Body composition: An important determinant of homocysteine and methionine concentrations in healthy individuals

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Abstract

Objective

Homocysteine is a sex-related risk factor for cardiovascular disease but the reason for dimorphism is unclear. It has been hypothesized that fat-free mass is an independent determinant of the circulating homocysteine and methionine concentrations.

Methods

The relationship of homocysteine to body composition was investigated in 52 healthy middle-aged 40–60 year olds. Plasma total homocysteine, methionine, folates, vitamins B6 and B12 concentrations were measured with fat mass, bone mineral content, lean body mass, fat-free mass, body water compartments and resting energy expenditure by Anthropometry, Dual X-ray Absorptiometry, Bioimpedentiometry and Indirect Calorimetry.

Results

Men had higher homocysteine (+28%) and methionine (+18%) concentrations than women, but a similar ratio between the two concentrations. Men also had higher lean body mass and fat-free mass. Homocysteine and methionine concentrations were significantly related to fat-free mass, lean body mass, total, extracellular and intracellular water both in simple correlations and in multivariate models including age, smoking habits and vitamin concentrations. Fat-free mass related measures explained the sex effect on homocysteine and methionine concentrations but not the ratio of homocysteine to methionine concentrations.

Conclusion

In healthy middle-aged adults homocysteine concentration independently relates to fat-free mass and to water components. Homocysteine and methionine concentrations increase together in relation to the proportion of fat-free mass but their ratio is unrelated to fat-free mass.

Introduction

Hyperhomocysteinemia is an established risk factor for cardiovascular disease [1], [2], [3], [4], [5], [6] and it is also probably involved in the risk of dementia [7]. In order to understand the determinants of homocysteine concentrations, in recent years a great effort was devoted to find mutations and common polymorphisms of the gene coding for the key enzymes in methionine metabolism [8], but nutritional factors are important as well. The latter were mainly investigated in terms of status, intake and supplementation of vitamins (folates, vitamin B12 and vitamin B6) whose deficiency causes hyperhomocysteinemia [9], [10], [11], [12], [13]. Interestingly, the carriers of common polymorphisms of enzymes related to hyperhomocysteinemia require higher concentrations of specific vitamins to achieve normo-homocysteinemia, leading to the concept that the nutritional requirements of specific populations may be different according to the prevailing genotypes [14], [15].

Further aspects beyond the adequacy of vitamin factors have been much less intensely investigated up to now. Each nutritional or metabolic factor should influence the rate of methionine appearance, its rate of cycling with homocysteine and the rate of homocysteine transulphuration. The rate of release of methionine stored in proteins and the metabolic demand of methionine methyl groups to synthesize creatine could be important determinants of methionine and homocysteine concentrations and fluxes. Both variables strongly depend on the protein and muscular mass of a given individual. Several investigators reported that plasma homocysteine concentration is related to the sex of an individual [16], [17], an important relationship to be studied, because men and women are exposed to different risks for cardiovascular diseases. It was speculated that sex-dependent differences in plasma homocysteine concentrations are related to different rates of methionine cycle [18]. Rapid methionine cycle should imply a greater demand for methyl groups. Guanidinoacetate accepts a great deal of methyl groups forming creatine, which is stored in skeletal muscle.

Preliminary evidence exists that homocysteine levels are positively linked to creatine turnover rates and to muscle mass as suggested in a large number of German individuals whose lean body mass was estimated using skinfold thickness or single-frequency bioelectrical impedance analysis (BIA) [19], [20]. Skinfold thickness is operator dependent and therefore imprecise, whereas BIA produces values of fat-free mass and fat mass comparable but not interchangeable to dual-energy X-ray (DXA), which is considered one of the most effective methods to assess body composition [21]. It was shown that in an elderly population sex-related differences in homocysteine disappeared when its concentrations were standardized by lean body mass values obtained using DXA [22]. On the other hand, Fugakawa et al. [23], investigating the methionine kinetics and its correlation to lean body mass using DXA, found no evidence of sex-related differences in homocysteine and methionine concentrations, and no relationship to lean body mass.

In contrast, recent evidence that moderate protein-energy depletion leads to hyperhomocysteinemia [24] disagrees with the view of homocysteine and methionine concentrations positively related to the abundance of fat-free mass. This is suggested by the fact that chronic inflammation is frequently associated to both hyperhomocysteinemia and to wasting of fat free mass in its protein and bone mineral components. It has therefore been proposed that chronic illness and malnutrition lead to hyperhomocysteinemia in an attempt to spare sulphur body stores via functional restraint of the trans-sulphuration cascade [25].

It is thus unclear whether the negative relationship between homocysteine and fat-free mass in sick people turns out to be positive in healthy people. We performed the present study to ascertain the relationship between fat free mass and homocysteine in healthy individuals. Since the unique precursor of homocysteine is the essential amino acid methionine, the simultaneous evaluation of the two metabolites may add to the understanding of the relationship existing with body composition. We therefore measured the methionine and homocysteine concentrations in 49 healthy individuals aged 40–60 years, and we related these parameters to the body composition, energy expenditure, and to the folates and vitamins B6 and B12 status.

Section snippets

Subjects

Fifty-two individuals (aged 40–60 years) were studied at the International Center for the Assessment of Nutritional Status (ICANS, Milano, Italy). The subjects were all Caucasians and equally distributed in term of sex within all quartiles of age. The volunteers were in good health; health status and risk profiles were documented by questionnaires including detailed information about family history, clinical history, diet and habits and by physical examination. Specifically, the subjects were

Lifestyle and menopausal state

As regards smoking, the subjects were divided into four groups: the majority of the subjects were non-smokers (45, 87%); one male smoked between 1 and 9 cigarettes/day; four subjects (2 males, 2 females) smoked between 10 and 19 cigarettes/day, and two males smoked more than 19 cigarettes/day. As regards coffee, 6 consumed less than 1 espresso/day, 37 between 1–4, 9 between 5–8, and none more than 8. As to menopausal state, 10 women were on eumenorrhoea, 6 were peri-menopausal (cessation of

Discussion

This study was performed in order to clarify the relationship between homocysteine concentration and body composition in middle-aged healthy people. Among body compartments, fat-free mass showed results independently related to homocysteine. These results agree with what had been suggested in few previous studies in which body composition was measured by different techniques not easily comparable to each other in the whole population [20], in middle-age [19] and in elderly groups [22]. In

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    This work was supported in part by grants from Ministero Italiano della Sanità (NURISK) and from Fondazione Telethon Onlus (Grant EC0880).

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