The Benefits of Exercise Training in Combination with Weight Loss Therapies

Abstract

The primary treatment for obesity involves calorie restriction (CR) to promote dietary weight loss achieved through interventions including behavioral modification, bariatric surgery, and anti-obesity medications. In adults with obesity, CR-induced weight loss enhances physical function and improves quality of life, while also reducing the burden of various obesity-related chronic conditions, including hypertension, diabetes, obstructive sleep apnea, and atherosclerotic heart disease. However, it is also associated with a decline in lean mass and bone mineral density (BMD), which increases the risk of sarcopenia and osteoporosis. When performed alongside CR, progressive resistance training (RT) attenuates this loss of lean mass and bone mass, while the addition of aerobic training (AT) further improves cardiorespiratory fitness. The individual benefits of RT and AT are complementary and combining both exercise training modalities during CR provides the most optimal benefits for body composition and physical function. The World Health Organization (WHO) recommends that adults engage in at least 150 minutes of moderate-intensity or 75 minutes of vigorous-intensity AT weekly and participate in RT activities involving major muscle groups at least two days per week. While this recommendation applies to the general adult population, regular exercise training that incorporates both RT and AT is particularly crucial for adults with obesity undergoing weight loss interventions. This clinical perspective highlights the benefits of exercise training alongside current weight loss strategies, such as lifestyle changes, bariatric surgery, and pharmacotherapy focusing on incretin-based therapies.

Graphical Abstract

Introduction:

Obesity, defined as the abnormal or excessive accumulation of fat (1), plays a significant pathological role in the development and progression of various chronic diseases, including hypertension, diabetes, heart disease, stroke, and cancer. It has also been shown to reduce both quality of life and life expectancy (2). In the United States today, the prevalence of obesity among adults is just over 40% based on the most used definition of body mass index (BMI) ≥ 30 kg/m² (3). Globally, adult obesity has more than doubled over the past 25 years, with rates of adolescent obesity quadrupling during this same time frame (1). Given the immense impact of obesity on the development of multiple medical comorbidities, effective treatments and their successful implementation continue to play a critical role in combating this growing public health crisis.

The treatment of obesity involves weight loss achieved through interventions, including behavioral modification, bariatric surgery, and pharmacological therapy (4). For adults with obesity, losing as little as 5% body weight can lead to significant improvements in blood pressure, hemoglobin A1c, LDL cholesterol, and markers of insulin sensitivity (5). In adults with both obesity and diabetes, a modest weight loss as little as 2 kg achieved through diet modification over the course of 6 months can reduce the need for glucose-lowering medications (6). Some patients undergoing bariatric surgery may even experience potential remission of diabetes (7). Furthermore, weight loss improves measurable outcomes in physical function and quality of life for patients with obesity (8).

Despite the numerous benefits of weight loss, concerns persist about the loss of lean body mass and bone mineral density (BMD) associated with weight loss interventions (9; 10). This is especially troubling for older adults undergoing weight loss interventions who risk worsening age-related sarcopenia and osteoporosis (11). Consequently, the most recent iteration of the American College of Cardiology/American Heart Association/The Obesity Society (AHA/ACC/TOS) guidelines for the management of obesity continues to assert that “the overall safety of weight loss interventions for patients aged 65 and older remains controversial” and “…there is a need for further research to understand the most appropriate strategies and prescriptions for weight loss for some key populations including older adults” (4). Considering that the worldwide population of adults aged 65 and older is expected to double within the next 30 years (12), mitigating the loss of lean mass associated with weight loss interventions will become increasingly important.

Exercise training that incorporates aspects of both aerobic training (AT) and progressive resistance training (RT) has positive effects on body composition, improves physical function, boosts strength, and improves quality of life for adults with obesity (13). While exercise training alone in the absence of calorie restriction (CR) has not been shown to result in significant weight loss, the addition of exercise training to CR-induced weight loss attenuates the decline in lean mass and BMD when adequate protein and micronutrient intake is ensured (6; 8). The World Health Organization (WHO) recommends that adults engage in at least 150 minutes of moderate-intensity or 75 minutes of vigorous-intensity AT per week in addition to participating in RT activities involving major muscle groups at least two days per week (14). While engaging in this amount of physical activity may not be safe or feasible for some individuals (e.g., those with decreased functional capacity), studies have shown that even most older adults with class 2+ obesity (BMI ≥ 35 kg/m²) can safely perform moderate-intensity physical activity (16).

This clinical perspective highlights the benefits of exercise training on body composition, BMD, and physical function when combined with currently available weight loss modalities, including lifestyle intervention, bariatric surgery, and anti-obesity medications with an emphasis on incretin-based therapeutics.

Lifestyle Interventions

Lifestyle intervention that includes behavioral modifications focused on adhering to a calorie-restricted diet and regular exercise has long been the cornerstone of obesity management (17). While CR-induced weight loss and exercise each improve physical function and quality of life, combining weight loss with concurrent exercise yields better outcomes than either intervention alone (8). In a one-year randomized controlled trial (RCT) focusing on older adults with obesity, a population particularly vulnerable to developing sarcopenia and osteoporosis, CR resulting in an average total weight loss of 10% improved physical function as assessed by modified Physical Performance Test (PPT) by 12%; however, combining CR with regular exercise training led to a 21% improvement in PPT scores compared to placebo. Moreover, the addition of exercise training to CR reduced the loss of lean mass from 5% to 3% and decline in BMD at the hip from 3% to 1% (18).

Studies have also explored the effects of specific exercise modalities – RT and AT in adults with obesity who are actively losing weight. RT stimulates muscle protein synthesis even during negative energy balance, promoting myogenesis, and is particularly crucial to mitigating the loss of muscle mass associated with CR in this population (19). As mechanical loading plays a key role in the process of bone formation (20), the preservation of skeletal muscle by RT during CR mitigates the loss of BMD at the total hip assessed by dual-energy x-ray absorptiometry (DXA)(10). AT lowers the risk of atherosclerotic heart disease (ASCVD), the leading cause of death in the U.S. (21). As assessed by peak oxygen consumption, the addition of AT to CR in dieting adults further improves cardiorespiratory fitness (22).

While each modality offers unique benefits when performed alongside CR, the simultaneous incorporation of both exercise types, known as combination training (CT), yields the most significant advantages for functional improvement and the preservation of lean mass (23) (Figure 1). In a 6-month RCT that directly compared the effects of AT, RT, or CT in older adults with obesity achieving an average CR-induced weight loss of 9% total body weight, physical function assessed using the PPT showed a greater improvement in CT (+21%) than in AT (+14%) or RT (+14%) alone (23). Although BMD at the hip decreased across all intervention groups, the decline was less pronounced with RT (−0.5%) and CT (−1%) compared to AT (−3%). Similarly, less lean body mass was lost with RT (−2%) and CT (−3%) compared to AT (−5%). Muscle strength assessed by one-rep max (1RM) also increased similarly in RT (+17%) and CT (+17%), while it was only maintained in AT. On the other hand, although cardiorespiratory fitness improved across all groups, the improvement seen in AT (+18%) and CT (+17%) was significantly more than in RT (+8%). Additionally, dynamic balance, evaluated by the obstacle course completion time and gait speed, improved more in CT compared to AT or RT. Overall, these findings indicate the complementary effects of RT and AT on physical function without interference effects from concurrent training.

Figure 1. Mean Percentage Changes in Physical Function, Lean Mass, and BMD at the Total Hip during the Interventions.

Measures of physical function included the Physical Performance Test (PPT; scores range from 0 to 36, with higher scores indicating better functional status), peak oxygen consumption, Functional Status Questionnaire (FSQ; scores range from 0 to 36, with higher scores indicating better functional status), and strength (measured as total one-repetition maximum [i.e., the total of the maximum weight a participant can lift, in one attempt, in the biceps curl, bench press, seated row, knee extension, knee flexion, and leg press]). Scores on the PPT were used as an objective measure of frailty (primary outcome), and scores on the FSQ were used as a subjective measure of frailty. The asterisk indicates P<0.05 for the comparison with the control group, the dagger P<0.05 for the comparison with the aerobic group, and the double dagger P<0.05 for the comparison with the resistance group. Percentage changes are presented as least-squares–adjusted means; T bars indicate standard errors. BMD denotes bone mineral density. (Reproduced from Villareal DT, Aguirre L, Gurney AB, et al. Aerobic or Resistance Exercise, or Both, in Dieting Obese Older Adults. N Engl J Med. 2017 May 18;376(20):1943–1955 Copyright (2017) Massachusetts Medical Society. Reprinted with permission.

The benefits of lifestyle intervention are well recognized, and their role as an essential treatment for obesity-related chronic diseases is clearly outlined in multiple societal guidelines (4; 13; 21). However, the data on the long-term sustainability of lifestyle intervention in actual clinical practice leaves much to be desired (24). Weight loss induced by CR, with or without exercise training, upregulates counter-regulatory hormones such as ghrelin, causing an increase in hunger as the body tries to return to its previous weight (25). Unsurprisingly, adults with obesity who initially succeed in losing weight through behavioral modifications often regain half of their lost weight within a year after reverting to old habits (26). The constant cycling between successful weight loss and weight regain is undeniably a significant source of frustration for both patients and clinicians. However, engaging in 275 minutes per week of physical activity is associated with more sustained weight maintenance after initial successful weight loss (27).

Further complicating matters, adults who struggle through multiple cycles of weight loss and regain are at risk of experiencing a progressive decline in lean mass and BMD with each unsuccessful attempt to maintain their weight. In one study focusing on postmenopausal women, a 5-month period of lifestyle intervention led to an average loss of 0.26 kg of lean mass per every 1 kg loss of fat mass; however, during the 12-month post-intervention period, only 0.12 kg of lean mass was recovered for every 1 kg of fat mass regained (28). Another study investigating changes in BMD at the total hip 30 months following a 1-year weight loss intervention trial found that patients continued to show a decline in BMD even with substantial weight regain (29). The progressive loss of lean mass with each unsuccessful weight loss cycle also has further implications for future weight loss efforts. Since the basal metabolic rate, the primary source of total energy expenditure, is primarily influenced by lean mass, CR becomes increasingly difficult to sustain as lean mass diminishes (30), highlighting the critical importance of exercise training for adults with obesity.

Bariatric Surgery:

A survey conducted by the International Federation of Surgery for Obesity (IFSO) in 2018 estimated that 700,000 bariatric surgery procedures were conducted worldwide, with sleeve gastrectomy (SG) (55.4%) and Roux-en-Y gastric bypass (RYGB) (29.3%) being the most popular procedures (31). Since 1991 when global guidelines for bariatric surgery were established, significant data have accrued suggesting that these procedures are safe and effective, even for older adults (32). RYGB results in an initial rapid weight loss in the first few years following surgery, achieving a maximum decrease in total body weight averaging 39% at roughly 1.8 years post-procedure (33) Although there are concerns surrounding weight regain after bariatric surgery (34), an observation study following over 1,100 patients after RYGB found that the average sustained total weight loss remained over 30% 10 years following the procedure (33). Eligible patients who undergo bariatric surgery experience decreased all-cause and cardiovascular mortality, along with a lower incidence of heart failure, myocardial infarction, and stroke (7). In patients with obesity-related chronic diseases such as type 2 diabetes, hypertension, and obstructive sleep apnea, RYGB appears to be particularly effective, with these conditions resolving or going into remission after surgery in many cases (35).

While bariatric procedures are certainly effective options for managing obesity in certain patients, concerns remain about their long-term complications. These include the loss of lean mass and BMD, as well as procedure-specific complications like nutritional deficiencies and osteoporosis, which are particularly prevalent in surgeries that bypass the duodenum (i.e., RYGB) (7). Although limited studies exist on the long-term effects of bariatric surgery on lean mass, a meta-analysis did reveal a sustained decline in fat-free mass within the first year following these procedures, with no evidence indicating that this loss plateaus (36). Additionally, a retrospective analysis found that RYGB was not only linked to an increased risk of falls and fractures that escalated over time, but these risks were also unrelated to the amount of weight lost or the presence of calcium and vitamin D supplementation (37).

Given this data, the role of exercise training, which encompasses both AT and RT modalities, is particularly crucial for mitigating these adverse effects. While engaging in exercise training after bariatric surgery does not result in additional weight loss, it effectively preserves lean mass, increases fat mass loss, and reduces waist circumference (38). AT plays a vital role in enhancing cardiorespiratory fitness post-surgery, which is closely linked to a reduced risk of cardiovascular and all-cause mortality (21). While able to improve relative cardiorespiratory fitness through weight loss, bariatric surgery alone does not lead to improvements in absolute cardiorespiratory fitness, highlighting the importance of AT (39). Similar to patients who achieve weight loss through lifestyle interventions (27), maintaining a physically active lifestyle for patients undergoing bariatric surgery is associated with sustained long-term weight loss maintenance (38).

Although exercise training is crucial for weight management following bariatric surgery, studies assessing physical activity among these patients reveal strikingly low adherence to a physically active lifestyle (40). One study found only 11% of patients reaching at least 150 minutes of moderate-intensity AT every week just one-year after surgery. Furthermore, compared to physical activity levels before surgery, approximately one-quarter of participants increased their sedentary behavior one year after surgery (40). Future studies exploring the optimal exercise training regimen and strategies to improve adherence to exercise training must consider the long-term consequences for this growing population.

Incretin-based Therapeutics:

Although lifestyle interventions focused on regular exercise and adherence to a calorie-restricted diet remain the first-line treatment for most adults struggling with obesity, they are limited by poor adherence and low sustainability rates among many adults in actual clinical practice (24). Bariatric procedures offer significant benefits for adults with obesity and associated chronic diseases who are unable to reach their weight loss goals through lifestyle changes (7). However, very few eligible adults with obesity seek out this treatment option (31). While the number of bariatric surgeries performed continues to rise, it is significantly outpaced by the growing obesity rates in the general population (1); thus, there is a substantial and ever-increasing demand for effective anti-obesity medications. Multiple weight loss medications, including the lipase inhibitor orlistat, naltrexone/bupropion, and phentermine/topiramate can be prescribed alongside lifestyle interventions to provide modest improvements in weight loss for select patients. Their low efficacy and sustainability have historically limited the popularity of these treatments in clinical practice. However, this situation has changed since the adoption of incretin-based therapeutics (41).

Initially developed for the treatment of type 2 diabetes, incretin therapies have been shown in several RCTs to induce significant weight loss compared to placebo. Liraglutide, the first incretin therapy approved by the Food and Drug Administration (FDA) for obesity management in patients without diabetes, induced and maintained a modest 8% decrease in body weight over a period of 56 weeks (42). Years later, a RCT involving the weekly semaglutide showed a 14.9% decrease in body weight after treatment for 68 weeks (43). More recently, similar trials indicate that tirzepatide and retatrutide induce even greater degrees of weight loss at 20.9% over 72 weeks and 24.2% over 48 weeks, respectively. (44). The magnitude of weight loss with these newer agents is similar to results previously seen only with bariatric surgery (7). Some incretin therapies, such as semaglutide, have also demonstrated additional benefits for obesity-related chronic diseases, including reductions in cardiovascular mortality and slowing the progression of diabetic kidney disease (42).

While there is considerable excitement about the potential benefits of adopting these newer treatment options, the well-documented decline in lean mass and BMD associated with that degree of weight loss must be considered. This is especially true for older adults, who are at risk of worsening age-related sarcopenia and osteoporosis and were largely underrepresented in the study populations for these landmark clinical trials (45). Women, especially after on the onset of menopause, represent another at-risk group due to having relatively less lean mass and an increased prevalence of osteoporosis compared to men (28). As expected, treatment with tirzepatide in its phase III trial led to a significant decline in lean mass of 6.0 kg, or 10.9%, over the 72-week trial period (44). Despite inducing a smaller magnitude of weight loss than tirzepatide, treatment with semaglutide resulted in an even more significant loss of lean mass of 6.9 kg, or 13.9%, over its 68-week trial period (43). The amount of lean mass lost in such a short time frame even exceeds the loss experienced by patients actively undergoing chemotherapy for certain cancers (44).

As the use of new anti-obesity medications rises, studies that offer insights into mitigating the unintended loss of muscle and bone mass associated with these treatments will be more crucial than ever. Given the established benefits of exercise training in reducing the loss of lean mass and BMD in patients undergoing CR-induced weight loss through behavioral modification (8) and those following bariatric surgery (38), RT, in particular, is poised to play a similarly vital role for patients losing weight on incretin therapy (44). Thus far, no RCTs have examined the impact of individual or combined exercise training modalities on body composition and physical function in adults with obesity who are actively losing weight while receiving incretin therapy. However, a 2021 study by Lundgren and colleagues evaluated how adding combined exercise training affects body composition during a weight maintenance period of one year in participants who started liraglutide after a successful 8-week weight loss phase (46). Participants undergoing combined therapy experienced double the fat mass loss compared to those receiving only liraglutide or exercise. Those in the exercise-only group saw an average increase of 2.1 kg in lean mass, while participants in the liraglutide-only group maintained their lean mass (0.0 kg). Meanwhile, participants in the combination group had a modest increase of 0.5 kg in lean mass. Although the differences in lean mass among groups did not achieve statistical significance, the overall weight loss was also minimal since the study focused on the weight maintenance period following active weight loss. Only those in the combined therapy group showed sustained improvements in glycated hemoglobin levels, insulin sensitivity, and cardiorespiratory fitness at the one-year follow-up in the trial.

Meta-analyses examining the relationship between fracture risk and incretin therapies in patients with diabetes have yielded inconsistent results, often hindered by the limited number of fracture occurrences, short treatment durations, absence of BMD evaluations, and the influence of other diabetes medications (47; 48). In contrast, a recent secondary analysis of the RCT by Lundgren and colleagues revealed that a year of liraglutide treatment led to reductions in BMD at the hip (−0.013 g/cm²) and spine (−0.016 g/cm²) relative to both placebo and exercise alone. Interestingly, combining exercise with liraglutide maintained hip BMD (−0.0006 g/cm²) and spine BMD (−0.010 g/cm²), even with a significant weight loss of 19.5 kg (49). This further highlights the importance of integrating exercise into weight loss programs that include incretin therapies to protect bone health.

Another concern regarding incretin therapies is the weight regain associated with stopping treatment. While treatment with semaglutide over the course of 68 weeks led to an average weight loss of 17.3%, patients regained roughly 67% of their initial weight loss within just one year following the discontinuation of the medication (50). In another study involving tirzepatide, nine months of initial treatment resulted in an average weight reduction of 20.9%; however, discontinuation led to a subsequent weight regain of 14.0% while continuation of therapy led to an additional 5.5% weight reduction just a year later (51). Participants in these studies show a similar pattern of weight cycling as seen in patients who lose weight through behavioral modifications (26), and they are likely to face the same challenges. This further emphasizes the importance of RT and AT in this patient population.

Conclusion:

Given the significant socioeconomic burden of obesity-related chronic diseases, there is a dire need for evidence-based, safe and effective weight loss interventions. The substantial weight loss associated with incretin therapies offers a promising additional solution to the ongoing obesity epidemic alongside lifestyle intervention and bariatric surgery; however, caution should be taken when prescribing these medications to particularly vulnerable populations, such as older adults (45). Moreover, a concerted effort by major medical societies to emphasize the critical importance of increasing physical activity and reducing sedentary behaviors is essential. Despite the cost-effectiveness and recognized benefits of exercise training, adherence to the WHO recommendations for adults in the general population remains notably low at just 17% (15). Nevertheless, there is hope that adults will increasingly adapt to these recommendations, as many nations now implement policies aimed at promoting health-enhancing physical activity to combat rising obesity rates (13). For instance, in the U.S., Medicare already covers intensive behavioral therapy for obesity and reimburses gym membership fees for eligible patients (52). At the individual level, physicians should emphasize to patients the importance of dietary counseling and frequent physical activity.

Given the current dearth of evidence available, further research is needed to determine the optimal exercise training strategies to mitigate the adverse long-term effects of incretin therapies on lean body mass while maximizing the benefits to cardiorespiratory health. Dedicated studies focusing on specific exercise training interventions where changes in physical function and lean body mass are primary outcomes should be conducted in adults with obesity who are started on incretin treatments.

Further research aimed at determining the optimal exercise training regimens for patients undergoing lifestyle intervention and bariatric surgery should also not be overlooked. Studies that focus on the amount of weight-bearing exercise required to effectively preserve muscle mass and BMD during weight loss interventions are still necessary. Additional factors, such as gender differences in exercise responses, the timing of exercise in relation to circadian rhythms, and the optimal protein intake to pair with exercise training remain understudied currently. Research exploring the optimization of micronutrient intake, such as calcium and vitamin D, alongside exercise training will be particularly important for patients undergoing bariatric surgery. Finally, long-term studies examining the role of exercise training interventions in reducing weight regain after a successful weight loss phase are essential.

Article Highlights.

• Weight loss achieved through calorie restriction causes a decline in lean mass and bone mineral density.

• Progressive resistance training stimulates muscle protein synthesis even during negative energy balance and is particularly crucial for mitigating the loss of lean mass associated with calorie restriction.

• Aerobic training further improves cardiorespiratory fitness during calorie restriction.

• Combining both exercise training modalities during calorie restriction provides the most optimal benefits for body composition and physical function.