Gender-specific pathway differences in the human serum metabolome

Abstract

The susceptibility for various diseases as well as the response to treatments differ considerably between men and women. As a basis for a gender-specific personalized healthcare, an extensive characterization of the molecular differences between the two genders is required. In the present study, we conducted a large-scale metabolomics analysis of 507 metabolic markers measured in serum of 1756 participants from the German KORA F4 study (903 females and 853 males). One-third of the metabolites show significant differences between males and females. A pathway analysis revealed strong differences in steroid metabolism, fatty acids and further lipids, a large fraction of amino acids, oxidative phosphorylation, purine metabolism and gamma-glutamyl dipeptides. We then extended this analysis by a network-based clustering approach. Metabolite interactions were estimated using Gaussian graphical models to get an unbiased, fully data-driven metabolic network representation. This approach is not limited to possibly arbitrary pathway boundaries and can even include poorly or uncharacterized metabolites. The network analysis revealed several strongly gender-regulated submodules across different pathways. Finally, a gender-stratified genome-wide association study was performed to determine whether the observed gender differences are caused by dimorphisms in the effects of genetic polymorphisms on the metabolome. With only a single genome-wide significant hit, our results suggest that this scenario is not the case. In summary, we report an extensive characterization and interpretation of gender-specific differences of the human serum metabolome, providing a broad basis for future analyses.Electronic supplementary materialThe online version of this article (doi:10.1007/s11306-015-0829-0) contains supplementary material, which is available to authorized users.

Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/chronic fatigue syndrome

“…This suggests that men, more than women, may utilize endogenous protein catabolism to provide substrates for the TCA cycle. Sex-specific differences in metabolism have been demonstrated, and may be operative in ME/CFS patients, involving fatty acids, amino acids, oxidative phosphorylation, and steroid metabolism (33). In contrast to the sex-specific effects on serum amino acids, the increased expression of PDKs and PPARD (mRNA in PBMCs) was similar in women and men with ME/CFS.…”

An energetic view of stress: Focus on mitochondria

“…This is, in part, due to the fact that sex hormones regulate mitochondrial function and biogenesis (Gaignard et al, 2017). Metabolomic signatures also, which indirectly reflect mitochondrial and cellular metabolism of the whole organism, show that up to one-third of metabolites at baseline differ between women and men (Krumsiek et al, 2015). In relation to stress, a recent meta-analysis of the literature on the effects of induced stress on mitochondrial structure and function revealed that all studies to date have been conducted in male rodents (Picard and McEwen, 2018b).…”

Metabolite profiles evaluated, according to sex, do not predict resting energy expenditure and lean body mass in healthy non-obese subjects

“…The reasons for the different metabolite concentrations are not always known. In case of glycine, it could be due to genetic polymorphisms [12,15,17], in case of citrate it is largely speculative. Since a further intermediate of the citrate cycle, α-ketoglutaric acid, is also higher in women [13,16,18,19,47,51,52], this may hint at a general difference in citrate cycle turnover between men and women.…”

“…The calculation of the metabolite patterns of REE and LBM for men and women separately showed no meaningful results. It is known from other studies that age and sex differences exist in the human plasma and urine metabolome [12][13][14][15][16][17][18]. Nevertheless, if and to which extent the discrimination of sex is responsible for the discrimination of body composition, has not been clarified definitely [20][21][22][23].…”

“…Metabolomics (blood, urine) can accurately distinguish age and sex differences in humans [12][13][14][15][16][17][18][19], but can only partially explain the components of body composition [20][21][22][23] such as LBM, muscle and fat mass. It remains unclear whether the discrimination of LBM is nothing more than the discrimination of sex, because most of the metabolites for sex seem to be identical to the metabolites discriminating LBM [24].…”