Higher Branched-Chain Amino Acid Intake Is Associated with a Lower Prevalence of Being Overweight or Obese in Middle-Aged East Asian and Western Adults¹²

Introduction

Overweight status and obesity, escalating health problems worldwide (1), are major risk factors for coronary heart disease and associated with higher risk of hypertension, dyslipidemia, diabetes, certain cancers, and other chronic disorders. Nutrition is important, along with other lifestyle factors, for prevention and reduction of excess body weight; diets with higher protein and lower carbohydrate content have been reported to promote weight loss with greater loss of body fat and reduced loss of lean body mass (2–6). BCAA, including leucine, isoleucine, and valine, are essential amino acids and recent studies support the idea that they may be responsible for some of the beneficial effects of high-protein diets. BCAA play an important role in protein synthesis as well as glucose metabolism, the latter particularly during periods of restricted energy intake (7–9). One study in wrestlers found that BCAA supplementation was more effective in reducing body fat than energy restriction alone (10) and others have reported beneficial effects on body weight and body fat among obese individuals (11, 12).

Most previous studies on BCAA intake and overweight status/obesity were limited to obese individuals or involved specific interventions such as energy restriction with supplementation (10–16). To our knowledge, no study has assessed this association in a multi-ethnic population. With its high quality dietary data, the population-based International Study of Macro-/Micronutrients and Blood Pressure (INTERMAP) Study provides a unique opportunity to test the hypothesis that BCAA intake is inversely associated with overweight status and obesity across different cultures among apparently healthy adults.

Methods

Results

BCAA intake was 2.6 ± 0.6% energy for the 4429 participants; intake (2.1 ± 0.4% energy) was significantly lower among Chinese participants and similar across the other 3 countries (2.7–2.8% energy). BMI was significantly lower among Chinese and Japanese participants (23.1 ± 3.3 kg/m² and 23.4 ± 2.9 kg/m²) compared with participants from the UK (27.4 ± 4.6 kg/m²) and US (28.6 ± 5.8 kg/m²). The prevalence of overweight status was 25.3, 26.3, 69.3, and 70.2% among participants from China, Japan, the UK, and the US, respectively. Prevalence of obesity was 1.9, 3.4, 22.4, and 33.3% across the 4 countries, respectively. Participant characteristics are presented by quartile of BCAA intake (Table 1). Compared with those in the first quartile of BCAA intake, participants in the 4th quartile were more likely to be male and less likely to be current smokers and had higher total protein, animal protein, and fat intake and lower carbohydrate, starch, and total energy intake.

With adjustment for potential dietary and nondietary confounders (age, gender, country, employment status, physical activity, smoking status, special diet, and intakes of total energy, total carbohydrate, saturated fat, and total protein), BCAA intake was inversely related to BMI and overweight status. The multivariable-adjusted OR of overweight status was 0.70 (95% CI = 0.57–0.86; P-trend < 0.01) for the 4th quartile of BCAA intake compared with the first (Table 2). To account for variation by location, we analyzed data by country and then pooled the results with meta-analysis weighted by the inverse of variance. The results did not change appreciably (Table 2).

Because of the low prevalence of obesity in China (1.9%) and Japan (3.4%), we examined the association between BCAA and obesity only among participants from the UK and the US. Multivariable adjusted OR of obesity were 0.75 (95% CI = 0.58–0.98; P-trend = 0.03) for the 4th quartile of BCAA intake compared with the first. A significant inverse association prevailed for the Western countries and for the UK separately. For the US, the inverse direction remained, but the trend became nonsignificant (P-trend = 0.12) (Table 3).

To test the robustness of our main findings, we conducted 2 sensitivity analyses. First, when we replaced total protein intake with urinary urea nitrogen in model 3 (Tables 2 and 3), the inverse associations were essentially the same. Second, when we replaced total protein intake with the other 17 of 20 naturally occurring amino acids, the inverse associations remained.

Discussion

In this international, population-based, cross-sectional study, dietary intake of BCAA was inversely associated with prevalence of overweight status among apparently healthy middle-aged adults from both East Asian and Western countries and with prevalence of obesity in Western countries.

Our findings are generally consistent with previous animal and human studies. Animal studies found that rats fed whey protein (with 50–75% higher leucine content than other common food proteins) had significantly lower body weight and fat mass gain compared with rats fed red meat or casein (25, 26). In other animal studies, leucine supplementation significantly decreased body weight in obese mice (15, 16) and body fat in rats under food restriction (13) but had no weight reduction effect in normal-weight mice (16). The magnitude of weight loss among rats consuming a high-protein diet was similar to that achieved with leucine supplementation in obese mice (13). Thus, leucine or BCAA were suggested to be responsible for the potential beneficial effects of high-protein intake on body weight. In humans, most randomized controlled trials (2–6) reported that diets high in protein significantly lowered body weight in obese individuals, although 1 trial reported no independent effect of diet composition (27). BCAA intake was found to reduce body weight and body fat in intervention studies (10–12). In a short-term study, 25 wrestlers consumed 1 of 3 energy-restricted diets comprised of high protein, high BCAA, or low protein (10). Those consuming the high-BCAA diet had the greatest weight loss (−4.0 kg; P < 0.05) and decline in body fat percent (−17.3%; P < 0.05) and a significant reduction in abdominal visceral adipose tissue (−34.4%; P < 0.05) (10).

Several potential mechanisms may account for the inverse association between BCAA intake and body weight; animal studies provide some evidence that leucine may increase energy expenditure. One study using mice as subjects found that leucine supplementation was not associated with weight gain in obese mice with increased food intake (16). Leucine supplementation was also found to stimulate an increase in plasma leptin, an adipose-derived hormone regulating energy intake and expenditure, and leptin levels were reduced by 40% in rats fed a leucine-deficient meal (28). Exogenous leptin administration can suppress appetite and food intake, resulting in decreased body weight in rats (29, 30). Some animal studies using rats or mice have found that leucine supplementation also increased activity of mammalian target of rapamycin, another major regulator of energy balance (31), and consequently lowered body weight (15, 16, 32).

Another possible mechanism for the effect of BCAA on body weight is improved glucose tolerance, because impaired glucose tolerance (IGT) is suggested to be a cause of obesity (33). Although data on IGT’s possible role in obesity development are limited, 1 human study found that higher intra-abdominal adiposity was an independent risk factor for IGT among Japanese Americans (34). At present, conflicting data exist on the role of BCAA as a mechanism for this association. Results of 1 study indicate that rats consuming a high-fat, high-BCAA diet developed insulin resistance (35). Similar findings have been reported in nonobese humans (36). Conversely, increased leucine intake prevented high-fat diet-induced hyperglycemia in obese mice (16, 37). Additionally, leucine was found to stimulate insulin release from the pancreas, thereby decreasing blood glucose (38, 39). Isoleucine also has a hypoglycemic effect via an insulin-independent pathway (40, 41). Although the beneficial effect of increased BCAA intake on body weight through improved glucose metabolism may be only modest in magnitude, it could be of public health significance because of the high prevalence of IGT in overweight and obese individuals (42).

BCAA intake in the INTERMAP population was consistent with that found in other study populations. For example, in intervention studies on adult women ages 40–56 y, mean BCAA intake in the control group was ~10 g/d (11, 12). In addition, a study using stable isotopes to measure whole-body leucine metabolism reported that daily leucine intake was ~6 g/d (43), similar to that found in our study (6.1 ± 2.0 g/d). Because long-term protein intake of 1.2–2.0 g/kg body weight appears to exert no harmful effect on renal function (11), increased BCAA intake (e.g. to 20 g/d) apparently would not be harmful to health.

The cross-sectional design of the INTERMAP Study limits inferences as to the causal relationship between BCAA intake and risk of overweight status/obesity. To our knowledge, however, this is the only population-based study that has examined this issue. It adds evidence to existing literature that significant inverse associations between BCAA intake and overweight status may explain at least partially the weight loss effect of high-protein diets reported by previous intervention studies (2–6).

In conclusion, we found significant inverse associations between BCAA intake and overweight status/obesity. Our findings suggest that weight loss induced by a high-protein/low-carbohydrate diet may be partially explained by BCAA intake. Further studies are needed to investigate this long-term association and to determine a potential causal relationship.