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Dietary sulfur amino acid restriction elicits a cold-like transcriptional response in inguinal but not epididymal white adipose tissue of male mice

ABSTRACT: Introduction: About 1 billion people are living with obesity worldwide. GLP-1-based drugs have massively transformed care, but long-term consequences are unclear in part due to reductions in energy expenditure with ongoing use. Diet-induced thermogenesis (DIT) and cold exposure (CE) raise EE via brown adipose tissue (BAT) activation and beiging of white adipose tissue (WAT). Methionine restriction (MetR) is a candidate DIT stimulus, but its EE effect has not been benchmarked against CE, nor have their tissue-level interactions been defined. Objective & Methods: In a 2×2 design (Control vs. MetR; room temperature, RT: 22 °C vs. CE: 4 °C for 24 h), we used male C57BL/6N mice to benchmark MetR-induced thermogenesis against CE and mapped how diet and temperature interact across tissues. Bulk RNA-seq profiled liver, iBAT, iWAT, and eWAT. Differential expression was modeled with main effects and a diet×temperature interaction. KEGG GSEA was used to assess pathway-level enrichment. Results: MetR increased EE at RT and shifted fuel use towards lipid oxidation, supporting MetR as a bona fide DIT stimulus. CE elevated EE across diets and blunted diet differences. Transcriptomic responses were tissue-specific: in liver, CE dominated gene induction while MetR and CE cooperatively repressed genes. The combination enriched glucagon/AMPK-linked and core metabolic pathways. In iBAT, CE dominated thermogenic and lipid-oxidation programs with minimal MetR contribution. In iWAT, MetR and CE acted largely additively with high concordance, enhancing fatty-acid degradation, PPAR signaling, thermogenesis, and TCA cycle pathways. In eWAT, robust co-dependent and synergistic differential expression emerged only with MetR+CE. Conclusion: MetR is a genuine DIT stimulus that remodels metabolism in a tissue-specific manner. Our study provides a tissue-resolved transcriptomic resource that benchmarks diet-induced (MetR) against cold-induced thermogenesis and maps their interactions across liver, iBAT, iWAT, and eWAT.

ORGANISM(S): Mus musculus

PROVIDER: GSE310044 | GEO | 2025/11/17

REPOSITORIES: GEO

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Project description:To explore the underlying mechanism for the regulatory role of branched-chain amino acids (BCAA) catabolism in hypothalamic RIP-Cre neurons to metabolic organs under normal chow diet feeding, we established RIP-Cre neurons selective BCAA catabolic enzyme branched-chain ketoacid dehydrogenase E1 subunit alpha(Bckdha) knockout mice, we conducted RNA sequencing on the inguinal adipose tissue (iWAT), epididymal adipose tissues (eWAT), and liverfrom wild type (WT, Bckdhaf/f) and knockout (KO, Bckdhaf/f;RIP-Cre) mice (two groups in total). Three biological replicates were performed for each group. Methods: RNA sequencing (RNA-Seq) and data analysis were performed by Gene Denovo Biotechnology (Guangzhou, China). Results: In comparison with findings in the Bckdhaf/f group, 393 up-regulated and 214 down-regulated differentially expressed genes (DEGs) were identified in eWAT from Bckdhaf/f;RIP-Cre group . Similarly, 41 up-regulated genes and 152 down-regulated DEGs were identified in iWAT from Bckdhaf/f;RIP-Cre compared to the Bckdhaf/f group. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that DEGs in eWAT were enriched in the categories including all subclass pathways in carbohydrate metabolism class, insulin resistance, PPAR signaling, oxidative phosphorylation, thermogenesis, carbon metabolism, fatty acid metabolism, biosynthesis of amino acids and degenerative disease pathways. Similarly, DEGs in iWATwere clustered in the pathways, including the TCA cycle, pyruvate metabolism, glucagon signaling, glycolysis and gluconeogenesis, and carbon metabolism. These changes indicated broad disturbance in WAT energy metabolism in Bckdhaf/f;RIP-Cre mice. Liver transcriptomes showed minor perturbances in subclasses in lipid metabolism, advanced glycation end products and their receptor (AGE-RAGE), PPAR, estrogen, prolactin signaling pathways. Notably, all 13 mitochondrial DNA encoded mRNA were all significantly down-regulated in eWAT of Bckdhaf/f;RIP-Cre mice, along with nucleus DNA encoded mitochondrial located mRNA. Conclusions: Our results using RNA-Seq indicated universal defects of mitochondrial gene expression in eWAT and iWAT.

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Dietary sulfur amino acid restriction elicits a cold-like transcriptional response in inguinal but not epididymal white adipose tissue of male mice

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