Comparative Effects of Intermittent Fasting and Swimming Exercise on Metabolic Markers and White Adipose Tissue Browning in High-Fat Diet-induced Obese Mice

Article information

Exerc Sci. 2026;35(2):192-199

Publication date (electronic) : 2026 May 15

doi : https://doi.org/10.15857/ksep.2025.00612

Eunhee Cho, MS ¹^,^†

, Subin Park, BS ¹^,^†

, Chaeeun Cho, PhD ¹

, Sewon Lee, PhD ²^,³^,⁴^,⁵^,

¹Department of Human Movement Science, Graduate School, Incheon National University, Incheon, Korea

²Division of Sport Science, College of Arts & Physical Education, Incheon National University, Incheon, Korea

³Sport Science Institute, College of Arts & Physical Education, Incheon National University, Incheon, Korea

⁴Health Promotion Center, College of Arts & Physical Education, Incheon National University, Incheon, Korea

⁵Research Center of Brain Machine Interface, Incheon National University, Incheon, Korea

Corresponding author: Sewon Lee Tel +82-10-5361-0295 Fax +82-32-835-0788 E-mail leesew@inu.ac.kr

†These authors contributed equally to the manuscript as first author.

Received 2025 November 9; Revised 2025 December 23; Accepted 2026 January 15.

Abstract

PURPOSE

This study aimed to compare the effects of intermittent fasting (IF) and swimming exercise (SE) on metabolic markers and white adipose tissue (WAT) browning in high-fat diet (HFD)-induced obese mice.

METHODS

Forty male C57BL/6J mice (six weeks old) were randomly assigned to four groups: normal chow diet (CON), high-fat diet (HFD), HFD with intermittent fasting (HFD+IF), and HFD with swimming exercise (HFD+SE). The IF protocol consisted of a 48-h feeding and 24-h fasting cycle, while SE was performed for 90 minutes per day, five days per week, at 32±1°C for eight weeks. Body weight, glucose, triglycerides, serum insulin, and HOMA-IR were analyzed. The protein expression of AMPK, PGC-1α, and UCP1 in skeletal muscle and subcutaneous WAT was evaluated using Western blotting.

RESULTS

After eight weeks, the HFD group showed significant increases in body weight, triglycerides, and HOMA-IR compared with the CON group (p<.05). Both IF and SE interventions partially ameliorated these metabolic impairments. IF significantly increased AMPK expression in the gastrocnemius muscle and UCP1 in subcutaneous WAT, whereas SE significantly elevated PGC-1α expression in skeletal muscle.

CONCLUSIONS

These findings suggest that IF improves metabolic health primarily through activation of the AMPK–UCP1 signaling pathway, while SE promotes mitochondrial biogenesis via PGC-1α upregulation. Both interventions exert anti-obesity effects through distinct molecular mechanisms, and their combination may offer a synergistic strategy for preventing obesity-related metabolic disorders.

Keywords: White adipose tissue browning; AMPK; Intermittent fasting; PGC-1α; Swimming exercise

INTRODUCTION

The mechanization and modernization of society have led to increased life expectancy and significant changes in dietary patterns, resulting in a global rise in obesity and metabolic disorders [1]. Obesity, defined as the excessive accumulation of body fat due to an imbalance between energy intake and expenditure, is mainly attributed to high-calorie diets, sedentary lifestyles, and reduced physical activity [2]. Excess body fat accumulation increases the risk of insulin resistance, type 2 diabetes, metabolic syndrome, and cardiovascular diseases, thereby posing a major public health concern [3,4].

Lifestyle modification, including dietary control and physical activity, remains the cornerstone of preventing and treating obesity. Regular exercise not only facilitates weight reduction but also improves insulin sensitivity, glucose regulation, and lipid metabolism [5,6]. The American College of Sports Medicine (ACSM) recommends at least 200 minutes per week of moderate-to-vigorous aerobic and resistance exercise to maintain health and manage body weight [7]. However, adherence to such exercise regimens can be challenging due to time and motivational constraints.

Meanwhile, intermittent fasting (IF) has recently attracted attention as an alternative non-pharmacological intervention. Unlike traditional calorie restriction, which continuously reduces habitual energy intake without inducing malnutrition [8,9], IF refers to a range of dietary patterns characterized by recurring cycles of fasting (or markedly reduced energy intake) interspersed with periods of normal feeding according to predefined schedules. Common IF protocols include time-restricted eating, which limits the daily food intake to a limited time window, and alternate-day fasting. In addition, prolonged fasting or fasting-mimicking diets lasting from 2 to 21 days or longer are often described as periodic fasting, and some studies classify these approaches within the broader spectrum of IF [10,11,17]. Previous studies have shown that IF improves metabolic health by reducing body weight, enhancing insulin sensitivity, and improving cardiovascular risk factors [12,13]. In rodent models, IF has been shown to extend lifespan and improve metabolic flexibility by promoting energy efficiency and lipid oxidation [14-16]. IF is also considered a safe and feasible intervention with minimal side effects compared to chronic calorie restriction [17,18].

Although exercise and IF engage distinct upstream physiological mechanisms, both are widely applied non-pharmacological strategies to improve overlapping metabolic outcomes, including obesity, insulin resistance, dyslipidemia, and chronic inflammation [19,20]. Despite these mechanistic differences, both interventions are commonly employed to modulate whole-body energy balance. Accordingly, a direct comparison between exercise and IF may provide mechanistic insight into whether divergent upstream stimuli converge on shared downstream energy-sensing pathways. Notably, both interventions have been reported to activate common signaling cascades, particularly the AMP-activated protein kinase (AMPK) signaling pathway [21,22]. In addition, exercise and IF have been shown to influence browning of white adipose tissue (WAT), including the induction of thermogenic gene programs associated with adipose tissue remodeling [23,24]. Such adaptations are linked to increased energy expenditure through uncoupling protein 1 (UCP1)-mediated thermogenesis and may contribute to the prevention and management of obesity and related metabolic diseases [25].

According to the 2023 National Survey on Sport Participation [26], swimming has consistently ranked among the top 10 physical activity modalities from 2019 to 2023, indicating its widespread adoption and high accessibility. From a physiological training perspective, swimming elicits metabolic and cardiovascular adaptations comparable to those induced by running [27,28], while offering the additional advantage of reduced mechanical loading on weight-bearing joints [29-31]. Accordingly, swimming is frequently recommended for individuals with low initial muscular strength, as well as for populations with obesity who may be vulnerable to musculoskeletal stress. Despite these practical and physiological advantages, relatively few studies have investigated swimming exercise in the context of obesity, particularly with respect to its potential effects on WAT remodeling and thermogenic regulation.

Therefore, the present study directly compares IF and SE within a unified experimental framework to clarify their relative efficacy and underlying molecular mechanisms regarding adipose tissue browning and metabolic health. However, most previous studies have investigated exercise or fasting interventions in isolation, and the specific metabolic effects of swimming exercise (SE), a whole-body aerobic modality, remain insufficiently characterized in the context of obesity. Accordingly, the present study aimed to compare the effects of IF and SE on obesity-related metabolic parameters and adipose tissue–associated thermogenic markers in high-fat diet–induced obese mice. This comparative approach was designed to provide mechanistic insight into distinct nonpharmacological strategies for metabolic improvement.

METHODS

1. Experimental design

Forty male C57BL/6J mice (6 weeks old) were housed under controlled temperature (20±1°C), humidity (50–80%), and a 12:12-hour light/dark cycle. Mice were randomly assigned to four groups (n=10): 1) normal chow diet (CON), 2) high-fat diet (HFD), 3) high-fat diet with intermittent fasting (HFD+IF), and 4) high-fat diet with swimming exercise (HFD+SE). All experimental procedures were approved by the Institutional Animal Care and Use Committee of Incheon National University (INU-ANIM-2019-12).

2. Diet and interventions

The HFD (D12492, Research Diets Inc., Denmark) consisted of 60% fat, 20% protein, and 20% carbohydrate. The CON group received standard chow. IF was implemented with a 48-hour feeding and 24-hour fasting schedule, during which water was available ad libitum [32,33]. High-intensity SE was performed using an adjustable-flow swimming apparatus following a one-week adaptation period according to previously published protocols [34-36]. Mice in the SE group swam for 90 minutes per session, five times per week for 8 weeks, in water maintained at 32±1°C. To provide a consistent and externally imposed stimulus, water flow was set at a constant rate of 5 L·min⁻¹ (Mille Pet Internal filter RP 400, Mille Pet, China). No additional tail loading was applied. This protocol was designed to induce sustained aerobic stress while minimizing excessive mechanical or cold-induced stress that could confound metabolic outcomes.

3. Sample collection and analysis

After the 8-week intervention, mice were anesthetized with 2.5% tribromoethanol (0.01 mL/g body weight). Blood glucose and triglyceride levels were measured from blood obtained by excising a small portion of the tail tip, using a blood glucose meter (Accu-Chek Performa, Roche Diagnostics, Mannheim, Germany) and a triglyceride measurement kit (Accutrend Plus, Roche Diagnostics, Mannheim, Germany). Subsequently, whole blood was collected via the inferior vena cava for insulin analysis. Serum insulin concentration was measured using an ELISA kit (ALPCO Diagnostics, Salem, NH, USA). Insulin resistance was calculated using the HOMA-IR index as follows:

HOMA−IR=(Insulin(mU/L)×Glucose(mmol/L)22.5

Skeletal muscle (gastrocnemius, soleus) and subcutaneous adipose tissue were excised and snap-frozen in liquid nitrogen, and stored at −80°C.

4. Western blot analysis

Protein expression of AMPK, PGC-1α, and UCP1 was determined using Western blotting. Tissues were homogenized in CelLytic MT lysis buffer (Sigma-Aldrich, St. Louis, MO, USA) with protease inhibitors cocktail (Sigma-Aldrich), and total protein concentration was determined by a BCA assay. Proteins were separated by SDS-PAGE, transferred to PVDF membranes, blocked with 5% skim milk, and incubated with primary antibodies against β-actin, AMPK, PGC-1α, and UCP1 (Cell Signaling Technology and Abcam, USA). Membranes were incubated overnight at 4°C with primary antibodies, followed by three 10-minute washes in TBST. β-Actin served as a loading control, and band intensities were quantified using a Chemidoc Touch Imaging System (Bio-Rad, Hercules, CA, USA). Secondary antibodies were then incubated for 1 hour at room temperature in 5% skim milk, followed by three additional washes in TBST for 10 minutes each (total 30 minutes). Bands were visualized and quantified using Chemidoc Touch Imaging System.

5. Statistical analysis

Data are expressed as mean±standard error of the mean (SEM). Statistical analysis was performed using SPSS version 28.0 (IBM Corp., Armonk, NY, USA). Body weight changes were analyzed using two-way repeated-measures ANOVA, while one-way ANOVA followed by Tukey's post hoc test was applied to compare differences among groups for other variables. Statistical significance was set at p <.05.

RESULTS

1. Body weight and blood biomarkers

At baseline, no significant differences in body weight were observed among the groups (p >.05). From week 2 onward, the HFD group showed a significantly greater increase in body weight compared with the HFD+SE group (p <.05). After 8 weeks, the HFD group exhibited significant increases in body weight, serum triglycerides, and HOMA-IR compared with the CON group (p <.05). Both IF and SE interventions attenuated these elevations. Serum triglyceride levels were significantly elevated in the HFD group compared with the CON and HFD+IF groups. The HFD+SE group showed a trend toward reduction, although the difference was not statistically significant (p>.05) (Figs. 1 and 2).

Fig. 1.

Changes in body composition during the 8-week intervention period. (A) Weekly changes in body weight. (B) Percentage changes in body composition before and after the intervention. Data are expressed as Mean±SEM. CON, control group; HFD, high-fat diet group; HFD+IF, high-fat diet with intermittent fasting; HFD+SE, high-fat diet with swimming exercise. *p<.05, ***p<.001 CON vs. HFD; ^‡p<.05 CON vs. HFD+IF; ^††p<.01, ^***_***p<.001, HFD+IF vs. HFD; ^┼p<.05, ^┼┼p<.01, ^┼┼┼p<.001, HFD+SE vs. HFD.

Fig. 2.

Comparison of blood biochemical profiles after the-8week intervention. (A) Non-fasting glucose. (B) Insulin. (C) HOMA-IR. (D) Triglyceride. Data are expressed as Mean±SEM. CON, control group; HFD, high-fat diet group; HFD+IF, high-fat diet with intermittent fasting; HFD+SE, high-fat diet with swimming exercise. *p<.05.

2. Expression of AMPK, PGC-1α and UCP1

In the gastrocnemius, AMPK expression was significantly increased in the HFD+IF group compared with CON and HFD groups, while PGC-1α expression was significantly elevated in the HFD+SE group (p <.05). In the soleus, AMPK and PGC-1α expression did not differ significantly among groups (Fig 3). UCP1 expression in subcutaneous fat was significantly higher in the HFD+IF group than in the CON and HFD groups (p <.05), whereas SE tended to increase UCP1 without statistical significance (p =.051) (Fig. 4).

Fig. 3.

Expression of metabolic proteins in skeletal muscle. (A) AMPK expression in the gastrocnemius. (B) AMPK expression in the soleus. (C) PGC-1α expression in the gastrocnemius. (D) PGC-1α expression in the soleus. Data are expressed as Mean±SEM. CON, control group; HFD, high-fat diet group; HFD+IF, high-fat diet with intermittent fasting; HFD+SE, high-fat diet with swimming exercise. *p<.05.

Fig. 4.

Expression of UCP1 in subcutaneous white adipose tissue (WAT). Data are expressed as Mean±SEM. CON, control group; HFD, high-fat diet group; HFD+IF, high-fat diet with intermittent fasting; HFD+SE, high-fat diet with swimming exercise. *p<.05.

DISCUSSION

The present study demonstrated that both IF and SE ameliorated HFD-induced metabolic dysfunctions in obese mice through distinct molecular pathways. The HFD group showed significant increases in body weight, triglyceride levels, and insulin resistance, whereas both the HFD+IF and HFD+SE groups exhibited partial improvements in these metabolic impairments. In particular, IF markedly enhanced AMPK protein expression in the gastrocnemius muscle and UCP1 expression in white adipose tissue, while SE significantly increased PGC-1α expression in the gastrocnemius. In the present study, IF and SE did not induce significant changes in blood glucose or insulin levels. However, previous studies have reported inconsistent findings regarding these metabolic indicators. Some animal studies have shown that IF reduces fat accumulation and improves insulin sensitivity, and that aerobic exercise exerts beneficial effects on insulin resistance [37-39]. Conversely, other studies have reported minimal or even increased glucose and insulin levels following IF or exercise interventions [40-42], similar to our findings. IF has been reported to elicit physiological stress responses, particularly in rodent models employing prolonged fasting cycles, through activation of the autonomic nervous system and the hypothalamic–pituitary–adrenal (HPA) axis, resulting in increased glucocorticoid levels such as corticosterone [43,44]. Fasting has also been shown to enhance sympathetic nervous system activity; in rodents, increased norepinephrine turnover has been associated with augmented sympathetic outflow, thereby promoting lipolysis and fatty acid mobilization [45]. Collectively, these stress-related neuroendocrine responses may influence metabolic outcomes and could partially account for the findings observed in the present study. Nevertheless, because glucose and insulin concentrations were measured under non-fasting conditions, future studies incorporating fasting measurements and longitudinal metabolic assessments are warranted to more fully characterize the metabolic adaptations to IF and exercise interventions.

To further elucidate tissue-specific metabolic responses, we analyzed the gastrocnemius and soleus muscles, which predominantly represent fast-twitch (type II) and slow-twitch (type I) fiber compositions, respectively, and differ markedly in their distinct metabolic characteristics [46]. In the present study, AMPK and PGC-1α expression levels were significantly altered in the gastrocnemius, but not in the soleus, indicating a muscle fibertype–dependent response to the interventions. Fast-twitch fibers rely more heavily on glycolytic metabolism and typically possess lower mitochondrial density, whereas slow-twitch fibers are enriched in mitochondria and preferentially support oxidative phosphorylation. These intrinsic differences may also influence reactive oxygen species (ROS) production and subsequent oxidative stress-related signaling pathways, thereby contributing to the differential molecular responses observed between muscle types [47-49].

IF was associated with increased total AMPK expression in skeletal muscle and upregulated UCP1 expression in adipose tissue, suggesting enhancement of energy-sensing and thermogenic-related metabolic adaptations. These observations are consistent with previous studies indicating that AMPK functions as a key metabolic sensor involved in the regulation of fatty acid oxidation and mitochondrial metabolism during stages of energy deficit [50,51]. Despite the increase in AMPK expression with IF, a concomitant elevation in PGC-1α expression was not observed. Recent systemic reviews have suggested that IF does not consistently engage the skeletal muscle AMPK-PGC-1α signaling axis, with such responses appearing to depend on fasting duration, nutritional status, and overall energy balance [52]. Moreover, evidence regarding the PGC-1α responses remains time- and protocol-dependent and is therefore heterogenous across studies [53]. Given that PGC-1α expression is known to increase transiently within several hours following fasting and subsequently return to baseline within 24–48 hours, its detectable level may vary substantially depending on the timing of tissue collection relative to the fasting-feeding cycle [53]. Accordingly, the non-fasted state of the mice at the time of sacrifice may have contributed to the absence of a detectable increase in PGC-1α expression in the present study.

Conversely, SE increased PGC-1α expression, a key regulator of mitochondrial biogenesis, implying adaptation to exercise-induced oxidative stress and calcium signaling [50,54]. Prior studies, including a 7-week treadmill training study in rats and a 10-day aerobic training study in humans, reported a reduction in basal AMPK after training, with significant AMPK activation observed only in individuals who remained relatively unadapted to the exercise stimulus [55,56]. These observations imply that repeated training enhances metabolic efficiency such that AMPK activation becomes attenuated. Accordingly, the increase in PGC-1α observed in the swimming group may reflect activation of AMPK-independent pathways.

The absence of a significant increase in UCP1 in the SE group may be attributable to the relatively warm water temperature (32°C), which likely imposed minimal thermogenic demand compared with cold exposure. Previous studies have demonstrated that environmental temperature is a critical determinant of adipose tissue thermogenic responses. For example, rats that swam in a cold environment (15±1°C) exhibited marked increases in UCP1 expression in both white and brown adipose tissues, whereas animals exercising in warm water (30±2°C) showed no significant changes in UCP1 expression [57,58]. Similarly, mice subjected to swimming in either tepid or cold water displayed significant elevations in PGC-1α expression compared with control animals; however, a significant increase in UCP1 expression was observed exclusively under the cold-water swimming condition [58]. These findings suggest that while exercise stimuli alone may be sufficient to induce mitochondrial biogenesis-related regulators such as PGC-1α, the induction of UCP1 appears to be more strongly dependent on cold-enhanced sympathetic activation and β-adrenergic (norepinephrine-mediated) signaling rather than on exercise-induced mitochondrial adaptations alone [59,60].

Collectively, the present findings indicate that IF and SE ameliorate high-fat diet–induced metabolic disturbances through distinct molecular adaptations. IF primarily enhanced energy-sensing pathways, as reflected by increased skeletal muscle AMPK expression and elevated UCP1 expression in subcutaneous adipose tissue, suggesting a potential improvement in adipose tissue metabolic function. In contrast, swimming exercise preferentially increased PGC-1α expression in skeletal muscle, indicating enhanced mitochondrial biogenesis and oxidative capacity. These differential responses highlight that dietary- and exercise-based interventions may modulate metabolic health through complementary, yet mechanistically distinct, pathways. Further studies incorporating combined interventions and functional assessments are warranted to clarify their interactive effects and translational relevance.

CONCLUSION

Both IF and SE effectively mitigated obesity-induced metabolic disturbances in high-fat diet-fed mice. IF reduced white adipose tissue-related metabolic markers via the AMPK–UCP1 signaling axis, whereas SE stimulated skeletal muscle mitochondrial biogenesis via PGC-1α activation. These results suggest that the two interventions contribute to metabolic health through distinct mechanisms and that each may be effective in preventing obesity.

Notes

ACKNOWLEDGMENT

This work was supported by an Incheon National University Research Grant in 2025.

CONFLICT OF INTEREST

The authors declare no conflicts of interest.

AUTHOR CONTRIBUTIONS

Conceptualization: E Cho, S Park, C Cho; Data curation: E Cho, S Park, C Cho; Formal analysis: E Cho, S Park; Funding acquisition: S Lee; Methodology: E Cho, S Park, C Cho; Project administration: S Lee; Visualization: E Cho, S Park; Writing - original draft: E Cho, S Park, C Cho; Writing - review & editing: S Lee.

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