. Low-density lipoprotein cholesterol concentrations were estimated using the Friedewald equation13). Immediately after exercise, plasma adrenaline, noradrenaline, serum insulin, glucose, FFA, and glycerol concentrations were assessed. Blood parameters were adjusted according to changes in plasma volume14).
Adipo-IR was calculated as the product of circulating insulin (pmol/L) and FFA (mmol/L) levels15). Whole-body insulin resistance was estimated using the homeostasis model assessment of insulin resistance (HOMA-IR), calculated as fasting insulin level (µU/mL) × fasting glucose level (mg/dL) / 40516).
CHO and fat oxidation rates during the exercise were calculated using the following equations17):
CHO oxidation rate (g/min)=4.585 × VCO2 (L/min) −3.226 × VO2 (L/min)
Fat oxidation rate (g/min)=1.695 × VO2 (L/min) −1.701 × VCO2 (L/min)
The sample size estimation was performed using the G*Power version 3.118). Based on the effect size (ES)(d=1.5–1.74) reported in previous studies examining the percentage of fat oxidation relative to total energy expenditure during exercise6, 8), a minimum sample size of 7–9 participants in each group was required to achieve 80% statistical power at a two-tailed alpha level of 0.05.
The Kolmogorov–Smirnov test was used to assess the normality of the data, and Levene’s test was applied to verify homoscedasticity. Differences in physical characteristics, exercise intensity (workload, HR, %HRmax, VO2, and %VO2), RER, and CHO, and fat oxidation during exercise between the LA and HA groups were examined using an unpaired t-test (parametric variables) or the Mann–Whitney U test (non-parametric variables). In addition, an analysis of covariance (ANCOVA) was performed with baseline HOMA-IR as a covariate to evaluate the differences in RER, CHO, and fat oxidation during exercise between the two groups. Two-way repeated-measures ANCOVA (group × time) adjusted for baseline HOMA-IR was performed to assess changes in blood parameters between the two groups. Pearson correlations were calculated to evaluate the associations of Adipo-IR, FFA, and glucose levels with RER, and substrate oxidation during exercise. Moreover, partial correlation analysis adjusted for HOMA-IR was performed to determine whether these associations were independent of whole-body insulin resistance. ES was calculated as Cohen’s d (small ≥0.20, medium ≥0.50, or large ≥0.80) for the unpaired t-test and post hoc test and r (small ≥0.10, medium ≥0.30, or large ≥0.50) for the Mann–Whitney U test. All statistical analyses were performed using SPSS version 31 (IBM Corp., Armonk, NY, USA). Statistical significance was accepted at the 5% level.
RESULTS
The physical characteristics of the LA and HA groups are shown in Table 1. Significant differences in insulin, FFA, HOMA-IR, and Adipo-IR levels were observed between the LA and HA groups (p<0.05), whereas no significant differences in other physical characteristics were noted between the two groups (p>0.05).
Table1. Participant’s physical and metabolic parameters.
| All (n=24) |
LA (n=12) |
HA (n=12) |
p-value | Effect size | ||||
| Representative value | min – max | Representative value | min – max | Representative value | min – max | |||
| Age (years) | 23.6 ± 3.6 | 20.0–34.0 | 22 (6) | 20.0–30.0 | 22 (6) | 20.0–34.0 | 0.932 | 0.025 |
| Height (cm) | 171.5 ± 6.6 | 158.0–187.6 | 169.6 ± 5.3 | 158.0–177.0 | 173.4 ± 7.4 | 162.0–187.6 | 0.165 | 0.586 |
| Body weight (kg) | 68.3 ± 6.9 | 50.5–83.4 | 67.7 ± 4.0 | 62.2–73.9 | 68.9 ± 9.1 | 50.5–83.4 | 0.686 | 0.167 |
| BMI | 23.2 ± 1.7 | 18.9–25.4 | 23.6 ± 1.4 | 21.7–25.4 | 22.8 ± 2.0 | 18.9–25.1 | 0.312 | 0.423 |
| %fat (%) | 17.9 ± 3.7 | 11.6–28.8 | 18.3 ± 4.4 | 11.6–28.8 | 17.5 ± 3.0 | 13.9–23.7 | 0.582 | 0.228 |
| Fat mass (kg) | 12.2 ± 2.9 | 7.6–20.5 | 11.8 (3.6) | 7.6–20.5 | 11.6 (2.7) | 8.7–17.0 | 0.843 | 0.048 |
| Fat-free mass (kg) | 56.1 ± 6.2 | 41.8–67.9 | 55.3 ± 4.2 | 50.8–62.8 | 56.9 ± 7.8 | 41.8–67.9 | 0.544 | 0.252 |
| SBP (mmHg) | 109 ± 11 | 92–135 | 111 ± 11 | 92–135 | 107 ± 10 | 95–125 | 0.407 | 0.345 |
| DBP (mmHg) | 66 ± 9 | 52–82 | 67 ± 9 | 52–82 | 66 ± 9 | 52–77 | 0.877 | 0.064 |
| VO2peak (mL/kg/min) | 39.9 ± 3.7 | 32.9–48.3 | 39.9 (2.3) | 36.1–47.9 | 39.1 (4.0) | 32.9–48.3 | 0.410 | 0.172 |
| TC (mg/dL) | 182 ± 39 | 141–276 | 189 ± 46 | 142–276 | 176 ± 31 | 141–235 | 0.421 | 0.335 |
| TG (mg/dL) | 103 ± 41 | 47–186 | 97 ± 40 | 47–158 | 109 ± 43 | 52–186 | 0.483 | 0.292 |
| HDLC (mg/dL) | 54 ± 9 | 41–77 | 57 (16) | 41–77 | 50 (7) | 42–62 | 0.600 | 0.384 |
| LDLC (mg/dL) | 108 ± 32 | 72–183 | 98 (53) | 72–183 | 95 (44) | 76–157 | 0.713 | 0.083 |
| Insulin (µU/mL) | 13.5 ± 5.9 | 1.6–11.3 | 4.1 ± 1.5 | 1.6–6.5 | 6.8 ± 2.4 | 3.8–11.3 | 0.002 | 1.393 |
| FFA (mmol/L) | 0.43 ± 0.15 | 0.24–0.89 | 0.37 (0.17) | 0.24–0.89 | 0.46 (0.10) | 0.31–0.74 | 0.017 | 0.484 |
| HOMA-IR | 1.24 ± 0.52 | 0.36–2.51 | 0.94 ± 0.34 | 0.36–1.48 | 1.54 ± 0.49 | 0.82–2.51 | 0.002 | 1.428 |
| Adipo-IR | 13.5 ± 5.9 | 4.2–26.4 | 8.8 ± 3.2 | 4.2–13.4 | 18.2 ± 3.7 | 14.3–26.4 | <0.001 | 2.714 |
Data are shown as mean ± standard deviation or median (interquartile range). P-values for the comparison between the LA and HA are presented. LA: low Adipo-IR; HA: high Adipo-IR; BMI: body mass index; SBP: systolic blood pressure; DBP: diastolic blood pressure; VO2peak: peak oxygen uptake; TC: total cholesterol; TG: triglyceride; HDLC: high density lipoprotein cholesterol; LDLC: low density lipoprotein cholesterol; FFA: free fatty acid; HOMA-IR: homeostasis model assessment for insulin resistance; Adipo-IR: adipose tissue insulin resistance.
The exercise intensity parameters of the LA and HA groups are presented in Table 2. Workload, HR, %HRmax, VO2, and %VO2peak during exercise were similar between the LA and HA groups (p>0.05).
Table 2. Absolute and relative exercise intensity parameters during the exercise.
| LA | HA | Difference of 95% CI | p-value | Effect size | |
| Workload (watts) | 45 (13) | 45 (5) | - | 0.977 | 0.014 |
| HR (beat/min) | 101 ± 11 | 104 ± 13 | −13.64, 6.64 | 0.482 | 0.292 |
| %HRmax | 53.6 ± 5.8 | 55.9 ± 6.6 | −7.52, 3.03 | 0.388 | 0.360 |
| VO2 (mL/min) | 1089 ± 114 | 1136 ± 170 | −169.57, 75.49 | 0.434 | 0.325 |
| %VO2peak | 40.0 ± 3.3 | 41.3 ± 3.1 | −4.02, 1.32 | 0.307 | 0.427 |
Data are shown as mean ± standard deviation or median (interquartile range). CI: confidence interval; LA: low Adipo-IR; HA: high Adipo-IR; HR: heart rate, VO2: oxygen consumption.
The hormone and metabolite responses in the LA and HA groups are shown in Table 3. No significant group ×time interactions were observed for adrenaline and insulin concentrations between the LA and HA groups (p=0.977 and 0.143, respectively). However, significant effects of time on adrenaline and insulin concentrations were observed (p<0.001). A significant group ×time interaction was noted for noradrenaline concentrations (p=0.049), and the increase in noradrenaline concentration was significantly greater in the HA group than in the LA group (p=0.049). No significant group ×time interaction for glucose concentration was observed between the LA and HA groups (p=0.792); however, a significant main effect of time was observed (p=0.005). Glycerol concentration tended to increase to a greater extent in the HA group than in the LA group; however, the group ×time interaction did not reach statistical significance (p=0.067). No significant trial ×time interaction was observed for FFA concentration (p=0.805), whereas significant main effects of group and time were observed (p=0.003 and 0.004, respectively).
Table 3. Hormone and metabolite responses to the exercise.
| Baseline | Immediately after exercise | p-value |
||||
| Interaction | Group | Time | ||||
| Adrenaline (ng/mL) | ||||||
| LA | 22.5 ± 18.6 | 40.3 ± 20.3 | 0.977 | 0.355 | <0.001 | |
| HA | 17.5 ± 6.2 | 32.4 ± 14.1 | ||||
| Noradrenaline (ng/mL) | ||||||
| LA | 235.0 ± 46.6 | 324.3 ± 85.0 | 0.049 | 0.117 | <0.001 | |
| HA | 220.8 ± 81.4 | 371.1 ± 134.9 | ||||
| Insulin (uU/mL) | ||||||
| LA | 4.1 ± 1.5 | 3.6 ± 1.5 | 0.143 | 0.113 | <0.001 | |
| HA | 6.8 ± 2.4 | 4.5 ± 1.8 | ||||
| Glycerol (mg/L) | ||||||
| LA | 4.9 ± 2.1 | 5.9 ± 2.3 | 0.067 | 0.075 | 0.001 | |
| HA | 4.5 ± 1.2 | 6.2 ± 1.6 | ||||
| FFA (mmol/L) | ||||||
| LA | 0.39 ± 0.18 | 0.48 ± 0.20 | 0.805 | 0.003 | 0.004 | |
| HA | 0.47 ± 0.11 | 0.53 ± 0.15 | ||||
| Glucose (mg/mL) | ||||||
| LA | 94.0 ± 4.2 | 90.4 ± 3.6 | 0.792 | 0.864 | 0.005 | |
| HA | 92.3 ± 6.0 | 89.1 ± 8.8 | ||||
P-values for the interaction, and the main effects of group and time, using analysis of covariance adjusted for baseline HOMA-IR, are presented. LA: low Adipo-IR; HA: high Adipo-IR; FFA: free fatty acid; HOMA-IR: homeostasis model assessment for insulin resistance.
RER and substrate oxidation during exercise in the LA and HA groups are shown in Table 4. In the unpaired t-test, RER and the percentages of CHO and fat oxidation differed significantly between the LA and HA groups (p<0.05), whereas CHO and fat oxidation (per body weight and fat-free mass) related to substrate oxidation showed a tendency toward significance (p=0.050–0.054). After adjusting for HOMA-IR, all parameters showed significant differences between the LA and HA groups (p≤0.03). The RER was significantly lower in the HA group than in the LA group (p=0.002). CHO oxidation (per body weight and fat-free mass) and its percentage were significantly lower (p≤0.03 and p≤0.005, respectively), whereas fat oxidation (per body weight and fat-free mass) and its percentage were significantly higher in the HA group than in the LA group (p≤0.004 and p≤0.005, respectively).
Table 4. Comparison of respiratory exchange ratio and substrate oxidation during exercise between LA and HA.
| Unadjusted (Mean ± SD) |
Adjusted for HOMA-IR (Mean ± SE) |
|||||||
| LA | HA | Difference of 95% CI | p-value | LA | HA | Difference of 95% CI | p-value | |
| RER | 0.86 ± 0.05 | 0.80 ± 0.06 | 0.09, 0.11 | 0.023 | 0.88 ± 0.02 | 0.78 ± 0.02 | 0.04, 0.15 | 0.002 |
| CHO oxidation (per BW, mg/kg/min) | 11.91 ± 3.79 | 8.86 ± 3.55 | −0.05, 6.17 | 0.054 | 12.91 ± 1.14 | 7.87 ± 1.14 | 1.35, 8.72 | 0.010 |
| CHO oxidation (per FFM, mg/kg/min) | 14.61 ± 4.55 | 10.80 ± 4.48 | −0.004, 7.64 | 0.050 | 15.93 ± 1.38 | 9.48 ± 1.38 | 2.00, 10.9 | 0.030 |
| Fat oxidation (per BW, mg/kg/min) | 3.63 ± 1.37 | 4.97 ± 1.68 | −2.63, −0.04 | 0.044 | 3.10 ± 0.45 | 5.50 ± 0.45 | −3.85, −0.94 | 0.003 |
| Fat oxidation (per FFM, mg/kg/min) | 4.47 ± 1.68 | 6.00 ± 2.00 | −3.10, 0.34 | 0.055 | 3.86 ± 0.55 | 6.61 ± 0.55 | −4.53, −0.98 | 0.004 |
| Percentage of CHO oxidation (%) | 58.9 ± 16.6 | 44.4 ± 17.6 | 0.001, 29.02 | 0.050 | 64.2 ± 5.2 | 39.1 ± 5.2 | 8.43, 41.89 | 0.005 |
| Percentage of fat oxidation (%) | 41.1 ± 16.7 | 55.6 ± 17.6 | −29.03, −0.001 | 0.050 | 35.8 ± 5.2 | 60.9 ± 5.2 | −41.89, −8.43 | 0.005 |
P-values for the comparison between the LA and HA are presented. SD: standard deviation; HOMA-IR: homeostasis model assessment for insulin resistance; SE: standard error; LA: low Adipo-IR; HA: high Adipo-IR; CI: confidence interval; RER: respiratory exchange ratio; CHO: carbohydrate; BW: body weight; FFM: fat-free mass.
Pearson’s and partial correlation coefficients between Adipo-IR, glucose, and FFA and RER, and substrate oxidation are shown in Table 5. No significant Pearson’s correlation coefficients were observed among Adipo-IR and RER, and substrate oxidation (r=−0.384–0.364, p>0.05). However, after adjusting for HOMA-IR, significant associations were detected between Adipo-IR and all parameters (pr=−0.746–0.746, p<0.05). Significant Pearson’s and partial correlation coefficients were observed between FFA levels and substrate oxidation parameters (baseline: r=−0.665–0.665; pr=−0.668–0.668; exercise: r=−0.509–0.451; pr=−0.537–0.465, all p<0.05), whereas no significant correlation coefficients were observed between blood glucose levels and substrate oxidation parameters.
Table 5. Pearson’s correlation coefficients (r) and partial correlation coefficients (pr) between Adipo-IR, FFA, and glucose, and RER and substrate oxidation during exercise.
| Adipo-IR index |
FFA |
Glucose |
||||||||
| Baseline |
Exercise |
Baseline |
Exercise |
|||||||
| r | pr | r | pr | r | pr | r | pr | r | pr | |
| RER | −0.361 | −0.714 | −0.622 | −0.627 | −0.359 | −0.371 | −0.052 | −0.041 | −0.024 | −0.014 |
| CHO oxidation (per BW, mg/kg/min) | −0.384 | −0.724 | −0.649 | −0.659 | −0.486 | −0.520 | −0.101 | −0.095 | 0.027 | 0.034 |
| CHO oxidation (per FFM, mg/kg/min) | −0.376 | −0.737 | −0.660 | −0.668 | −0.509 | −0.537 | −0.102 | −0.093 | 0.020 | 0.030 |
| Fat oxidation (per BW, mg/kg/min) | 0.333 | 0.736 | 0.646 | 0.643 | 0.431 | 0.430 | 0.062 | 0.042 | 0.005 | −0.013 |
| Fat oxidation (per FFM, mg/kg/min) | 0.322 | 0.712 | 0.613 | 0.609 | 0.411 | 0.408 | 0.076 | 0.057 | 0.029 | 0.012 |
| Percentage of CHO oxidation (%) | −0.364 | −0.746 | −0.665 | −0.668 | −0.451 | −0.465 | −0.094 | −0.080 | −0.005 | 0.008 |
| Percentage of fat oxidation (%) | 0.364 | 0.746 | 0.665 | 0.668 | 0.451 | 0.465 | 0.094 | 0.080 | 0.005 | −0.008 |
Bold values indicate significant correlations. FFA: free fatty acid; RER: respiratory exchange ratio; CHO: carbohydrate; BW: body weight; FFM: fat free mass.
DISCUSSION
To the best of our knowledge, this is the first study to investigate the effects of ATIR on metabolic responses and substrate utilization during exercise. Consistent with our hypothesis, the primary findings showed that CHO oxidation was lower, whereas fat oxidation during exercise was higher in men with high ATIR than in those with low ATIR, independent of whole-body IR as expressed by HOMA-IR. Additionally, ATIR was associated with substrate utilization after adjusting for whole-body IR. Contrary to our hypothesis, lipolysis did not differ according to ATIR; however, FFA availability was higher in men with high ATIR. Thus, ATIR could be a potential factor that influences substrate utilization during exercise.
Although the difference was not statistically significant, glycerol concentrations tended to be higher in the HA group than in the LA group. This finding indicates increased lipolysis in the HA group and appears to support our hypothesis. However, the difference in the increase in glycerol concentration between the LA and HA groups is likely attributable to the difference in the increase in noradrenaline concentration during exercise rather than the decreased insulin sensitivity in adipocytes. As noradrenaline stimulates lipolysis during exercise19), the elevated glycerol concentrations could be explained by the greater noradrenaline response during exercise in the HA group. However, the mechanism underlying the augmented noradrenaline response remains unclear. Even in individuals with obesity and type 2 diabetes, when FFA and insulin levels at baseline and during exercise are comparable to those in lean individuals, the noradrenaline response during exercise does not differ from that in healthy individuals20). In contrast, obese men with higher FFA and insulin levels at baseline and during exercise compared to lean men demonstrate a greater increase in noradrenaline concentration during exercise8). Thus, FFA and insulin levels could influence the noradrenaline response during exercise. In the present study, insulin levels did not significantly differ, whereas the FFA levels in the HA group were significantly higher than those in the LA group. Therefore, the higher FFA levels likely stimulate noradrenaline secretion during exercise. Studies in both rats and humans have demonstrated that experimentally elevated circulating FFA concentrations via lipid infusion stimulate sympathetic nervous system activity and increase noradrenaline concentrations21, 22). Thus, elevated FFA levels may, at least in part, explain the greater noradrenaline response observed in the HA group in this study.
Whole-body IR influences substrate oxidation during exercise6, 7); however, consistent findings have not been reported. Arad et al.7) have demonstrated that lipid oxidation during exercise was lower in individuals with poor whole-body insulin sensitivity. By contrast, Braun et al.6) have reported that whole-body IR individuals exhibited lower CHO oxidation and a lower percentage of energy derived from CHO, as well as higher fat oxidation during exercise than whole-body insulin-sensitive individuals. However, because whole-body IR is strongly associated with ATIR1), the results of previous studies may reflect the combined effects of whole-body IR and ATIR. Our finding that substrate utilization differed according to ATIR even after adjusting for whole-body IR (HOMA-IR) suggests that ATIR may independently affect substrate metabolism during exercise. Our results also highlight the potential importance of ATIR in regulating substrate utilization during exercise, indicating that interventions targeting ATIR could modulate exercise metabolism and improve metabolic health independent of whole-body IR.
Substrate oxidation during exercise is influenced by various factors, including body composition8, 23), aerobic capacity24), glucose availability10, 25), and FFA availability. In the present study, body composition, aerobic capacity, and circulating glucose levels did not significantly differ between the LA and HA groups; however, circulating FFA levels were significantly higher in the HA group than in the LA group. Additionally, circulating FFA levels were correlated with substrate oxidation parameters, whereas circulating glucose levels were not correlated with them. Therefore, the differences in circulating FFA availability may substantially influence substrate oxidation during exercise4, 5). Moreover, the correlation coefficients between Adipo-IR and substrate oxidation parameters were higher than those between circulating FFA levels and substrate oxidation. Although the mechanisms are unclear, ATIR may have a greater influence on substrate utilization during exercise than circulating FFA levels alone.
Currently, a cut-off value for the Adipo-IR has not been established. However, data have been reported for Japanese individuals in previous studies26,27,28). In two studies involving young Japanese women (mean age: approximately 20 and 25 years, respectively)27, 28), participants were divided into tertiles according to the Adipo-IR, with the mean values in the first, second, and third tertiles reported as 8.2, 15.6, and 37.8, and 8.4, 16.5, and 48.2, respectively. Additionally, in a study of middle-aged normal-weight Japanese men and women (mean age: approximately 45 years old)26), the median values in the first, second, and third tertiles were reported as 13.2, 25.2, and 46.2 for men and 13.7, 26.5, and 52.1 for women. Based on these previous data, the participants in the present study can be classified within the first and second tertiles of the Adipo-IR distribution, suggesting a low-to-moderate Adipo-IR. Despite the relatively low-to-moderate Adipo-IR in this population, significant differences in substrate utilization during exercise were observed. Thus, even modest variations in ATIR could influence the metabolic responses to exercise.
This study has some limitations. First, the participants were young men. Therefore, our findings may not be generalizable to women, adolescents, older adults, or individuals with metabolic disorders. Second, the Adipo-IR index and HOMA-IR were used as indicators of ATIR and whole-body IR, respectively. These indices are not estimated by gold-standard methods such as the hyperinsulinemic–euglycemic clamp. However, their validity has been demonstrated in previous studies15, 16, 28), and they are widely used as practical and reliable surrogate markers in clinical and research settings29, 30). Third, the relative contributions of blood glucose, muscle glycogen, blood FFA, and non-blood FFA to substrate utilization could not be determined in the present study. Because the sources of substrate oxidation may differ according to the ATIR, this aspect warrants further investigation. Lastly, the exercise intensity in the present study was relatively low. Whether metabolic responses and substrate utilization differ according to ATIR during moderate-to-high-intensity exercise remains to be elucidated. Nevertheless, the present study provides the novel insight that ATIR, assessed using the Adipo-IR index, may independently influence substrate metabolism during exercise.
ATIR was associated with substrate utilization during exercise, independent of whole-body IR. Individuals with higher ATIR had lower CHO oxidation and higher fat oxidation during exercise, even after adjusting for HOMA-IR. ATIR may play a distinct role in the regulation of substrate utilization during exercise.
Funding
This study was supported by the Japan Society Promotion of Science Grant-in-Aid for Scientific Research© Grant Number 22K11552.
Conflict of interest
The authors declare that there is no conflict of interest regarding the publication of this article.
Acknowledgments
The authors would like to thank all the participants for their participation in this study, and Takashi Kurosaki for his valuable support and cooperation in data collection.
Funding Statement
This study was supported by the Japan Society Promotion of Science Grant-in-Aid for Scientific Research© Grant Number 22K11552.
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