Metabolic Perturbations and Ectopic Fat Deposition in Men With Low Birth Weight: Effects of a 4-Week Carbohydrate Overfeeding Challenge

Low birth weight (LBW) is a risk factor for type 2 diabetes (T2D). We hypothesized that 4 weeks of carbohydrate overfeeding (COF) with +25% energy would unmask key T2D perturbations among 22 nonobese LBW men, including five with screen-detected metabolic dysfunction–associated steatotic liver disease (MASLD), compared with 21 healthy control participants with normal birth weight (NBW). Body weight, lean and fat mass, and 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 participants. The differential COF responses were most pronounced in LBW participants without MASLD, including increased resting energy expenditure. Plasma adiponectin was lower, whereas fibroblast growth factor 21 levels increased more during COF in LBW participants. Subcutaneous adipose tissue (SAT) density was lower in LBW participants and decreased during COF in both groups. Serum alanine, phosphatidylcholines, and triglycerides increased significantly more in LBW participants during COF. Multiomics analysis of SAT RNA sequencing, serum lipidomics, and metabolomics uncovered impaired peroxisome proliferator–activated receptor signaling as well as aberrant collagen and extracellular matrix regulation in LBW participants. The results document differential and MASLD-independent metabolic perturbations in LBW participants during COF. Article Highlights Individuals with low birth weight (LBW) are at increased risk of type 2 diabetes. Four weeks of carbohydrate overfeeding (COF) was associated with differential elevations in fasting glucose, lipids, alanine, insulin resistance, and resting energy expenditure in LBW participants versus control participants. Multiomics analyses indicated reduced peroxisome proliferator–activated receptor signaling, as well as differential expression of genes involved in collagen and extracellular matrix metabolism in LBW participants during COF. Interestingly, the COF perturbations in LBW participants became more pronounced when excluding five LBW men with screen-detected metabolic dysfunction–associated steatotic liver disease. The findings support the notion of unhealthy subcutaneous adipose tissue expandability potentially underlying a reduced metabolic buffering capacity in nonobese LBW men.