Consequences of obesity on one-carbon metabolism across different study models: in silico transcriptomic analyses

Abstract

Obesity is a complex, multifactorial disorder marked by profound disruptions in energy homeostasis and nutrient handling. One-carbon metabolism (1-CM) – the network that fuels cellular methylation and nucleotide biosynthesis – is particularly vulnerable in obesity; individuals with a body mass index (BMI) > 30 kg/m² consistently exhibit reduced circulating levels of key 1-CM micronutrients, yet the underlying regulatory mechanisms remain poorly understood. In this study, 1‑CM gene expression was characterized across three complementary models: (i) adipose and skeletal muscle samples from post‑mortem donors in the GTEx cohort; (ii) white and brown adipose tissue from mice subjected to a high‑fat diet; and (iii) primary adipocytes isolated from human and mouse specimens. A comprehensive list of 1–CM–related genes, curated through UniProt annotation and a targeted literature review, was overlaid onto differential expression results obtained using both the limma and DESeq2 pipelines. Genes with an adjusted p-value < 0.05 were deemed significant. In the GTEx study of 42 tissues analyzed, subcutaneous, visceral adipose, and skeletal muscle (gastrocnemius) tissues were significantly compromised. In these three tissues, a downregulation of folate cycle genes (MTHFD1/2, SHMT2, ALDH1L1) and vitamin B12-processing enzymes (MMACHC, MTRR) was observed. Subcutaneous and visceral adipose tissues showed reduced expression of FOLR1, SLC25A32, and purine biosynthesis genes (GART, ATIC). Skeletal muscle exhibited partial compensatory upregulation (DHFR, ALDH1L1). In the animal model, the differentially expressed genes (DEGs) revealed the upregulation of de novo purine synthesis genes (Atic and Gart), DNA methylation (Dnmt3a, Dnmt3b, and Dnmt1), and folate uptake (Folr1 and Folr2). Folate species interconversion genes, including Mthfr and Aldh1l1, were downregulated. In primary human adipocytes, 41 1-CM genes were differentially expressed (28 upregulated, 13 downregulated; log₂FC range: –4.33 to +4.15). GLDC (–4.33), MTHFD2 (–3.20), MTHFD1L (–1.65), and DNMT1 (–2.90) were markedly suppressed. Conversely, SARDH (+4.10), LRP2 (+4.15), and SHMT1, as well as BHMT2 and ALDH1L1, were upregulated. Folate and B12 transporters (TCN2, SLC19A1, FOLR2) were also elevated.