Lipidomic and metabolomics profiling in low birth weight men reveals a dysmetabolic phenotype associated with increased liver fat

Background and aims: Being born with a low birth weight (LBW) is associated with an increased risk of developing Type 2 Diabetes (T2D) in adulthood. The subcutaneous adipose tissue (SAT) plays a central role in T2D pathophysiology. We hypothesized, that LBW individuals have an impaired SAT expandability, resulting in ectopic lipid deposition in the liver, thereby contributing to the pathophysiological events linking LBW with T2D development. Using untargeted metabolomics and lipidomics analyses, as well as state-of-the-art magnetic resonance (MR) spectroscopy for liver fat determinations, we aimed to assess the extent to which increased liver fat is associated with dysmetabolic traits in early middle-aged, non-obese LBW men.

Materials and methods: Forty-eight healthy, non-obese males aged 35-39 years, born at term with a LBW (BW<10th percentile, n=26) and age- and BMI-matched NBW controls (BW: 50-90th percentile, n=22) were included in the study. We measured body composition, hepatic fat content using 1H MR spectroscopy and hepatic glucose production determined by isotopic tracers. Untargeted serum metabolomics and lipidomics were performed using mass-spectrometry.

Results: LBW subjects had a significantly increased hepatic fat content compared to NBW controls (P=0.014). Interestingly, 5 of the LBW subjects (20%) and none of the NBW subjects, fulfilled the diagnostic criteria of non-alcoholic fatty liver disease (NAFLD), displaying a median hepatic fat content of 9.45%. This subgroup showed several metabolic derangements compared with NBW and LBW men without NAFLD, including hepatic insulin resistance (P=0.02) and increased fasting levels of triglycerides (TG) (P=0.03). Untargeted serum metabolomics of 65 distinct metabolites, identified 7 metabolites which showed different levels between LBW subjects with NAFLD and NBW controls (P<0.05). This included ornithine and citrulline, suggesting an upregulation of the urea cycle in LBW subjects with NAFLD. Furthermore, a pathway analysis highlighted tRNA charging as the top canonical pathway, driven by differences in amino acid levels between NBW and LBW subjects, in which LBW subjects with NAFLD exhibited elevated levels of nearly all the amino acids. Lipidome profiling included 279 lipids and revealed increased levels of phosphatidylcholines and TGs (P<0.05) in the LBW subjects with NAFLD compared to both LBW without NAFLD and NBW subjects. Both lipid species had differential structural composition in the LBW subjects with NAFLD, including an increased amount of long chain fatty acids and fewer double bonds (0-7 bonds).

Conclusion: Increased liver fat content may play a key role linking LBW with increased risk of developing T2D. The most adverse metabolic phenotype was seen in the LBW subgroup with NAFLD, displaying hepatic insulin resistance and dyslipidemia. Metabolomics and lipidomics analysis emphasize this phenotype by revealing an altered amino acid profile as well as changes in the composition and structural organization of lipids known to be associated with overt T2D.