The alarming rise in obesity and related metabolic disorders underscores the critical role of nutrition in achieving weight loss, reversing metabolic dysfunction, and sustaining overall health. While various dietary approaches can support a healthy weight and well-being, conventional wisdom for the past half-century has largely favored low-fat, low-saturated fat, and high-carbohydrate diets. Although low-fat diets may benefit some, the current reality is that most adults grapple with excess body fat and some level of metabolic impairment. Regardless of the weight loss strategy employed, prioritizing nutritional considerations is paramount. This review will highlight the fundamental importance of nutrition during caloric restriction for promoting healthy weight loss.
When caloric intake is significantly reduced to induce substantial weight loss - often seen after bariatric surgery or with very low-calorie diets and glucagon-like peptide-1 (GLP1) analogues - it becomes crucial to preserve muscle mass and consume nutrient-dense foods to ensure adequate intake of essential micronutrients. This article will examine the scientific evidence concerning nutritional factors in maintaining lean tissue, functionality, and overall health during significant weight loss. This includes a focus on the optimal quantity and quality of protein necessary to achieve nitrogen balance and maximize lean tissue and health.
The Escalating Obesity Crisis: A Global Challenge
The prevalence of obesity in the United States has more than tripled over the past half-century, with approximately 4 out of 10 adults now classified as obese (BMI ≥ 30 kg/m2) and an additional one-third considered overweight (BMI 25 to < 30 kg/m2). Childhood obesity rates are climbing even faster. A significant portion of adults (over 100 million people) are either prediabetic or diabetic, and only a small percentage of Americans exhibit good metabolic health. Beyond the stigma, personal suffering, and reduced health span associated with obesity and diabetes, these conditions place an immense financial strain on the economy, with over $400 billion spent annually on managing diabetes alone - representing one-fifth of all healthcare expenditures and exceeding the cost of all cancers combined. The obesity and diabetes epidemics are not confined to the United States but represent a global problem. Unfortunately, there are few signs of curbing the obesity crisis. Projections estimate that a significant portion of the population will be obese in the coming years.
The Cornerstone of Weight Loss: The Unique Role of Nutrition
Diet is a fundamental component of any weight loss therapy. Notably, diet is the only intervention that is essential. People with excess adiposity can choose to not have invasive surgery, engage in exercise, or take medications. But they must consume a diet and make decisions every day on what type of foods to consume. Another unique aspect of nutrition is that it can interfere with or augment outcomes of other weight loss strategies. For example, a poorly formulated diet (e.g., deficient in protein, minerals, or some other essential nutrient) may attenuate or cancel out any positive effects of exercise or anti-obesity medications on weight loss. The greater the degree of caloric restriction and weight loss, the more likely nutritional deficiencies occur. There is also the issue of weight regain, which happens frequently with all weight loss approaches, especially if individuals discontinue GLP1 receptor agonist therapy. For all these reasons, nutrition must be viewed as the foundation of safe, effective, and sustainable weight loss and maintenance.
Traditional Weight Loss Strategies: A Spectrum of Approaches
Traditional weight loss strategies span from lifestyle behavioral and metabolic interventions (exercise training and diet interventions) to medical approaches that include surgery and pharmacotherapy, and various combination of these approaches.
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Bariatric Surgery: A Powerful but Invasive Tool
Bariatric surgery, encompassing various invasive surgical procedures, has proven highly effective in achieving significant short-term and sustained (20-year) weight loss. Studies have shown average weight loss at a single center at 1, 10, and 20 years was 18, 20, and 22%, respectively. There is also evidence that bariatric surgery improves obesity-related comorbidities including diabetes and cardiovascular disease. While generally safe, bariatric surgery carries risks, including early complications like leaks, stenosis, bleeding, GERD, and thromboembolic events, and late complications such as band erosion, obstruction, gallstone disease, Dumping syndrome, ischemia, anemia, calcium loss, kidney stones, and osteoporosis. Furthermore, bariatric surgery often necessitates re-operative surgery, is expensive, and requires individuals to have a BMI > 40 kg/m2 without accompanying disease or ≥ 35 kg/m2 with an accompanying disease.
Pharmacotherapy: The Promise and Pitfalls of Anti-Obesity Medications
The history of drugs for obesity has mostly been marked by failure. There are only a few currently FDA-approved anti-obesity medications and - except for GLP1-analogues - they produce only moderate weight loss (< 10%) and have adverse side effect profiles. The recently FDA-approved GLP1 receptor agonists Semaglutide (Wegovy) and Tirzepatide (Zepbound) are associated with average weight loss similar to that of bariatric surgery (i.e., ~15 to 25%) with fewer side effects and possibly many other benefits beyond obesity. This degree of effectiveness represents a major advancement in the treatment of obesity, but it should be noted these drugs do not address the fundamental causes of obesity and they do require consumption of a properly formulated diet.
The Role of Exercise: More Than Just Weight Loss
Diet and exercise are considered first line approaches for weight management, but surprisingly the evidence supporting the role of exercise alone in weight loss is weak compared to other approaches, which often results in individual discouragement. While frequent exercise training is associated with a wide range of health benefits, exercise interventions alone have a small role in weight loss. This may seem paradoxical based on the clear increase in energy expenditure elicited by physical activity, but there are compensatory responses to exercise training that limit weight loss such as increased caloric intake and/or decreased energy expenditure. There is also wide variability in how individuals translate exercise-induced energy deficits into weight loss, which is highly dependent on genetics.
Diet Composition: Navigating the Macronutrient Maze
The role of diet in weight loss has a slightly better track record than exercise training, but there exists a high degree of nonconsensus related to the ideal macronutrient composition to promote healthy weight loss. Most large-scale nutrition interventions for obesity have involved low-fat diets in line with the major tenets of the Dietary Guidelines for Americans and major professional medical organizations for the last four decades. The largest and longest low-fat diet study - the Women’s Health Initiative - showed that postmenopausal women randomized to a low-fat diet intervention had minor weight loss at 1-yr that was not sustained after 7-yr with similar lack of benefit on breast cancer, type 2 diabetes, and cardiovascular disease. In fact, there were plausibly harmful effects of the low-fat dietary pattern on future risk of coronary heart disease in the subset of women with insulin resistance.
Many studies over the last two decades have compared low-fat to low-carbohydrate dietary patterns on weight loss. Summarizing this large body of literature, low-carbohydrate diets are at least as effective as low-fat diets for weight loss, and often outperform them in the short-term. Low-carbohydrate diets appear to be especially superior to low-fat diets in individuals who are insulin resistant.
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The Power of Combination: Diet and Exercise Synergies
It is common to combine dietary and exercise interventions, which tend to produce greater weight loss than either approach alone and help preserve muscle mass during weight loss. However, long-term weight loss success is still moderate even when intensive behavioral strategies are employed. For example, the Look AHEAD trial randomized over 5,000 overweight individuals with type 2 diabetes to an intensive lifestyle intervention (ILI: low-fat diet, exercise, behavior modification, meal replacements, etc.) or standard diabetes support. The role of diet pattern prior to and after surgery has also been examined with some evidence pointing toward superior effects of a pre-bariatric surgery low-calorie ketogenic diet over a Mediterranean and other diet approaches.
The Essential Role of Protein: Preserving Lean Mass
Protein is considered an “essential” nutrient because some of the constituents of protein, amino acids, must be obtained from the diet to prevent deficiency symptoms. In nature, there are nine essential amino acids, two essential fatty acids (linoleic acid and α-linoleic acid) and no essential carbohydrates. Resupplying the amino acid pool with an adequate quantity, and quality, of protein is necessary to prevent excess loss of lean mass during weight loss.
Understanding Fat-Free Mass and Protein Turnover
The fat-free mass (FFM) compartment comprises skeletal muscle, bones, organs, and extracellular fluid. Skeletal muscle constitutes ~40% of adult body weight and half of the physiological amino acid pool. FFM exists in a state of dynamic equilibrium whereby a fine balance of remodeling processes between protein synthesis and breakdown - together referred to as “protein turnover” - are required to maintain organ integrity, synthesize neurotransmitters and hormones, and produce glucose (i.e., gluconeogenesis) during prolonged fasting or to a lesser extent during a ketogenic diet. A healthy adult can turnover ~5.0-6.0 g protein/kg per day, or in other words traffic nearly half a kilogram of protein per day between diet and FFM-stored amino acids to sustain homeostasis.
Mechanisms for Augmenting Skeletal Muscle
There are two main physiological mechanisms that can augment the skeletal muscle component of FFM. De novo skeletal muscle tissue can be synthesized via satellite cell differentiation - a set of specialized cells located proximally to skeletal muscle basal lamina - that can develop into new muscle fibers (i.e., hyperplasia) in the presence of robust stimuli, such as resistance training or injury. Single muscle fibers can also increase in diameter (i.e., hypertrophy) and thereby increase their total cross-sectional area when exposed to the same stimuli, all whilst preserving the original number of fibers.
The Composition of Weight Loss: Fat Mass vs. Fat-Free Mass
A gross estimate is that for every kilogram of body weight lost, approximately three-fourths originate from fat mass (FM) and one-fourth from FFM (3:1 ratio). However, many modulating factors can affect this ratio such as genetics, diet, training status, concurrent resistance training, weight-loss magnitude, and body composition model assumptions. To accurately evaluate the composition of weight loss, non-invasive imaging techniques have advantages due to their excellent sensitivity and accuracy over metabolite excretion and anthropometric measurements, including discerning discrete changes between tissue compartments. Dual-energy X-ray absorptiometry (DXA) is often used as the gold standard to assess fat and lean mass, and bone density responses in many diet and training studies. Despite having advantages over other common body composition methods (e.g., underwater weighing, skin folds, bioelectrical impedance, air displacement plethysmography, etc.), an important limitation of DXA lies in its FFM algorithm, whereby fluid is calculated as lean tissue. Thus, DXA underestimates lean mass under conditions where fluid may be lost (e.g., after profuse sweating, onset of a ketogenic diet, glycogen-depleting exercise, heavy diuretic use, etc.) or vice versa overestimates lean mass when fluid is retained (e.g., edema, carbohydrate loading, etc.).
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Determining Protein Requirements: Nitrogen Balance
Dietary protein is the only nitrogen-containing macronutrient, and thus requirements for protein are often determined using the nitrogen balance method, which calculates nitrogen ingested and subtracts nitrogen excreted. Positive nitrogen balance reflects greater protein synthesis than degradation and FFM preservation or gain, whereas negative nitrogen balance reflects greater protein breakdown than synthesis and net loss of FFM over time. The current recommended dietary allowance (RDA) for maintaining nitrogen balance is 0.8 g protein/kg/day, which translates to about 10%-15% of the total daily energy expenditure. This threshold value was determined by the USDA and WHO/FAO based on 24-h urinary nitrogen excretion patterns to achieve nitrogen balance in the majority of healthy sedentary adults. Relevant to this review, the adequacy of the RDA for protein in the context of major weight loss is also dubious, as studies have indicated skeletal muscle protein synthesis is down-regulated and protein degradation accelerated during energy deficits. A ~10% decrease in daily calories has been shown to increase protein requirements 50%. Complicating interpretation of protein requirements during weight loss is the fact that the mechanisms regulating protein turnover are modulated by the degree of energy deficit and time.
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