Serum lipidomics, serum metabolomics, and adipose tissue RNA-seq analysis from low and normal birth weight individuals
- Sofie Olund Villumsen, sofie.olund.villumsen.02@regionh.dk
Allan Vaag, allan.vaag@med.lu.se
Human low birth weight (LBW) subjects and matched normal birth weight (NBW) subjects studied before and after 4 weeks of high carbohydrate overfeeding, and again after 12 weeks of lifestyle rehabilitation with diet and/or physical activity.
Blood samples were collected and quantified. Adipose tissue biopsies were obtained and processed for bulk RNA sequencing.
Bioinformatic analyses aims to find both lipidomics, metabolomics and transcriptomic effects and link them with each other.
- Metabolomics - analysis of the metabolomics data.
- Lipidomics - analysis of the lipidomics data.
- RNAseq - analysis of the RNAseq data.
- Multi-omics - analysis of the integration of metabolomics, lipidomics, and RNAseq.
Low birthweight (LBW) is a risk factor of type-2 diabetes (T2D). We hypothesized that 4-weeks carbohydrate overfeeding (COF) would unmask key T2D perturbations among 22 non-obese LBW men, compared with 21 normal birthweight (NBW) controls. Five LBW versus 0 NBW subjects had screen-detected non-alcoholic fatty liver disease (NAFLD). Body composition, hepatic fat and glucose production, insulin resistance, energy expenditure, serum metabolomics and lipidomics, as well as abdominal subcutaneous adipose tissue histology and transcriptomics, were measured before and after COF with +25% energy. Body weight, lean and fat mass, as well as hepatic fat content, increased to the same extent in both groups during COF, whereas fasting glucose and insulin resistance increased significantly more in LBW compared with NBW subjects. The differential COF responses were most pronounced among LBW subjects without NAFLD and included disproportional increased resting energy expenditure. Plasma adiponectin was lower, and FGF-21 levels increased more during COF, in LBW subjects. Subcutaneous adipocyte density was lower in LBW subjects and decreased during COF in both groups. Serum alanine, phosphatidylcholines, and triglycerides levels increased significantly more in LBW subjects during COF. Multi-omics analysis of adipose tissue RNA-sequencing, serum lipidomics and metabolomics uncovered impaired PPAR signaling, as well as collagen and extracellular matrix regulation as top affected pathways in LBW subjects. Except for fasting glucose in LBW subjects, COF-induced perturbations reverted to baseline after 12 weeks. The results provide causal evidence of differential metabolic perturbations in LBW subjects during COF, which may not be explained by body composition or liver fat differences per se.
Key words: Carbohydrate overfeeding, low birthweight, hepatic fat content, hepatic glucose production, insulin resistance, resting energy expenditure, metabolomics, lipidomics, adipose tissue morphology, RNA-seq.