A systematic review and meta-analysis for effects of exercise interventions on accumulation of subcutaneous, visceral, and ectopic fat in overweight and obese adults: a randomized controlled trial

(1) Background: Overweight and obese adults seek effective exercise interventions to reduce accumulated fat, but the effectiveness of these interventions vary across studies. The purpose of this meta-analysis was to investigate the effectiveness of exercise interventions in overweight and obese adults based on measurement of accumulated fat distributions. (2) Methods: Databases were used to select eligible studies for this meta-analysis. Randomized controlled trials with a control and experimental group were included. Degrees of effectiveness of exercise interventions were computed to assess the benefits on reducing weight and subcutaneous, visceral, and ectopic fat accumulation. (3) Results: A total of twenty-one studies were included in this meta-analysis. Participation in exercise interventions showed beneficial effects in reducing weight and subcutaneous and visceral fat. The effectiveness of exercise interventions on ectopic fat accumulation could not be assessed due to the limited number of studies measuring ectopic fat. Additionally, effectiveness of exercise interventions that depended on measurements of accumulated fat varied. The average exercise intervention for overweight and obese individuals was moderate to vigorous intensity, 4 times per week, 50 minutes per session, and 22 weeks duration. (4) Conclusions: Participating in exercise interventions has favorable effects on reducing weight and accumulation of subcutaneous and visceral fat.


Introduction
There are two billion overweight or obese individuals worldwide, and more than 25% of these are over 18 years old [1]. Obesity in this population rose from about 4.5% in 1975 to about 13% in 2016, while the number of those overweight increased from about 22% to about 39% [1]. An accumulation of fat is a crucial factor that increases morbidity and mortality. Overweight and obese adults had a higher rate of chronic diseases. A previous meta-analysis reported that being overweight and obese were associated with a higher rate of disease-specific and all-cause mortality [2]. Additionally, ectopic fat, which accumulates in all organs or tissues including skeletal muscle, liver, pericardium, perirenal tissues, and perivascular areas, may also be a cause of chronic disease including cardiorenal metabolic risks [3]. Ectopic fat deposited in skeletal muscle and the liver may influence systemic metabolic energy, and pericardial fat is associated with coronary atherosclerosis [4]. Also, pericardial, perivascular, and renal sinus fat may affect adjacent anatomic organs leading to direct lipotoxicity resulting in cytokine secretion [5,6]. Decreasing accumulation of fat is preventive healthy behavior.
Participation in exercise or dietary interventions leads to reduced accumulations of fat and improvement in the cardiorenal metabolic risks. A recent meta-analysis among obese children and adolescents demonstrated that exercise or diet had favorable effects on accumulation of fats including ectopic fat [7]. However, the effects of exercise for overweight and obese adults may be different than children and adolescents. Also, outcomes of exercise interventions on changes in accumulated fat may be different. This can be ascertained through measuring methods of fat: computed tomography (CT), magnetic resonance imaging (MRI), volume-localized 1H-magnetic resonance spectroscopy (MRS), and dual-energy X-ray absorptiometry (DAX) that identify accumulations of fat in different organs. Also, depending on the different methods, clinically useful measurements of accumulated fat need to be defined. Therefore, the purpose of this meta-analysis was to understand the effects of exercise intervention on overweight and obese adults and to investigate fat distribution differences and ectopic fat measurements.

Searching processes
We followed the Preferred Reporting Items for Systematic Reviews and Meta-analysis statements (PRISMA) [8] and used the MEDLINE and EMBASE databases to identify relevant studies from January 1990 to July 2019 for this meta-analysis. Search terms for eligible articles were accumulated fat; ectopic fat (liver, hepatic, visceral, abdominal, intrahepatic, intramyocellular, myocardial, cardiac, pancreatic); obesity (overweight, adipose tissues); and exercise (aerobic, endurance, strength, resistance). Inclusion criteria were: reporting results of the effects of pre-and post-exercise interventions; recruiting overweight or obesity adults; randomized controlled trials; indicating determination methods for being overweight and obese; and describing measurement technologies including CT, MRI, MRS, and DAX. Exclusion criteria were being a pilot study, systematic review, or meta-analysis review. Missing results for ectopic fat deposits was another exclusion criterion. We also manually searched references cited in review articles to identify further relevant studies. The Cochrane Collaboration's Risk of Bias Tool was used to assess the quality of the selected studies [9].

Statistical analysis
We used Comprehensive Meta-analysis 2nd version software (Biostat, Englewood, USA). The standardized mean difference statistic, which is the difference in treatment and control group means divided by the pooled standard deviation, was used to calculate the effect size. Heterogeneity between study results was tested with the Q test. If p-values were less than 0.10, we considered the results to be homogeneous. Based on the values of I2, we determined inconsistency; <50% of I2 for small inconsistency, and ≥50% of I2 for large inconsistency. Risk of bias across studies was assessed by visual inspection of the funnel plot.

Results
We described the selection process in Figure 1. A total of 21,400 studies from the initial search were found; 21,322 of these were initially excluded due to not being related to our topic of exercise intervention and ectopic fat. Finally, a total twenty-one studies were selected for meta-analysis . The basic characteristics of the selected studies including the first author's name, country in which the study was conducted, design of the study, numbers of participants, levels of body mass index (BMI), sex, contents of exercise interventions, and major findings are presented in Table 1. All participants had to be older than 18 years. Exercise types in selected studies consisted of 12 studies using aerobic exercise; 3 studies using resistance exercise; one study using interval exercise; and 5 studies using combined exercise including aerobic exercise such as jogging, walking, and cycling, and resistance exercise such as squats, leg extensions, leg curls, elbow flexions, triceps extensions, lateral pull-downs, bench presses, military presses, lower back extensions, and bent leg sit-ups. The average duration of participating in exercise interventions was 22 weeks, 4 times per week for about 50 minutes. The average number of participants for each exercise intervention was 35. The average intensity of exercise was from moderate to vigorous intensity exercise.

Effects of exercise interventions on weight
Overweight and obese individuals who participated in exercise interventions had significantly decreased weight (d= -0.61 [95% confidence interval, -0.82-0.41; p = 0.00; k=14]). The degree of effectiveness included all exercise interventions.

Discussion
Authors should discuss the results and how they can be interpreted in perspective of previous studies and of the working hypotheses. The findings and their implications should be discussed in the broadest context possible. Future research directions may also be highlighted. This meta-analysis found that participating in exercise interventions had a positive influence on reducing weight and subcutaneous, visceral, and ectopic fat in overweight or obese individuals. Only a limited number of studies regarding the effects of exercise intervention on overweight or obese adults are available for review. Studies with ectopic fat measurements are particularly rare. We conducted a meta-analysis to find the effects of exercise intervention on overweight or obese adults as measured by accumulation of fat.
Exercise intervention had a beneficial effect on reducing weight and fat accumulation, including both subcutaneous and ectopic fat, among overweight or obese adults. Fat distributions accumulate as subcutaneous, visceral, and ectopic fat in other organs depending on their capacities for fat storage [31]. A recent meta-analysis of three studies reported that overweight or obese children and adolescents had beneficial effects from exercise intervention. These children and adolescents had reductions in subcutaneous, visceral, and ectopic fat accumulation after completing exercise interventions [7]. However, no meta-analysis study focusing on adults has been performed. This metaanalysis selected all studies that reported effects of exercise interventions on reducing weight and fat accumulation in overweight or obese adults. We found degrees of effectiveness on subcutaneous and visceral fat, but we were unable to ascertain the same effectiveness on ectopic fat due to the limited number of studies in which ectopic fat was measured. This should be addressed in future studies as a recent meta-analysis of three studies, two of which were conducted in the same laboratory, found that hepatic fat in obese children and adolescents who participated in exercise interventions was decreased.
While the exercise interventions were effective in reducing the accumulated fat in overweight or obese adults, the degrees of effectiveness varied according to method of measurement, either CT or MRI. CT and MRI were used to measure subcutaneous and visceral fat in all selected studies. Visceral fat as measured by CT demonstrated a substantial effect with large heterogeneity while subcutaneous fat measured by CT and visceral fat measure by MRI demonstrated less effectiveness and smaller heterogeneity. Subcutaneous fat reduction measured by MRI was not significantly effective due to a small sample size and large heterogeneity. Also, we were unable to compute the effectiveness of exercise intervention on ectopic fat deposition; no MRI studies on liver adipose tissues had been conducted in overweight or obese adults. Considering the differences in measurement methods, further studies are needed to delineate clinically meaningful measurements of accumulated fat. Exercise interventions consisted of moderate to vigorous intensity, 50 minutes per session, and 4 times per week for 22 weeks. Exercise types included aerobic, resistance, combined aerobic and resistance, and interval training. These are important for designing an evidence-based exercise intervention for overweight or obese adults. Current findings of exercise intensity and durations were higher than recommendations of the American College of Sports Medicine (ACSM) for long-term weight loss, which is 200-300 minutes per week of moderate intensity exercise. Maintaining weight loss and preventing weight regain after completing exercise interventions need to be addressed in future studies through long-term follow-up.
There are four potential mechanisms for the findings of this study. First, exercise helps to increase skeletal muscle including increased muscle mass and strength, skeletal muscle glucose uptake, and fatty acid oxidation [32]. Second, the effects of exercise on liver tissues may include increased hepatic uptake of fatty acids and decreased hepatic glucose production, cholesterol synthesis, and glycogen synthesis [33]. Third, in adipose tissue, exercise works to reduce fat mass and leptin and resistin production and increase lipolysis and adiponectin production [34]. Last, participating in exercise decreased chronic inflammation and increased growth factor production leading to endocrine changes that improve systemic mechanisms. This study had some limitations. First, selected studies were still too limited for generalizing to all overweight or obese adults. Second, while reliability and validity were found, all measurements of each organ's adipose tissues were different in the selected study. Third, we suggested a guideline for exercise interventions in overweight or obese individuals based on descriptions of the selected studies, but the guideline requires improvement in detail. Last, this meta-analysis included all races, but an exercise guideline should be developed considering differences in race.

Conclusions
Overweight or obese adults who participated in exercise interventions demonstrated weight and subcutaneous and visceral fat reduction. All types of exercise including aerobic and resistance exercise were effective; and moderate to vigorous intensity exercise programs, 4 times per week, for 50 minutes, and 22 weeks duration may be the most effective based on the available evidence.