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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\u2013associated 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\u2013activated 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Article Highlights<\/jats:title>\n                    <jats:p>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\u2013activated 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\u2013associated 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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.2337\/db25-0307","type":"journal-article","created":{"date-parts":[[2025,10,20]],"date-time":"2025-10-20T19:01:37Z","timestamp":1760986897000},"page":"2044-2059","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":1,"title":["Metabolic Perturbations and Ectopic Fat Deposition in Men With Low Birth Weight: Effects of a 4-Week Carbohydrate Overfeeding Challenge"],"prefix":"10.2337","volume":"74","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6653-9020","authenticated-orcid":false,"given":"Charlotte","family":"Br\u00f8ns","sequence":"first","affiliation":[{"name":"Steno Diabetes Center Copenhagen 1 , Herlev, Denmark"},{"name":"Department of Endocrinology, Rigshospitalet, Copenhagen University Hospital 2 , 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University of Southern Denmark 6 , Odense, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4400-6741","authenticated-orcid":false,"given":"Rashmi B.","family":"Prasad","sequence":"additional","affiliation":[{"name":"Lund University Diabetes Center, Lund University 4 , Malm\u00f6, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8748-3831","authenticated-orcid":false,"given":"Torben","family":"Hansen","sequence":"additional","affiliation":[{"name":"Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen 3 , Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Else Rub\u00e6k","family":"Danielsen","sequence":"additional","affiliation":[{"name":"Department of Radiology, Rigshospitalet, Copenhagen University Hospital 7 , Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerrit","family":"van Hall","sequence":"additional","affiliation":[{"name":"Clinical Metabolomics Core Facility, Rigshospitalet, Copenhagen University Hospital 8 , Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8724-6016","authenticated-orcid":false,"given":"Lauren M.","family":"Sparks","sequence":"additional","affiliation":[{"name":"Translational Research Institute 9 , AdventHealth, Orlando, FL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3728-2606","authenticated-orcid":false,"given":"Natalia","family":"L\u00f3pez-Andr\u00e9s","sequence":"additional","affiliation":[{"name":"Navarrabiomed Centro de Investigaci\u00f3n Biom\u00e9dica 10 , Pamplona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allan","family":"Vaag","sequence":"additional","affiliation":[{"name":"Steno 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