Metabolic syndrome (MetS) is usually identified through the presence of at least three of five metabolic abnormalities, namely insulin resistance, hypertension, hypertriglyceridemia, abdominal obesity, and low levels of high-density lipoprotein cholesterol (HDL-C) (1). A recent report in 2022 has estimated the global prevalence of MetS to be between 12.5% and 31.4%, based on the modified Adult Treatment Panel III (ATP III) criteria (2). Given its high prevalence and significant association with mortality (3, 4), MetS remains an important public health concern. Prevention and management of MetS and its associated components heavily rely on lifestyle modifications, including dietary changes, weight control, and physical activity (5).

Branched-chain amino acids (BCAA) constitute a subset of essential amino acids that comprise valine (Val), leucine (Leu), and isoleucine (Ile). These amino acids play crucial roles in protein metabolism, mental health, and cognitive function, as evidenced by various studies (6). There is considerable controversy surrounding the association between BCAA intakes and risk of MetS and its components, with several studies not being derived from population-based samples. Some research indicates an inverse relationship between BCAA consumption and the risk of obesity (7, 8), diabetes (9), hypertension (10), and MetS (11), as well as a reduced risk of cardiovascular diseases (12). Conversely, some other studies have reported that higher dietary BCAA intake correlates with an increased risk of general obesity (13), diabetes (14), hypertension (15, 16), dyslipidemia (17), and MetS (18). Given these conflicting findings, the present study aims to clarify the potential association between BCAA intake and MetS, along with its individual components, by analyzing data from a large-scale population-based study conducted in Kavar County. This investigation aimed to enhance the understanding of the association by considering several confounders and examining the association based on the dietary source (plant-based or animal-based) of BCAAs.

Table 1 presents the characteristics of the subjects included in the study. The mean age of the total study population was 48.18 years (SD = 8.91). Out of the total population of 4,860, 2,392 (49.2%) were observed to exhibit MetS, with a considerably higher proportion of females (56.8%) than males (P < 0.001). Individuals with MetS had a greater tendency to be Persian, non-smokers, and non-drinkers, as well as to have lower educational levels and physical activity but higher BMI. They also had significantly lower dietary intakes of total energy (P = 0.034), saturated fatty acids (P = 0.002), and BCAA (P = 0.033) compared to others. Furthermore, subjects with MetS had significantly lower intakes of arginine (P = 0.031), cysteine (P = 0.004), phenylalanine (P = 0.014), proline (P = 0.015), serine (P = 0.010), threonine (P = 0.035), tyrosine (P = 0.040), and tryptophan (P = 0.018) (Supplementary Table 1).

The characteristics of the study participants, segregated according to the quartiles of the dietary energy-adjusted BCAA intake, are given in Table 2. The individuals in the highest quartile were more likely to be male, Persian, and highly educated with a considerable wealth score index level than those in the lowest quartile. Additionally, this group had significantly lower age, and physical activity levels but higher BMI, cholesterol, LDL-C levels, and fiber, saturated fatty acids, and protein intake compared to the lowest quartile. The intakes of Val (median: 31.7 mg/kg/day, minimum: 3.7, maximum: 115.5), Leu (median: 44.1 mg/kg/day, minimum: 4.5, maximum: 164.4), and Ile (median: 26.6 mg/kg/day, minimum: 2.8, maximum: 100.4) by the included subjects were within recommended dietary allowance (RDA) levels (27).

The ORs and 95% CIs for the odds of MetS based on dietary intake levels of BCAA are provided in Table 3. In the crude and adjusted models, there were no significant association between the quartiles of Val, Leu, Ile, and total BCAA intake and the odds of MetS. However, the fully adjusted model demonstrated a notable inverse linear association between 1-S.D. increment of dietary Val (OR = 0.85, 95% CI: 0.78–0.94, P = 0.001), Leu (OR = 0.85, 95% CI: 0.77–0.93, P = 0.001), Ile (OR = 0.84, 95% CI: 0.76–0.93), and total BCAA (OR = 0.85, 95% CI: 0.77–0.93) intake and the odds of MetS. Moreover, in an additional analysis, no significant association was identified between the ratio of animal-based to plant-based BCAA intake and the likelihood of MetS (OR per 1-S.D. increase = 1.05, 95% CI: 0.95–1.17, P = 0.300).

We further assessed the association between BCAA intake and components of MetS. Multivariable analysis showed that subjects in the third and fourth quartiles of Val, Leu, Ile, and total BCAA intakes had lower odds of hyperglycemia (Table 4). Additionally, we detected a significant association between 1-S.D. increment of dietary Val, Leu, Ile, and total BCAA intake and the odds of hyperglycemia and hypertriglyceridemia. Nevertheless, no association was observed between the intake of these specific amino acids and other components of MetS (Figure 2). Furthermore, the animal-based to plant-based BCAA intake did not exhibit any significant association with the components of MetS (data not shown).

In the current study, an inverse association between BCAA intake and the odds of MetS, hyperglycemia, and hypertriglyceridemia was identified, with odds reduction of 15%, 16%, and 11% per SD, respectively. Nonetheless, it is important to note that the observed associations were relatively weak due to the proximity of ORs to a value of one, which indicates triviality (28). Similar finding was found regarding Val, Leu, and Iles. We also detected no association between the animal-based to plant-based BCAA intake and odds of MetS and its components. This may suggest that focusing on increasing total BCAA intake could be more beneficial for preventing MetS than emphasizing the source of those BCAAs. However, further studies should be conducted in this regard.

Our findings are consistent with a previous cross-sectional study conducted on middle-aged Brazilian men, which demonstrated a negative association, independent of energy intake, physical activity, work position, and smoking status, between Leu and BCAA intake and the odds of MetS and hypertriglyceridemia (11). In a different cross-sectional study involving 8691 adults, no significant association was observed between BCAA intakes and odds of abdominal obesity (13). Nagata et al. (9) also conducted a cohort study and revealed that the consumption of a high percentage of BCAA as a part of total protein intake was significantly associated with a 43% reduction in the risk of diabetes in women, after controlling for demographic, anthropometric, lifestyle, medical, and dietary variables including total protein intake (9). However, in another cross-sectional study on female twins, higher BCAA intake was associated with lower insulin resistance, hypertension, and inflammation but not MetS, dyslipidemia, and central obesity. It is important to note that these associations were independent of genetics and several potential confounders, such as total protein intake (10). Higher BCAA intake also has been linked to a lower risk of cardiovascular diseases in patients with diabetes (12). In contrast, Isanejad et al. reported a weak positive relationship between dietary intake of BCAA and diabetes in postmenopausal women. This association remained significant even after making adjustments for total meat intake; however, the study did not account for total protein intake (29). Another study, conducted on three prospective cohorts - the Nurses’ Health Study, the Nurses’ Health Study II, and the Health Professionals Follow-up Study - showed a weak association between BCAA intake and the incidence of diabetes, which persisted despite attenuation after adjusting for meat and total protein intake (14). The presence of contradictory evidence may be attributed in part to heterogeneities in study designs, populations studied, the amounts and dietary sources of consumed BCAA, and the factors adjusted for. Notably, total protein intake has been linked to metabolic syndrome and diabetes (18, 30). Therefore, to ascertain an independent association between BCAA and MetS, not influenced by its role as a marker of protein consumption, we controlled the mentioned association for the total protein intake. It should be noted that several studies have found a weak association within the trivial range, with odds ratios ranging from 0.8 to 1.2. As such, further research is needed to determine the clinical applicability of these findings.

Several prior studies have examined the relationship between circulating BCAA and cardiometabolic risk factors. While some studies have reported a positive association between elevated plasma BCAA levels and insulin resistance, obesity, MetS, and cardiovascular diseases, the findings are not consistent across all studies. The regulation of circulating BCAA is influenced by the intestinal microbiome and metabolic dysfunction. However, there is a weak or null correlation between circulating BCAA levels and its dietary intakes (31). Further research is needed to elucidate the relationship between circulating and dietary BCAA intake, as well as the impact of protein quality on this association.

The precise mechanisms that underlie the relationship between BCAA consumption and MetS remain incompletely understood. It has been suggested that BCAA may reduce the accumulation of triglycerides in the liver and skeletal muscles, (32), thereby potentially mitigating the development of hypertriglyceridemia and insulin resistance (33, 34). This beneficial effect may be mediated by upregulation of peroxisome proliferator-activated receptor-alpha and uncoupling protein in these tissues (32). Furthermore, BCAA has been reported to attenuate hepatic lipid accumulation by reducing lipogenesis and increasing microbiota-mediated production of acetic acid (35). More studies should be performed to shed light on the other plausible mechanisms of BCAA as well as the potential effect of other amino acids in this regard.

Our research has several limitations that should be acknowledged. Firstly, the participants were recruited solely from an urban area in Kavar, a small county located in the Fars province in southwest Iran. Therefore, the generalizability of our findings to other populations or all Iranians may be limited. Secondly, the cross-sectional design of our study restricts our ability to establish causality and highlights the need for clinical trial. Lastly, despite adjusting for several confounding variables, there remains a possibility of residual confounders that may have influenced our results.

The results of this population-based cross-sectional study indicate that the total dietary intake of BCAA, as well as the individual intakes of Val, Leu, and Ile, were inversely associated with MetS, hyperglycemia, and hypertriglyceridemia. Additionally, no notable differences in this association were observed between animal-derived and plant-derived sources of BCAA.