Metabolic Perturbations and Ectopic Fat Deposition in Low Birthweight Subjects– Effects of a 4 Week Carbohydrate Overfeeding Challenge

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posted on 2025-10-20, 00:10 authored by Charlotte Brøns, Line Ohrt Elingaard-Larsen, Louise Justesen, Sofie Olund Villumsen, Anne Cathrine Baun Thuesen, Leonie Mieke Engelhard, Sidsel Seide Gertsen, Mathias Ried-Larsen, Rashmi B. Prasad, Torben Hansen, Else Rubæk Danielsen, Gerrit van Hall, Lauren M. Sparks, Natalia López-Andrés, Allan Vaag

Low birthweight (LBW) is a risk factor for type-2 diabetes (T2D). We hypothesized that 4-weeks carbohydrate overfeeding (COF) with +25% energy would unmask key T2D perturbations among 22 non-obese LBW men, including 5 with screen-detected metabolic dysfunction–associated steatotic liver disease (MASLD), compared with 21 healthy normal birthweight (NBW) controls. 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 MASLD, including increased resting energy expenditure. Plasma adiponectin was lower, whereas FGF-21 levels increased more during COF in LBW subjects. Subcutaneous adipose tissue (SAT) density was lower in LBW subjects and decreased during COF in both groups. Serum alanine, phosphatidylcholines, and triglycerides increased significantly more in LBW subjects during COF. Multi-omics analysis of SAT RNA-sequencing, serum lipidomics and metabolomics uncovered impaired PPAR signaling, as well as aberrant collagen and extracellular matrix regulation in LBW subjects. The results document differential and MASLD independent metabolic perturbations in LBW subjects during COF.