High-Quality Weight Loss in Obesity: Importance of Skeletal Muscle

Abstract

Treatment responses to behavioral, surgical, and pharmacological approaches in obesity are highly variable in quantity and quality. Here we refer to high-quality weight loss as a high proportion of fat to skeletal muscle mass lost. Given the role of skeletal muscle in energy expenditure, glucose homeostasis, metabolic flexibility, mobility, and strength, excessive loss of skeletal muscle during weight loss is a concern for overall health. Challenges in accurately measuring body composition, especially skeletal muscle, limit our understanding of muscle loss during obesity treatment. Recent incretin-related pharmacotherapies improve muscle metabolic health by enhancing glucose uptake and reducing muscle lipids but, like other weight loss interventions, are associated with muscle loss. Newer pharmacological interventions are being developed to minimize muscle loss, but many questions remain. This article examines the metabolic importance of skeletal muscle and its measurement clinically, as well as key genetic and metabolic factors influencing skeletal muscle and the quality of weight loss. Genetics can affect muscle composition (e.g., fiber types) and function. Together with metabolic factors, including neurohormonal responses and skeletal muscle metabolic efficiency and adaptation, there is variability in weight loss outcomes. In future research investigators should continue to focus on factors affecting skeletal muscle and on personalized strategies to optimize weight loss quality preserving the physical and metabolic functions of skeletal muscle.

Article Highlights

• High-quality weight loss, i.e., a high proportion of fat to skeletal muscle lost during the treatment of obesity, is advantageous for metabolic and physical health.

• Precise and accurate determinations of skeletal muscle mass in clinical settings are often challenging.

• In prevention of excessive loss of skeletal muscle during weight loss, advantages include minimization of metabolic adaptation that makes it difficult to sustain weight loss, improved glucose homeostasis and metabolic flexibility, and better mobility and strength.

• Effective approaches to preserving skeletal muscle include sufficient dietary protein and inclusion of exercise (especially resistance exercise) during weight loss; new pharmacological approaches are under development.

Video 1.

Download video file ^{(1.2GB, mp4)}

American Diabetes Association 84th Scientific Sessions: Diabetes Journal Symposium–Shifting from Quantity to Quality.

Graphical Abstract

Introduction

The causes of obesity are complex and multifactorial. Treatment options include behavioral, surgical, and pharmacological approaches. With the recent advent of new pharmacotherapies including the incretin-related medications, never has there been such a range of therapeutic approaches for obesity, and options are expected to increase (1).

Regardless of treatment approach, there is great interindividual variability in weight loss response (2). Variability in response to all current forms of therapy emphasizes the need to understand the complex interplay of genetic and metabolic factors influencing both the quantity and quality of weight loss to improve outcomes, especially for low responders. Beyond the quantity of weight lost, improved personalized interventions should optimize the quality of weight loss. We refer here to high-quality weight loss as a high proportion of fat versus skeletal muscle lost. Measurements of body composition most often are reported as fat mass (FM) and fat-free mass (FFM). There are limitations in the precision and accuracy of methods, particularly with those for FFM. Within FFM, a component of great importance is skeletal muscle, as low muscle mass is an independent risk factor for all-cause and cardiovascular disease–driven mortality (3). In response to dietary and surgical approaches and pharmacotherapies the proportion of weight lost as FM is in the range of 70%–75%, while that as FFM is in the range of 25%–30%, and the loss of FFM is usually higher with more rapid and greater degrees of weight loss (4,5). Skeletal muscle mass represents approximately half the value of FFM, though this is a rough approximation. As discussed herein, while weight loss is generally associated with some loss of skeletal muscle, it is well-known that even moderate amounts of weight loss are associated with overall improvements in metabolic health, including insulin sensitivity, raising questions about the importance of the quantity and quality of skeletal muscle, including total and relative masses and its composition (e.g., fiber type, lipid content). In addition, there are many challenges in accurately measuring skeletal muscle mass in clinical settings. Thus, in comparing FFM and muscle mass losses associated with different weight loss regimens, it is also important to note differences (or similarities) in total body weight loss such as those in response to diet-induced calorie restriction, bariatric surgery, or pharmacological treatments.

A vast number of factors impact obesity risk and weight loss responses to treatment. Some include the type of intervention, levels of movement and physical activity and sleep, and the use of certain medications. Genetic predisposition is important. From genome-wide association studies >400 BMI-associated loci have been identified (6), many of which are involved in appetite regulation, energy expenditure, and fat storage; a subset of these loci may be more specifically related to the quality of weight loss. Common or rare variants affecting expression or function of leptin, adiponectin, and other adipokines influence metabolic processes such as insulin sensitivity and lipid metabolism, which in turn can affect weight loss outcomes. Gene-metabolic interactions, such as a person’s response to a specific therapeutic approach (e.g., a given diet or a pharmaceutical approach), provide additional layers of complexity that are incompletely understood.

Metabolic factors, which can include neurohormonal factors, and metabolic mechanisms impacting metabolic rate and efficiency, also contribute to weight loss responses. Basal metabolic rate, which accounts for the majority of daily energy expenditure, particularly for sedentary individuals, varies significantly and is influenced by factors such as age, sex, and body composition (e.g., skeletal muscle). During weight loss, metabolic adaptation—a reduction in basic metabolic rate beyond what is predicted by changes in body mass—can hinder weight loss progress and promote weight regain (7). This phenomenon includes complex molecular processes in skeletal muscle and is compounded by neurohormonal changes, including reductions in leptin and increases in ghrelin, which increase appetite and lower metabolic rate (8). Insulin resistance, a precursor to type 2 diabetes mellitus (T2DM), also plays a role in weight loss response. As discussed below, individuals with higher baseline insulin resistance can have less favorable weight loss outcomes (9). This article examines the metabolic importance of skeletal muscle, its measurement clinically, and key genetic and metabolic factors influencing skeletal muscle and the quality of weight loss.

Challenges Associated With Clinical Measures of Body Composition

Prior to highlighting mechanisms contributing to the quality of weight loss, it is important to note some of the strengths and limitations of methods typically used for clinical measurements of body composition. A comprehensive review of methods was recently published, and only key points are covered here (10). In obesity and weight loss, measures of greatest interest are the amounts of adipose and skeletal muscle tissues. Tinsley and Heymsfield (11) recently addressed challenges associated with the terms “fat mass” (FM) and “fat-free mass” (FFM) in assessing body composition and the importance of the consistent use of accurate terminology. The most common and accessible body composition tools are bioimpedance analysis (BIA), DXA, and anthropometry. Other less commonly used approaches include air displacement plethysmography, MRI, computed tomography, and ultrasound.

The fundamental principle of BIA is electrical impedance, given that FFM conducts the small electrical current applied, while FM (nonpolar lipids, i.e., mainly triglycerides) resists or impedes the current. BIA typically relies on a two-compartment model with FM providing an estimate of the total amount of adipose tissue and FFM providing an estimate of total amount of muscle (skeletal, smooth, and cardiac), visceral organs and tissues, bones, tendons, and skin. While BIA is convenient, noninvasive, and cost-effective, its accuracy is influenced by factors such as hydration status, and with BIA body fat can be overestimated or underestimated in individuals with very high (e.g., obesity) or very low (e.g., athletes) body fat percentages (10). BIA cannot differentiate between visceral and subcutaneous fat, which have different metabolic implications, as described below. Thus, there are problems with precision and accuracy. BIA and DXA estimations of appendicular lean mass are surrogate measures of skeletal muscle mass in the limbs and are based on equations (12). Total appendicular lean mass accounts for roughly 75% of whole-body skeletal muscle mass (12). Given the importance of skeletal muscle in metabolic health, appendicular assessments are more relevant to insulin sensitivity and metabolism than are FFM or total lean soft tissue mass, which is calculated as FFM less the amount of bone mass.

DXA is less often used clinically due to limited availability in some clinical settings and low levels of radiation exposure (similar to other X-ray procedures). The technology applies two low-dose X-ray beams at different energy levels to distinguish tissue types based on their density and composition. Soft tissues (fat and lean mass) and bone absorb X-rays differently, allowing DXA to distinguish FM, lean mass, and bone mineral content. Previously, DXA could not differentiate between abdominal tissues, which limited its utility; however, it can now evaluate intra-abdominal adipose tissue volume using CoreScan technology (e.g., 13). However, DXA does not measure the small but highly variable amounts of ectopic lipid, such as that in liver, skeletal muscle, and bone. While muscle biopsies are required, histological approaches can be used to assess ectopic lipid and can provide quantitative estimates of percent intracellular lipids. For example, Goodpaster et al. (14) showed using histological approaches in biopsied skeletal muscle (vastus lateralis) that lipid content is higher in individuals with obesity and T2DM than in lean individuals (mean 3.62% ± 0.65% vs. 1.42% ± 0.28%, respectively; P < 0.05 [mean ± SD]) but is not different between individuals with obesity who have T2DM and those who do not (3.62% ± 0.65% vs. 2.53% ± 0.41% [mean ± SD]).

Anthropometric measurements of adiposity, such as waist-to-hip ratio and skinfold thicknesses, provide a practical low-cost first-line assessment tool but should be supplemented with advanced methods of analyzing body composition (e.g., DXA). Waist-to-hip ratio is often a more clinically relevant index than BMI, but in some cases there are inconsistencies in measurement sites (e.g., for the waist), negatively impacting precision.

Fundamentally problematic with any approach is the assumption that FFM values are estimates of skeletal muscle content. FFM and skeletal muscle content should clearly not be considered as synonymous. The quantity of FFM can be roughly double that of the mass of skeletal muscle, though the proportion varies. In the reference adult it is estimated that total body muscle mass is 48% of FFM (12). FFM measurements in obesity can result in overestimations due to obesity-associated increases in the latter as well as connective tissue associated with the expansion of liver and pancreas and sometimes also skeletal muscle.

Because of these challenges, accurate data on skeletal muscle loss in obesity therapies are limited. In view of this, Heymsfield et al. (15) developed the first-ever models predicting relative reductions in skeletal muscle during calorie restriction and then validated their model in longitudinally monitored samples. In healthy adults (N = 897) skeletal muscle was measured with MRI. MRI provides accurate determinations of muscle quantity, but the high cost, need for highly trained personnel, substantial space requirements, and long scan times as well as long postscan processing times restrict its use mainly to research applications (10). Model predictions of decreased skeletal muscle with calorie restriction (CR) were assessed in two longitudinal studies of nonelderly, nonexercising adults with overweight or obesity. One study was 12–14 weeks’ duration (n = 74) and the other 12 months’ duration (n = 26). Male and female adult reductions in skeletal muscle were 2.0–2.5 kg and 1.0–1.5 kg per 10-kg weight loss, respectively, reflecting baseline differences in total muscle mass. Providing estimates of skeletal muscle loss represents an advance over the historic “quarter FFM” rule according to which it is estimated that ∼25% of weight loss is FFM. However, many factors such as dietary intake, physical activity, aging, and metabolic and hormonal factors can impact the individual changes in FFM loss, relative to total weight loss (11). Regardless, predictive values such as these provide a very useful reference for future evaluation of interventions to preserve skeletal muscle mass in obesity therapies.

Altogether, while standardization is still needed and there are the above-described limitations, DXA has been described as the current reference standard (not the gold standard) for measurements of skeletal muscle mass and body composition, in view of its overall feasibility, accuracy, safety, and low operational costs (12).

Why Does Quality of Weight Loss Matter?

The quality of weight loss is an important determinant of associated metabolic improvements and long-term metabolic health outcomes. Not all weight loss is equal: the loss of fat over skeletal muscle is best, and the location and type of fat lost are also important in metabolic health. Visceral fat (i.e., omental, mesenteric, and retroperitoneal depots) is highly metabolically active and continuously releases fatty acids into the portal vein. It thus can have more of a negative impact for hyperinsulinemia, inflammation, dyslipidemia, and atherosclerosis than subcutaneous fat (16). However, there is evidence that changes in visceral FM are only weakly correlated with insulin sensitivity and triglycerides and that reduced subcutaneous fat cell size correlates strongly with improved insulin sensitivity (17). Moreover, ectopic lipid in skeletal muscle, liver, and pancreas is also associated with metabolic dysfunction, and even moderate weight loss can result in its reduction and improved metabolic health (18). Thus, the quality and quantity of the loss of FM and ectopic lipid are clinically important.

There are many reasons why it is important to minimize skeletal muscle loss during weight loss. Beyond structural and contractile functions, skeletal muscle is a key regulator of metabolic health, influencing postprandial glucose uptake, resting and activity-associated energy expenditure, and whole-body metabolic flexibility. Skeletal muscle is the major site of glucose uptake after the consumption of a mixed meal (19) and is thus critical in blood glucose homeostasis. Preservation of muscle mass during weight loss is likely to be central to improved insulin sensitivity. Haines et al. (20) demonstrated that muscle mass (appendicular lean mass by DXA) is associated with insulin sensitivity independent of adipose depots in healthy young men with overweight/obesity, at risk for T2DM. Skeletal muscle also contributes significantly to total body energy expenditure and is important to sustained weight loss in the long term (21). Even when the body is at rest, skeletal muscle is responsible for ∼20% of metabolic rate, and this proportion increases with movement and physical activity (22). As skeletal muscle is critical in postprandial glucose uptake as well as the uptake of fatty acids between meals, the metabolic flexibility of skeletal muscle is important for whole-body metabolic health and cardiovascular health (23). Metabolic flexibility of skeletal muscle refers to its capacity to switch between glucose and fatty acid oxidation. Disrupted metabolic flexibility in skeletal muscle is also specifically associated with risk for T2DM (24).

Skeletal Muscle Loss and Compositional Changes During Weight Loss

The quality of weight loss is impacted by preintervention levels of musculature. Sarcopenic obesity is defined as the coexistence of excess adiposity and low muscle mass/function (25). For example, Rodrigues et al. (26) conducted a prospective study in 140 middle-aged women undergoing bariatric surgery, focusing on sarcopenic obesity outcomes using DXA, and found that patients with the most severe sarcopenia presurgery lost more FM while having the smallest reduction in total skeletal muscle mass postsurgery. Muscle mass was estimated as appendicular lean mass adjusted to body weight. As sarcopenic obesity is more common in older adults and in those with T2DM (27), the absolute loss of muscle during weight loss may be lower in these populations. The effects of severe versus moderate energy restriction on FFM and skeletal muscle mass are thought to be important. Using approaches including DXA and MRI, Seimon et al. (28) found that severe energy restriction led to greater weight loss and fat loss in postmenopausal women but also to more significant reductions in lean mass (i.e., FFM and thigh muscle area), compared with moderate restriction. With regard to decreases in skeletal muscle during weight loss associated with incretin medications, in the trials Semaglutide Treatment Effect in People with Obesity (STEP) 1 (29) and Study of Tirzepatide (LY3298176) in Participants With Obesity or Overweight (SURMOUNT-1) (30), semaglutide (2.4 mg/week) and tirzepatide (5, 10, and 15 mg/week), respectively, were associated with net losses of 10.1% and 7.9% of initial lean mass over the 68- to 72-week treatment periods (21). Body composition, including muscle mass, was assessed using DXA. These levels of muscle loss are in line with those that occurred with other weight loss approaches (31).

Skeletal muscle compositional characteristics also have an impact on response to weight loss interventions. Greater proportions of type I fibers (slow twitch, “oxidative”), compared with type II fibers (IIa, IIx; fast twitch; “glycolytic”), are associated with greater metabolic demands and fatigue resistance, while lower proportions are associated with higher glycolytic activity and higher velocity contraction capabilities. The proportions of fiber types vary greatly among individuals and, as discussed below, are affected by genetics, age, and exercise. We recently conducted a systematic review of the association of muscle fiber type with measures of obesity (32), which outlines the negative relationship between type I fiber content and BMI, as well as a positive relationship between the proportion of type IIx (highly glycolytic) fibers and BMI. Vastus lateralis proportions of type IIx and type I fibers are positively and negatively associated, respectively, with body fat (33). Type I fibers and muscle mitochondrial density are associated with improved insulin sensitivity and metabolic capacity. As reviewed by Serrano et al. (34), adults with higher proportions of type I fibers accumulate less body fat during overfeeding and individuals with lower proportions of type I fibers are more susceptible to obesity even when calorie or fat intakes are reduced. Those with greater proportions of type I fibers (rectus abdominus) also have greater overall weight loss at 1 year post–gastric bypass surgery (35). Our own work showed a positive association of type I fibers (vastus lateralis) with weight loss on a 900-kcal hypocaloric meal-replacement diet (faster and greater weight loss response) (36), which is not subsequently impacted by 6 weeks of supervised mixed aerobic and resistance exercise training (37).

Overall the effects of obesity therapies on muscle mitochondrial content include no change, increases, or decreases (e.g., 38,39). These mixed conclusions are in part related to differences in interventions and in analytical methods (e.g., immunohistology, Western blotting; citrate synthase activity; mtDNA/nuclear DNA). Also impacting conclusions is the selective atrophy of fiber types with higher concentrations of mitochondria (i.e., types I and IIA) prior to and following weight loss and the use of different data normalization methods. Treatments that include exercise can preserve or increase muscle mitochondrial content and are advantageous because greater muscle mitochondrial content is associated with greater glucose and fat oxidation capacity. Therefore, the quality of weight loss—characterized by a higher proportion of fat loss, a lower proportion of muscle loss, and the preservation of mitochondrial content in muscle—is important for effective therapy responses.

Genetic and Metabolic Factors Impacting High-Quality Weight Loss

There is a complex interplay of genetic and metabolic factors affecting both predisposition to obesity and responses to obesity therapies. Genetic contributors to weight loss and weight loss composition in response to energy restriction have been less well studied than those impacting predisposition to obesity. The 15q26.1 locus near ST8SIA2 and SLCO3A1 was significantly associated with weight loss after Roux-en-Y gastric bypass in one study (40), but this finding awaits replication. In the Look AHEAD (Action for Health in Diabetes) trial, single nucleotide polymorphisms (SNPs) at the ABCB11 and TNFRSF11A loci associated with weight loss at 1 year (41). SNPs near FTO and MC4R have also been associated with weight loss and metabolic improvement.

In most studies a candidate gene approach has been used. Leveraging 1000 Genomes imputed genotypes, we carried out GWAS analysis in 551 patients in an intensively supervised weight loss program with the replication of promising signals in an independent sample of 1,331 patients who later completed the program. We used the genome-based restricted maximum likelihood (GREML) algorithm implemented in Genome-wide Complex Trait Analysis (GCTA) software to estimate the sum contribution of all SNPs (N = 4,681,082 SNPs) to variance in weight loss. We found that genome-wide SNPs (Minor Allele Frequency >0.01) explained 49% of phenotypic variance in weight loss response to dietary restriction (42). We also reported rs679482, intronic to SGCG (sarcoglycan γ), highly expressed in skeletal muscle, to concordantly associate with weight loss in discovery and replication samples, reaching GWAS significance in the combined meta-analysis (β = −0.35; P = 1.7 × 10⁻¹²). As a component of the sarcoglycan complex, SGCG is important for muscle development and integrity. The relationship of this SNP with changes in skeletal muscle mass following bariatric surgery is of potential interest.

Regarding skeletal muscle preservation in response to weight loss, a gene product of particular interest is myostatin, a member of the transforming growth factor-β (TGF-β) superfamily that has an inhibitory role in muscle development. Loss-of-function mutations in the myostatin gene, MSTN (previously known as GDF80), are associated with a hypermuscular phenotype (43). Genotypes of a common SNP in the MSTN locus, rs11333758, differed significantly in high-elite and mixed-sport high-elite athletes as compared with findings in control participants. Additionally, a similar difference by athletic status was reported for rs3764955 near the myostatin receptor gene, ACVR2A, that affects the biological activity of myostatin (44). Myostatin mRNA levels decrease substantially after weight loss (45). The complex roles of myostatin in lean mass preservation during weight loss and the potential therapeutic leveraging of this axis are covered in a recent review (5). The dual-specific monoclonal antibody bimagrumab (BYM-338) targets ActRII A and B receptors in the myostatin-activin-follistatin pathway. In a phase 2 randomized clinical trial of 75 patients with T2DM and BMI between 28 and 40 kg/m² who received bimagrumab or placebo for 48 weeks along with diet and exercise counseling, those who received bimagrumab had a significantly larger decrease in total body FM and glycated hemoglobin and increase in lean mass than patients who received placebo (46). Moreover, FM did not change at 12 weeks following the cessation of treatment. A recent systematic review and meta-analysis on the effect of bimagrumab on body composition (47) highlights safety alongside enhanced lean mass and reduced FM in patients with sarcopenia, as well as generally minimal effects on muscle strength and physical performance. Additional compounds under development include the anti-myostatin antibody, trevogrumab (REGN-1033), and the activin A/B/C inhibitor, garetosmab (REGN-2477) (5). Although these results are exciting, these are still early days in the clinical application of myostatin-related compounds and further research is needed (e.g., changes in muscle fiber type, lipid content, insulin sensitivity).

Metabolic factors are closely intertwined with genetic factors and also contribute to the variable quality of weight loss. Hormones play a central role in regulating muscle protein synthesis, breakdown, and overall metabolic health. During weight loss, neurohormonal changes can significantly impact the preservation of skeletal muscle, and energy-deficit states typically result in metabolic adaptation mechanisms that can limit weight loss and make it difficult to sustain the weight loss. The work of Rosenbaum et al. (48) supports the conclusion that neurohormonal-driven mechanisms in skeletal muscle are the greatest contributors to this hypometabolic adaptation occurring with weight loss. Their results identify increased muscle contractile efficiency, as measured during cycling ergometry, following diet-induced weight loss, and they associate the increased contractile efficiency with decreases in sympathetic nervous system (SNS) tone and in the thyroid hormone axis (48). In other words, after weight loss the energy cost of muscle movement is substantially decreased, and this increased metabolic efficiency of muscle contraction has a substantial whole-body effect on energy balance, with a decreased capacity to lose further weight and to “keep off” the lost weight. Our own work has focused on cell-autonomous mechanisms of bioenergetic efficiencies, and we found that mitochondrial proton leak “energy wastage” is higher in muscle mitochondria, permeabilized myofibers, and primary muscle cells of those in the top quintile than of those in the lowest quintile for weight loss in a standard clinical hypocaloric meal-replacement program (37,49,50). The mechanisms controlling proton leak uncoupling in muscle mitochondria are still very poorly understood.

Insulin and glucagon are well-known as key anabolic and catabolic hormones, respectively, and are relevant to sarcopenic obesity. During weight loss, fasting insulin levels can decrease in association with improved insulin sensitivity and increases in glucagon. Conditions in which there is increased glucagon secretion commonly are associated with decreased ability to synthesize proteins in skeletal muscle, and this may result in sarcopenia (51). The satiety hormone, leptin, has major roles in the control of appetite and energy metabolism, and leptin signaling in muscle stimulates muscle cell proliferation and differentiation, leading to increased muscle mass (52). The hunger hormone, ghrelin, originating from the cells lining the stomach, stimulates appetite and promotes muscle protein synthesis through its primary targets in the brain and the release of GH, and its secondary peripheral action in the release of IGF-1 from the liver. During caloric restriction, ghrelin levels increase, which may help preserve muscle mass through stimulating anabolic pathways. The protective effect of ghrelin in fasting- and denervation-induced muscle atrophy is mediated by mTOR and Akt signaling (53).

Diet Composition and Exercise Approaches to Minimizing Skeletal Muscle Loss

Investigators in many studies have examined effects of dietary protein on FFM and weight loss. Hudson et al. (54) conducted a systematic review and meta-analysis to assess the effects of protein intakes greater than the Recommended Dietary Allowances (RDA) on changes in whole-body lean mass in intentional catabolic and anabolic states. They found that protein intakes above the RDA (0.8 g/kg/day) benefited lean mass changes, particularly during energy restriction and resistance training. After bariatric surgery, guidelines include a minimal daily protein intake of 60 g/day and up to 1.5 g/kg ideal body wt/day (55). This is also consistent with the overall conclusions of Cava et al. (4) that high protein dietary intakes help preserve lean body and muscle mass during weight loss but generally do not improve muscle strength in the absence of increased exercise.

Exercise is one of the most effective strategies for preserving skeletal muscle during weight loss, influencing muscle metabolism through both mechanical and metabolic mechanisms. However, physical activity on its own is rarely an effective strategy for weight loss. Aerobic exercise has a greater benefit than resistance training in terms of cardiovascular fitness and improves insulin sensitivity, mitochondrial function, and oxidative capacity (56). Combining aerobic exercise with resistance training may provide synergistic benefits for muscle preservation and metabolic health. The effects of exercise may be particularly important in older adults with obesity at risk of T2DM and sarcopenic obesity. For example, Brennan et al. (57) examined the effect of diet-induced weight loss (WL group) versus weight loss combined with exercise (WLEX) (aerobic plus resistance exercise) and versus a health education control (HEC) group for 6 months. WLEX prevented reductions in lean mass (DXA) and strength that were observed in the WL group. Exercise also resulted in more robust improvements in skeletal muscle insulin sensitivity, and cardiorespiratory fitness, and reduced intramuscular adipose tissue compared with findings in the WL group. Locatelli et al. (58) conducted a narrative review on the impact of incretin-based weight loss medications on lean mass and of resistance exercise to optimize body composition changes. They found that GLP-1 receptor agonists and related compounds induced substantial weight loss (15%–24%) but also significant lean mass loss (∼10%). The authors propose that tailored resistance exercise training be recommended alongside incretin therapy to preserve lean mass while achieving fat loss. Collectively, findings demonstrate the potential benefits of high protein intake and exercise (particularly resistance type) in minimizing skeletal muscle loss and improving muscle metabolic health.

Limitations and Challenges

Despite progress, many challenges remain in our understanding of the factors influencing the quality of weight loss and muscle mass preservation. Some of the key challenges include the difficulty in rigorously assessing FM, FFM, and skeletal muscle mass in the clinical setting. Improved clinically applicable approaches for body composition assessments and their standardization are needed. It is difficult to draw conclusions regarding interindividual variability in weight loss as most studies are not focused on variability in weight loss responses, often because the studies are insufficiently powered to do so, and because most are focused on short-term weight loss outcomes. Elucidation of genetic contributors will require large multicenter GWAS supplemented by whole-genome sequencing approaches. While studies in clinical populations are necessary, identification of molecular mechanisms induced by metabolic factors requires preclinical studies in animal or cell models. Fundamental questions remain relating to amount of muscle loss relative to the rate and extent of total weight loss following different approaches (e.g., dietary, surgical, pharmacological) and impact on muscle metabolic and physical functions.

Discussion

Responses to obesity therapies vary from person to person. We refer to high-quality weight loss as a high proportion of FM to skeletal muscle loss. Commonly used clinical methods for the assessment of skeletal muscle including BIA, anthropometry, and DXA; of the three, DXA can provide the most precise and accurate values. The preservation of skeletal muscle during obesity therapies is important metabolically due to this tissue’s role in postprandial glucose homeostasis, whole-body metabolic flexibility, and overall metabolic rate, all of which play critical roles in sustained weight loss and improved health. The variable preservation of skeletal muscle during obesity treatment is influenced by a complex interplay of factors, including genetics, neurohormonal factors, pre-treatment muscle levels, diet, and exercise. Novel pharmacologics associated with the myostatin pathway are being developed, and initial studies show effective weight loss and greatly minimized skeletal muscle loss. It will be important to determine the impact of the latter on indices of muscle composition (e.g., fiber type, lipid content) and insulin sensitivity.

Future research priorities should focus on 1) better standardized measures of muscle mass (and FM) that are clinically applicable, 2) mechanisms promoting muscle mass preservation during weight loss therapies, and 3) improved personalized interventions that integrate knowledge of these factors to optimize muscle preservation and overall outcomes in obesity treatment.

Funding Statement

M.-E.H., R.R.M.D., and R.M. are funded by a grant from the Canadian Institutes of Health Research Institute of Nutrition, Metabolism and Diabetes (grant 183651).