The present study aimed to investigate the relationship between the urinary metabolite profile and changes in body mass and composition during an intervention with a HP breakfast meal in young women with overweight in comparison with a LP breakfast meal. Our study revealed that regardless of HP or LP intervention, the urine metabolome at the baseline could predict the body mass, lean body mass, and fat mass changes. In special, body mass changes showed a Pearson correlation with 19 significant metabolites of which 8 (valine, TMAO, lactate, glucose, dimethylamine, creatinine, citrate, betaine) were the same correlating with lean body mass and fat mass changes; and 11 (2-furoyglycine, 3-aminoisobutyrate, allantoin, formate, fumarate, glycine, hippurate, indole-3-lactate, succinate, trigonelline, urea) were exclusively to body mass changes (Fig. 1 and Fig. 2). In addition, individuals who responded to the HP breakfast meal as reflected in a reduction in body mass concomitantly had a significant reduction in urinary excretion of N,N-dimethylglycine, trigonelline, and trimethylamine during the intervention (Fig. 3). In contrast, individuals who did not achieve a reduction in body mass as a result of HP breakfast meal intervention did not display these metabolite changes. This finding suggests that differences in endogenous metabolism related to the metabolic phenotype might contribute to variations in the response to an intervention with a HP breakfast in comparison with a LP breakfast.
N,N-dimethylglycine is an amino acid derivative that the human body produces when metabolizing choline into glycine. N,N-dimethylglycine is also a byproduct of homocysteine metabolism where homocysteine and betaine are converted to methionine and N,N-dimethylglycine by betaine-homocysteine methyltransferase. In women, a high concentration of urinary N,N-dimethylglycine has been identified as a predictor of diabetes (Friedrich, et al., 2015). In addition, a study examining the association between the urine metabolome and 5-year changes in markers of glucose homeostasis found that N,N-dimethylglycine were among the metabolites showing highest association to glucose homeostasis markers (Fridrich et al., 2018). It has also previously been found to be a useful predictor for progression in knee osteoarthritis (Loeser, et al., 2016). The results from these former studies indicate that a reduction in urinary N,N-dimethylglycine is associated with lower diabetes risk and lower inflammatory status. It remains to be established if the beneficial effects can be associated with the involvement of N,N-dimethylglycine in homocysteine metabolism.
Trigonelline is an alkaloid, and high amounts have been found in arabica coffee, fenugreeks and peas. Trigonelline is also a product of the niacin metabolism. Intriguingly, similar to N,N-dimethylglycine, urinary trigonelline was also identified as a predictive marker for diabetes, glucose homeostasis and osteoarthritis in the above-mentioned studies (Friedrich, et al., 2015; Loeser, et al., 2016; Friedrich, et al., 2018). Studies on oral administration of trigonelline have also revealed beneficial effects on insulin resistance and glucose tolerance in both murine models (Yoshinari, et al., 2009; Yoshinari & Igarashi, 2010) and humans (van Dijk, et al., 2009). While these studies suggest a positive association between trigonelline and glucose metabolism, the present study identified a decrease in urinary trigonelline with a reduction in body mass. However, as the present study identified decreases in trigonelline in participants that lost weight as response to the intervention, the present findings are consistent with a study on obese subjects undergoing gastric bypass, which reported that higher urinary trigonelline levels were associated with an obese phenotype (Calvani, et al., 2010). Involvement of the gut microbiota in urinary trigonelline excretion has been proposed (Calvani, et al., 2010), but remains to be established.
Trimethylamine (TMA) is a metabolite that can be generated from microbial metabolization of choline, betaine and carnitine. In the liver, TMA is oxidized to trimethylamine-N-oxide (TMAO) by hepatic flavin-containing monooxygenase 3 (FMO3). Studies have linked circulating levels of TMAO with diabetes (Dambrova, et al., 2016; Li, et al., 2022), and the 5-year longitudinal study by Friedrich et al. (Friedrich, et al., 2018) also found a positive association between urinary TMA levels and HbA1c, a diagnostic marker of diabetes. Thus, the observed decrease in urinary TMA excretion for responders to the HP breakfast in the present study might also reflect that the responders experienced an improved glucose homeostasis.
In addition to the three metabolites discussed above, pathway analysis also revealed that endogenous metabolism differed among women that responded to breakfast interventions with a body mass loss and non-responders (Fig. 2). Thus, citrate cycle (TCA) metabolism was found to differ. Intriguingly, a study based on a knowledge discovery from databases proposed that an inhibition of the TCA cycle is a crucial event in the chain of metabolic processes leading to obesity. The inhibition disturbs energy metabolism and results in ATP deficiency with simultaneous fat accumulation (Wlodek & Gonzales, 2003). Glyoxylate/dicarboxylate metabolism was also found to differ between women that responded to breakfast intervention with a body mass loss and non-responders, addressing the important role that glycine seems to play in body mass loss. Proffit et al. have shown that glyoxylate/dicarboxylate metabolism is upregulated in metabolic disorders (obesity, Type 2 diabetes, and atherosclerosis cardiovascular disease) (Proffitt, et al., 2022), while Song proposed a relationship between glyoxylate pathway and fat-induced hepatic insulin resistance (Song, 2000).