The worldwide rise in obesity has become the public health issue of our day—and for good reason. The data paints a dismal picture of our current state, but suggest an even more foreboding future. As waistlines expand, so do cardiometabolic diseases (including diabetes, hypertension, dyslipidemia, and coronary heart disease), along with stroke, apnea, and osteoarthritis. This increased morbidity increases suffering, decreases quality of living, reduces life expectancy, and places a large burden on already burdened health care resources.[1],[2]

Reversing the obesity epidemic will no doubt require advances on many fronts (public health policy, education, habit modification, exercise), but it is the understanding of the mechanisms by which the body regulates and stores fat and maintains lean body mass that is key to uncovering effective tools for weight loss and maintenance.


The debate surrounding ideal macronutrient proportions for weight loss continues in both the lay and research communities. While consensus remains elusive, high-protein/reduced-carbohydrate diets appear to be more effective for fat loss, retention of lean body mass, and glycemic control than high-carbohydrate diets[3],[4] – although long-term compliance for very-high-protein/low-carbohydrate diets continues to be problematic.[5]

Ultimately, any dietary routine must return to the concept of energy balance and establish a negative energy balance for weight loss to be effective. While creating a negative energy balance appears to be a straightforward concept, it is not.

Energy balance may indeed be negative at the beginning of almost any dietary routine that includes caloric reduction, but the loss of lean body mass seen during typical caloric restriction means a reduction in resting metabolic rate. When metabolism plummets, it becomes increasingly difficult to maintain a negative energy balance (if caloric intake remains consistent).

Under these conditions, a dieter is faced with two paths when weight loss stalls: further caloric restriction, or somehow preventing the loss of lean body mass while simultaneously reducing fat mass. Caloric restriction has it obvious limits (as well as compliance issues); it is the maintenance of lean body mass, then, that becomes one of the key features of successful weight loss.

Manipulation of the dietary composition of macronutrients becomes important when it is understood that macronutrients are not simply a source of calories, but act as signaling agents that alter feeding behavior, energy partitioning, blood sugar control, protein synthesis – and by extension – metabolism.[6]

Maintenance of Lean Body Mass

It is well established that lean body mass makes up a large proportion of resting metabolic rate[7],[8] and alterations to lean body mass are the only effective ways to modify metabolism (either favorably, or unfavorably).

There are two primary anabolic stimuli for skeletal muscle protein synthesis (and the maintenance of lean body mass): exercise and protein ingestion.

It is well established that sustained mechanical loading of skeletal muscles elicits muscular hypertrophy, whereas a chronic lack of tension/loading contributes to atrophy.[9] The exact mechanism of hypertrophy is beyond the scope of this paper, but even a single bout of resistance exercise can result in elevated muscle protein synthesis that continues 48-hours post recovery.[10] While exercise does stimulate protein synthesis, it simultaneously contributes to muscle protein catabolism. Without proper nutrient intake, a net loss of muscle mass occurs with exercise.[11],[12]

Protein Builds Muscle

The association of protein consumption and its ability to stimulate muscle development has its roots back at least as far as ancient Rome and Greece. Food historians suggest that meat was an integral part of many ancient Olympic competitors’ routines.[13]

By the early 1900s, the evidence that higher-protein diets stimulate lean muscle mass was fairly well established, but the exact mechanism remained elusive. As research continued, the discovery of the essential amino acids, by William Cumming Rose,[14] clarified their role in muscle protein synthesis.

It is now widely accepted that increasing plasma (and subsequently) muscular intracellular amino acid concentrations stimulates muscle protein synthesis (MPS).[15] This anabolic response is typically transient, reaching maximum stimulation approximately two hours post-ingestion/infusion and rapidly returning to previous resting-condition levels.[16],[17]

The essential amino acids in general, and leucine in particular, were eventually found to be the stimulus for protein synthesis. The non-essential amino acids appear to have no effect on muscle protein synthesis[18] and, while all essential amino acids are important to maximize muscle protein synthesis,[19],[20] the branched-chain amino acid (BCAA) leucine is unique in its ability to independently stimulate muscle protein synthesis in both animal and human models.[21],[22]


Nutrients humans consume are partitioned for use as fuel, substrate for cellular processes or cellular development (bone, muscle, skin, blood…), or are incorporated in neurotransmitters, hormones, or transport proteins. Two macronutrients are different and act directly as metabolic stimuli: glucose and leucine. Glucose (and to some extent fructose), in concert with insulin, directs fat storage, while leucine regulates muscle protein synthesis.

The branched chain amino acids (leucine, isoleucine, and valine) are unique among the essential amino acids for their ability to transit the splanchnic bed (gut and liver) following protein digestion and absorption, and pass directly into circulation; and from there, primarily be delivered to muscle.[23] Branched-chain amino acids can be directly oxidized in skeletal muscle, especially during exercise, without prior conversion into glucose.[24],[25]

A number of investigators discovered the unique ability of leucine to stimulate protein metabolism as early as the 1970s and 1980s.[26],[27],[28] Leucine was discovered to be a metabolic messenger for the stimulation of muscle protein synthesis that independently directs protein muscle synthesis in both animal and human models.[29],[30]

These unique qualities are what have led to the investigation of leucine as a potential intervention in the promotion and retention of lean body mass for age-related sarcopenia, athletic performance, and weight loss.

Leucine exerts a distinct metabolic message to the same extent as a complete protein or mixture of amino acids for increasing protein synthesis through the following mechanisms:

  • Leucine ingestion stimulates tissue protein synthesis via a mammalian target of rapamycin pathway (mTOR) in a dose-dependent fashion.[31],[32],[33]
  • Leucine increases mitochondrial biogenesis.[34]
  • Leucine promotes energy partitioning (decreased energy storage in adipocytes and increased fatty acid utilization in muscle).[35],[36]
  • Leucine acts as strong insulin secretagogue when administered in combination with a carbohydrate; increased protein synthesis is facilitated by increased insulin.[37],[38]
  • Leucine is able to extend the postprandial duration of muscle protein synthesis.[39]

Weight Loss

Leucine has been shown to have the following effects helpful for weight loss:

  • Leucine exerts an antiproteolytic effect.[40],[41]
  • Leucine exerts a thermogenic effect.[42],[43]
  • Leucine augments weight and adipose tissue loss during energy restriction.[44]
  • Activation of the mTOR pathway in the brain appears to decrease food intake and body weight.[45]
  • Leucine stimulates a rise in plasma leptin. [46]
  • Leucine acts as a direct fuel.[47]

In animal models, leucine supplementation has been shown to decrease diet-induced obesity by increasing resting energy expenditure, improving glucose control, and cholesterol in rats without changes in food when compared to controls.[48]

Short-term human studies, have shown that leucine induces a decrease in muscle protein breakdown, [49] and a rapid increase in muscle protein synthesis both in athletes and normal/overweight individuals.[50],[51],[52],[53]

Long-term studies utilizing leucine as a possible solution for sarcopenia in the elderly have been disappointing,[54],[55]but short term studies have shown that a whey-added-leucine-carbohydrate beverage along with exercise stimulates protein muscle synthesis similarly in the elderly and young adults.[56] A 24-week trial of overweight/obese subjects consuming 2.25 grams leucine along with 30 mg of pyridoxine a day reported greater reduction of weight and body fat compared with the placebo control group; at 24 weeks, 86% of the weight loss in the leucine + pyridoxine group was fat. [57] A four-week study demonstrated significant increases in fat oxidation and insulin sensitivity and significantly reduced oxidative and inflammatory stress.[58]

Studies have shown that a mixture of leucine, along with a carbohydrate and soy or whey protein can be effective at improving body composition and fat loss. A six-month study of overweight and obese participants consuming a high-soy protein/low-fat diet can improved body composition by losing fat and preserving muscle mass.[59] This leucine supplementation, combined with exercise appears to be the most effective way for maintaining lean body mass for weight loss.[60],[61],[62]

Reports indicate that the optimum quantity of leucine needed to stimulate muscle protein synthesis is 2-3 grams per serving. Maximal protein stimulation occurs after consuming approximately 2 – 3.5 g leucine.[63] Two weight loss trials were conducted to determine the optimal dose for weight loss and concluded that providing a minimum of 2.5 g of leucine at each of three meals (10 grams of leucine per day from all sources) was the most efficacious.[64],[65] These studies used subjects following the USDA Food Guide Pyramid guidelines as controls who were less effective at maintaining lean body mass than those supplemented with leucine, confirming the difficulty with obtaining optimum levels of leucine through the diet alone.

The study by Westcott et al, [66] was supported by Shaklee and utilized meal replacement shakes with added leucine, as per the Shaklee 180 program. Subjects randomized to this nutritional program combined with exercise gained significantly more lean mass than a non-intervention control group and an exercise-only treatment group. The nutrition-plus-exercise intervention resulted in decreased fat mass, with concurrent improvements in blood pressure and no decrease in bone mineral density. It should be noted that exercise is an integral element of the Shaklee 180 program.

A pilot clinical study of Shaklee 180 supported by Shaklee evaluated changes in weight, body composition, and markers of metabolic risk during a 12-week intervention in mildly overweight (mean BMI at baseline: 31.5) subjects. In 14 participants who completed the 12-week trial, the average weight loss was 15.4 pounds, while their lean body mass was unchanged. Improved measures of cardiovascular fitness (improved total- and LDL-cholesterol, triglycerides). Waist circumference was reduced significantly by a mean of 4.1 Inches (10.4 cm).[67]


Weight loss continues to be a challenging public health problem. It is clear that increased protein content of a meal not only increases satiety and modulates feeding behavior, but also is the main metabolic messenger for the synthesis and maintenance of lean body mass. The majority of leucine-related literature confirms the significance of leucine as an anabolic agent that is useful for weight loss and maintenance. The leucine content of a meal may be the critical factor for determining the quantity and quality of proteins necessary at a meal for stimulation of muscle protein synthesis and/or decreased muscle breakdown, and the maintenance of lean body mass and metabolism.[68]


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